In the context of immunoglobulins, is the type of heavy chain in IgA. : see T cell. : see T-cell receptor. The antigens are expressed on red blood cells. They are used for typing human blood for transfusion. Individuals who do not express A or B antigens on their red blood cells naturally form antibodies that interact with them. The removal of antibodies specific for one antigen from an antiserum to render it specific for another antigen or antigens is called . in adaptive immunity are cells that aid in the response but do not directly mediate specific antigen recognition. They include phagocytes, mast cells, and NK cells. The is a disease caused by infection with the human immunodeficiency virus (HIV-1). AIDS occurs when an infected patient has lost most of his or her CD4 T cells, so that infections with opportunistic pathogens occur. : see adaptive immune response. Immunization with antigen is called to distinguish it from the transfer of antibody to an unimmunized individual, which is called passive immunization. is a highly aggressive, undifferentiated form of lymphoid malignancy derived from a progenitor cell that is thought to be able to give rise to both T and B lineages of lymphoid calls. Most of these leukemias show partial differentiation toward the B-cell lineage (so called B-ALL) whereas a minority show features of T cells (T-ALL). are found in the blood shortly after the onset of an infection. These proteins participate in early phases of host defense against infection. An example is the mannan-binding lectin. The is a change in the blood that occurs during early phases of an infection. It includes the production of acute-phase proteins and also of cellular elements. The or is the response of antigen-specific lymphocytes to antigen, including the development of immunological memory. Adaptive immune responses are generated by clonal selection of lymphocytes. Adaptive immune responses are distinct from innate and nonadaptive phases of immunity, which are not mediated by clonal selection of antigen-specific lymphocytes. Adaptive immune responses are also known as . The are key linkers between receptors and downstream members of signaling pathways. These proteins are functionally heterogeneous, but all use a similar domain, known as an SH2 domain, as the means of interacting with the phosphotyrosine residues generated by the receptor-associated tyrosine kinases. The protein known as Vav is an adaptor protein of this type. The are mucosal-associated lymphoid tissues located in the nasal cavity. The enzyme defect leads to the accumulation of toxic purine nucleosides and nucleotides, resulting in the death of most developing lymphocytes within the thymus. It is a cause of severe combined immunodeficiency. mediate the binding of one cell to other calls or to extracellular matrix proteins. Integrins, selecting, members of the immunoglobulin gene superfamily, and CD44 and related proteins are all adhesion molecules important in the operation of the immune system. An is any substance that enhances the immune response to an antigen with which it is mixed. is immunity conferred on a naive or irradiated recipient by transfer of lymphoid cells from an actively immunized donor. This is called or . drain fluid from the tissues and carry macrophages and dendritic cells from sites of infection in most parts of the body to the lymph nodes. is the strength of binding of one molecule to another at a single site, such as the binding of a monovalent Fab fragment of antibody to a monovalent antigen. See also avidity. is the purification of a substance by means of its affinity for another substance immobilized on a solid support. For example, an antigen can be purified by affinity chromatography on a column of beads to which specific antibody molecules are covalently linked. refers to the increase in the affinity for the specific antigen of the antibodies produced during the course of a humoral immune response. It is particularly prominent in secondary and subsequent immunizations. : see . is the clumping together of particles, usually by antibody molecules binding to antigens on the surfaces of adjacent particles. Such particles are said to . When the particles are red blood cells, the phenomenon is called hemagglutination. are peptide antigens that activate their specific T cells, inducing them to make cytokines and to proliferate. They are thought to differ from antagonist peptides by their ability to induce T-cell receptor dimerization. : see acquired immune deficiency syndrome. are variants of a single genetic locus. refers to the fact that in a heterozygous individual, only one of the alternative C-region alleles of the heavy or light chain is expressed in a single B cell and in an immunoglobulin molecule. The term has come to be used more generally to describe the expression of a single receptor specificity in cells with the potential to express two or more receptors. are antigens that elicit hypersensitivity or allergic reactions. is constriction of the bronchial tree due to an allergic reaction to inhaled antigen. The lining of the eye, called the conjunctiva, manifests in sensitized individuals exposed to allergens. An is a response to innocuous environmental antigens, or allergens, due to preexisting antibody or primed T cells. There are various immune mechanisms of allergic reactions, but the most common is the binding of allergen to IgE antibody on mast cells, which causes asthma, hay fever, and other common allergic reactions. is an allergic reaction in the nasal mucosa, also known as hay fever, that causes runny nose, sneezing, and tears. is a symptomatic reaction to a normally innocuous environmental antigen. It results from the interaction between the antigen and antibody or primed T cells produced by earlier exposure to the same antigen. are classically defined as polymorphisms at the MHC locus; they stimulate intense reactions to allografted tissues, hence their naming. Two individuals or two mouse strains that differ at the MHC are said to be . The term can also be used for allelic differences at other loci. Rejection of grafted tissues from unrelated donors usually results from T-cell responses to allogeneic MHC molecules expressed by the grafted tissues. See also syngeneic; xenogeneic. An is a graft of tissue from an allogeneic or nonself donor of the same species; such grafts are invariably rejected unless the recipient is immunosuppressed. describes the stimulation of T cells by MHC molecules other than self; it marks the recognition of allogeneic MHC molecules. Such responses are also called . are allelic polymorphisms that can be detected by antibodies specific for the polymorphic gene products; in immunology, allotypic differences in immunoglobulin molecules were important in deciphering the genetics of antibodies. An , or partial agonist, is a peptide, usually closely related to an agonist peptide in amino acid sequence, that induces only a partial response from T cells specific for the agonist peptide. The of complement activation is not triggered by antibody, as is the classical pathway of complement activation, but by the binding of complement protein C3b to the surface of a pathogen; it is therefore a feature of innate immunity. The alternative pathway also amplifies the classical pathway of complement activation. or systemic anaphylaxis is an allergic reaction to systemically administered antigen that causes circulatory collapse and suffocation due to tracheal swelling. It results from binding of antigen to IgE antibody on connective tissue mast cells throughout the body, leading to the disseminated release of inflammatory mediators. are small fragments of complement proteins, released by cleavage during complement activation. These small fragments are recognized by specific receptors, and they recruit fluid and inflammatory cells to sites of their release. The fragments C5a, C3a, and C4a are all anaphylatoxins, listed in order of decreasing potency in vivo. Peptide fragments of antigens are bound to specific MHC class I molecules by . These are residues of the peptide that have amino acid side chains that bind into pockets lining the peptidebinding groove of the MHC class I molecule. Each MHC class I molecule binds different patterns of anchor residues, called anchor motifs, giving some specificity to peptide binding. Anchor residues exist but are less obvious for peptides that bind to MHC class II molecules. is a state of nonresponsiveness to antigen. People are said to be when they cannot mount delayed-type hypersensitivity reactions to challenge antigens, whereas T cells and B cells are said to be anergic when they cannot respond to their specific antigen under optimal conditions of stimulation. are peptides, usually closely related in sequence to an agonist peptide, that inhibit the response of a cloned T-cell line specific for the agonist peptide. An is a protein that binds specifically to a particular substance - its antigen. Each antibody molecule has a unique structure that enables it to bind specifically to its corresponding antigen, but all antibodies have the same overall structure and are known collectively as immunoglobulins or Igs. Antibodies are produced by plasma cells in response to infection or immunization, and bind to and neutralize pathogens or prepare them for uptake and destruction by phagocytes. : see antigen-binding site. The or immunoglobulin repertoire describes the total variety of antibodies in the body of an individual. is the killing of antibody-coated target cells by cells with Fc receptors that recognize the constant region of the bound antibody. Most ADCC is mediated by NK cells that have the Fc receptor FcβRIII or CD16 on their surface. An is any molecule that can bind specifically to an antibody. Their name arises from their ability to generate antibodies. However, some antigens do not, by themselves, elicit antibody production; those antigens that can induce antibody production are called immunogens. Both libraries of cDNA clones in expression vectors and bacteriophage libraries encoding random peptide sequences have been used to identify the targets of specific antibodies and, in some cases, of T cells. Such libraries are termed . are noncovalently associated groups of antigen and antibody molecules that can vary in size from small soluble complexes to large insoluble complexes that precipitate out of solution; they are also known as immune complexes. The of an antibody, or , is found at the surface of the antibody molecule that makes physical contact with the antigen. Antigen-binding sites are made up of six hypervariable loops, three from the light-chain V region and three from the heavy-chain V region. In an , the antigen binds to a specific antibody, and its presence is detected by a second antibody that must be labeled and directed at a different epitope. An is the portion of an antigenic molecule that is bound by a given antibody or antigen receptor; it is also known as an epitope. Influenza virus varies from year to year by a process of in which point mutations of viral genes cause small differences in the structure of viral surface antigens. Periodically, influenza viruses undergo an through reassortment of their segmented genome with another influenza virus, changing their surface antigens radically. Such antigenic shift variants are not recognized by individuals immune to influenza, so when antigenic shift variants arise, there is widespread and serious disease. Many pathogens evade the adaptive immune response by in which new antigens are displayed that are not recognized by antibodies or T cells elicited in earlier infections. describes the display of antigen as peptide fragments bound to MHC molecules on the surface of a cell; T cells recognize antigen when it is presented in this way. are highly specialized cells that can process antigens and display their peptide fragments on the cell surface together with molecules required for T-cell activation. The main antigen-presenting cells for T cells are dendritic cells, macrophages, and B cells. is the degradation of proteins into peptides that can bind to MHC molecules for presentation to T cells. All antigens except peptides must be processed into peptides before they can be presented by MHC molecules. T and B lymphocytes collectively bear on their surface highly diverse capable of recognizing a wide diversity of antigens. Each individual lymphocyte bears receptors of a single antigen specificity. : see epitope spreading. are antibodies against immunoglobulin constant domains, useful for detecting bound antibody molecules in immunoassays and other applications. These can be divided into made in a different species, made in the same species against allotypic variants, and , made against unique determinants to a single antibody. is antibody raised in another species against human T cells. An (plural: ) is the fluid component of clotted blood from an immune individual that contains antibodies against the molecule used for immunization. Antisera contain heterogeneous collections of antibodies, which bind the antigen used for immunization, but each has its own structure, its own epitope on the antigen, and its own set of cross-reactions. This heterogeneity makes each antiserum unique. Sites by poisonous snakes can be treated by identification of the snake and injection of an specific for that snake's venom. is a failure of bone marrow stem cells so that formation of all cellular elements of the blood ceases; it can be treated by bone marrow transplantation. , or programmed cell death, is a form of cell death in which the cell activates an internal death program. It is characterized by nuclear DNA degradation, nuclear degeneration and condensation, and the phagocytosis of cell residua. Proliferating cells frequently undergo apoptosis, which is a natural process in development, and proliferating lymphocytes undergo high rates of apoptosis in development and during immune responses. Apoptosis contrasts with necrosis, death from without, which occurs in situations such as poisoning and anoxia. The is a gut-associated lymphoid tissue located at the beginning of the colon. In this book, we have termed primed effector T cells , because these cells can be triggered to perform their effector functions immediately on contact with cells bearing the peptide:MHC complex for which they are specific. They contrast with memory T cells, which need to be activated by antigen-presenting cells to differentiate into effector T cells before they can mediate effector responses. The is a skin reaction in which antigen is injected into the dermis and reacts with IgG antibodies in the extracellular spaces, activating complement and phagocytic cells to produce a local inflammatory response. refers to data that seem to demonstrate some finding, but fail to do so because they are collected from a population that is selected in a biased fashion. is a disease characterized by staggering, multiple disorganized blood vessels, and an immunodeficiency in a protein called ATM, which contains a kinase thought to be important in signaling of double-stranded DNA breaks. , or , is the increased tendency seen in some people to produce immediate hypersensitivity reactions (usually mediated by IgE antibodies) against innocuous substances. Pathogens are said to be when they can grow in their host and induce immunity without producing serious clinical disease. Antibodies specific for self antigens are called . A graft of tissue from one site to another on the same individual is called an . Diseases in which the pathology is caused by adaptive immune responses to self antigens are called . is a pathological condition with low levels of red blood cells (anemia), which is caused by autoantibodies that bind red blood cell surface antigens and target the red blood cell for destruction. An adaptive immune response directed at self antigens is called an ; likewise, adaptive immunity specific for self antigens is called . In the disease , antibodies against a patient's platelets are made. Antibody binding to platelets causes them to be taken up by cells with Fc receptors and complement receptors, causing a fall in platelet counts that leads to purpura (bleeding). describes immune responses directed at self antigens. is the sum total of the strength of binding of two molecules or cells to one another at multiple sites. It is distinct from affinity, which is the strength of binding of one site on a molecule to its ligand. The of T-cell selection in the thymus states that T cells must have a measurable affinity for self MHC molecules in order to mature, but not so great an affinity as to cause activation of the cell when it matures, as this would require that the cell be deleted to maintain self tolerance. is a potent immunosuppressive drug that is converted to its active form in vivo and then kills rapidly proliferating cells, including lymphocytes responding to grafted tissues. is a member of the TNF receptor family that specifically binds to 4-1BB ligand. is a member of the TNF family that binds to 4-1BB. : see β sheet. A , or , is one of the two major types of lymphocyte. The antigen receptor on B lymphocytes, usually called the B-cell receptor, is a cell-surface immunoglobulin. On activation by antigen, B cells differentiate into cells producing antibody molecules of the same antigen specificity as this receptor. B cells are divided into two classes. , also known as CD5 B cells, are a class of atypical, self-renewing B cells found mainly in the peritoneal and pleural cavities in adults. They have a far less diverse repertoire of receptors than do , also known as conventional B cells, which are generated in the bone marrow throughout life, emerging to populate the blood and lymphoid tissues. A is one of the fundamental structural building blocks of proteins, consisting of adjacent, extended strands of amino acids () that are bonded together by interactions between backbone amide and carbonyl groups. β Sheets can be parallel, in which case the adjacent strands run in the same direction, or antiparallel, where adjacent strands run in opposite directions. All immunoglobulin domains are made up of antiparallel β-sheet structures. A or a is another way of describing the structure of the immunoglobulin domain. The light chain of the MHC class I proteins is called . It binds noncovalently to the heavy or (α chain. The major T-cell co-stimulatory molecules are the , (CD80) and (CD86). They are closely related members of the immunoglobulin gene superfamily and both bind to the CD28 molecule on T cells. They are expressed differentially on various antigen-presenting cell types. We use the term B7 molecules to refer to both B7.1 and B7.2. Many infectious diseases are caused by , which are prokaryotic microorganisms that exist as many different species and strains. Bacteria can live on body surfaces, in extracellular spaces, in cellular vesicles, or in the cytosol, and different bacterial species cause distinctive infectious diseases. : see bronchial-associated lymphoid tissue. is an immunodeficiency disease in which MHC class II molecules are not expressed on cells as a result of one of several different regulatory gene defects. Patients with bare lymphocyte syndrome are severely immunodeficient and have few CD4 T cells. In MHC class I deficiency, or bare lymphocyte syndrome (MHC class I), the most common defect is mutation in either TAP1 or TAP2. are white blood cells containing granules that stain with basic dyes, and which are thought to have a function similar to mast cells. is the large active fragment of complement component factor B. It is produced when factor B is captured by bound C3b and cleaved by factor D. Bb remains associated with C3b and is the serine protease component of the alternative pathway 03 convertase. The , or , is the cellsurface receptor of B cells for specific antigen. It is composed of a transmembrane immunoglobulin molecule associated with the invariant Igα and Igβ chains in a noncovalent complex. A complex of CD19, TAPA-1, and CR2 makes up the ; co-ligation of this complex with the B-cell antigen receptor increases responsiveness to antigen by about 100-fold. The in the spleen is the zone of the white pulp primarily made up of B cells. are substances that cause B cells to proliferate. The protein known as Bcl-2 protects cells from apoptosis by binding to the mitochondrial membrane. It is encoded by the gene, which was discovered at the breakpoint of an oncogenic chromosomal translocation in B-cell leukemia. : see tyrosine kinase. The adaptor protein operates in B cells in the same way as LAT does in T cells; it has multiple tyrosine residues that are targets for phosphorylation, and recruits signaling molecules to membrane lipid rafts. are surface molecules on red blood cells that are detectable with antibodies from other individuals. The major blood group antigens are called ABO and Rh (Rhesus), and are used in routine blood banking to type blood. There are many other blood group antigens that can be detected in cross-matching. In transfusion medicine, is used to determine whether donor and recipient have the same ABO and Rh blood group antigens. A cross-match, in which serum from the donor is tested on the cells of the recipient, and vice versa, is used to rule out other incompatibilities. Transfusion of incompatible blood causes a transfusion reaction, in which red blood cells are destroyed and the released hemoglobin causes toxicity. is a disease characterized by low T-cell numbers, reduced antibody levels, and an increased susceptibility to respiratory infections, cancer, and radiation damage. It is caused by mutations in a DNA helicase. : see B cell. () is a CXC chemokine that attracts B cells and activated T cells into the follicles of peripheral lymphoid tissues by binding to the CXCR5 receptor. is a secreted member of the TNF family of cytokines. It is secreted by T cells and plays critical roles in germinal center and plasma-cell formation, and possibly dendritic-cell maturation. The is the site of hematopoiesis, the generation of the cellular elements of blood, including red blood cells, monocytes, polymorphonuclear leukocytes, and platelets. The bone marrow is also the site of B-cell development in mammals and the source of stem cells that give rise to T calls upon migration to the thymus. Thus, bone marrow transplantation can restore all the cellular elements of the blood, including the cells required for adaptive immunity. A is formed by transferring bone marrow from one mouse to an irradiated recipient mouse, so that all of the lymphocytes and blood cells are of donor genetic origin. Bone marrow chimeras have been crucial in elucidating the development of lymphocytes and other blood cells. A is commonly given after a primary immunization, to increase the titer of antibodies. is a vasoactive peptide that is produced as a result of tissue damage and acts as an inflammatory mediator. The lymphoid cells and organized lymphoid tissues in the respiratory tract have been termed the (). These tissues are very important in the induction of immune responses to inhaled antigens and to respiratory infection. : see X-linked agammaglobulinemia. is caused by Epstein-Barr virus (EBV) and occurs mainly in sub-Saharan Africa. The is an outpouching of the cloaca found in birds. It is an aggregate of epithelial tissue and lymphoid cells and is the site of intense early B-cell proliferation. The bursa of Fabricius is required for B-cell development in birds, as its removal or early in life causes an absence of B cells in adult birds. An equivalent structure has not been detected in mammals, where B-cell development follows a different pathway. The constant regions of the polypeptide chains of immunoglobulin molecules are made up of one or more constant domains or of similar structure; each immunoglobulin chain also has a single variable or V domain. : see . The of complement components comprises one molecule of bound to two molecules each of the zymogens and . Clq initiates the classical pathway of complement activation by binding to a pathogen surface or to bound antibody. This binding activates the associated Cl r, which in turn cleaves and activates Cl s. The active form of Cls then cleaves the next two components in the pathway, and . () is a protein that inhibits the activity of activated complement component Cl by binding to and inactivating its Clr:Cls enzymatic activity. It also inhibits other serine proteases including kallikrein. Deficiency in ClINH is the cause of the disease hereditary angioneurotic edema, in which the production of vasoactive peptides, kinins, leads to subcutaneous and laryngeal swelling. The complement fragment is the major product of the C3 convertase, and the principal effector molecule of the complement system. It has a highly reactive thioester bond which allows it to bind covalently to the surface on which it is generated. Once bound, it acts as an opsonin to promote the destruction of pathogens by phagocytes and removal of immune complexes; C3b is bound by the complement receptor CR1, while its proteolytic derivative, iC3b, is bound by the complement receptors CR1, CR2, and CR3. The generation of the enzyme on the surface of a pathogen or cell is a crucial step in complement activation. The classical pathway C3 convertase is formed from membrane-bound C4b complexed with the protease C2b. The alternative pathway of complement activation uses a different but homologous C3 convertase, formed from membrane-bound C3b complexed with the protease Bb. These C3 convertases have the same activity, catalyzing the deposition of large numbers of C3b molecules that bind covalently to the pathogen surface, leading to opsonization and the activation of the effector cascade that causes membrane lesions. is a breakdown product of C3b that remains attached to the microbial surface, where it can bind to CD21, the complement receptor CR2. can inactivate the classical pathway C3 convertase if it forms on host cells, by displacing C2b from the C4b:C2b complex. It binds to C4b attached to host cells, but cannot bind C4b attached to pathogens. This is because it has a second binding site specific for sialic acid, a terminal sugar on vertebrate cell surfaces, but not on pathogens. is an inactive complement component that is cleaved by the to release the potent inflammatory peptide and a larger fragment, , that initiates the formation of a membraneattack complex from the terminal components of complement. The receptor for the C5a fragment of complement, the , is a seven-transmembrane spanning receptor that couples to a heterotrimeric G protein. Similar receptors bind to and . The complement components , , and form a complex with the active complement fragment in the late events of complement activation. This complex inserts into the membrane and induces polymerization of to form a pore known as the membrane-attack complex. The cytosolic serine/threonine phosphatase has a crucial role in signaling via the T-cell receptor. The immunosuppressive drugs cyclosporin A and tacrolimus (also known as FK506) form complexes with cellular proteins called immunophilins that bind and inactivate calcineurin, suppressing T-cell responses. The protein is an 88 kDa protein found in the endoplasmic reticulum. It binds to partly folded members of the immunoglobulin superfamily of proteins and retains them in the endoplasmic reticulum until folding is completed. is the molecular chaperone that binds initially to MHC class I, MHC class II, and other proteins that contain immunoglobulinlike domains, such as the T-cell and B-cell antigen receptors. Antibodies or antigens can be measured in various assays. In these assays, antigens are captured by antibodies bound to plastic (or vice versa). Antibody binding to a plate-bound antigen can be measured using labeled antigen or anti-immunoglobulin. Antigen binding to plate-bound antibody can be measured by using an antibody that binds to a different epitope on the antigen. are foreign proteins to which small nonimmunogenic antigens, or haptens, can be coupled to render the hapten immunogenic. In vivo, self proteins can also serve as carriers if they are correctly modified by the hapten; this is important in allergy to drugs. is a form of necrosis seen in the center of large granulomas, such as the granulomas in tuberculosis. The term comes from the white cheesy appearance of the central necrotic area. are a family of closely related cysteine proteases that cleave proteins at aspartic acid residues. They have important roles in apoptosis. : see clusters of differentiation. The is the complex of α:β or γ:δ T-cell receptor chains with the invariant subunits CD3γ, δ, and ε, and the dimeric ζ chains. The cell-surface protein is important for recognition by the T-call receptor of antigenic peptides bound to MHC class II molecules. It acts as a co-receptor by binding to the lateral face of the MHC class II molecules. are T cells that carry the co-receptor protein CD4. They recognize peptides derived from intravesicular sources, which are bound to MHC class II molecules, and differentiate into CD4 TH1 and CD4 TH2 effector cells that activate macrophages and B-cell responses to antigen. are a class of atypical, self-renewing B cells found mainly in the peritoneal and pleural cavities in adults. They have a far less diverse receptor repertoire than conventional B cells, and since they are the first B cells to be produced they are also known as B-1 cells. The cell-surface protein is important for recognition by the T-cell receptor of antigenic peptides bound to MHC class I molecules. It acts as a co-receptor by binding to the lateral face of MHC class I molecules. are T cells that carry the co-receptor CD8. They recognize antigens, for example viral antigens, that are synthesized in the cytoplasm of a cell. Peptides derived from these antigens are transported by TAP, assembled with MHC class I molecules in the endoplasmic reticulum, and displayed as peptide:MHC class I complexes on the cell surface. CD8 T cells differentiate into cytotoxic CD8 T cells. : see B-cell co-receptor. B-cell growth is triggered in part by the binding of , also known as , expressed on activated helper T cells, to on the B-cell surface. , or the leukocyte common antigen, is a transmembrane tyrosine phosphatase found on all leukocytes. It is expressed in different isoforms on different cell types, including the different subtypes of T cells. These isoforms are commonly denoted by the designation of CD45R followed by the exon whose presence gives rise to distinctive antibody-binding patterns. : see . : see complementarity determining region. () are cell-surface proteins that are involved in binding cells together in tissues and also in less permanent cell-cell interactions. , or a , describes any adaptive immune response in which antigen-specific T cells have the main role. It is defined operationally as all adaptive immunity that cannot be transferred to a naive recipient with serum antibody. Cf. humoral immunity. is the B-cell receptor for antigen. See also B-cell antigen receptor. is the study of the cellular basis of immunity. are sites of lymphocyte development. In humans, B lymphocytes develop in bone marrow, whereas T lymphocytes develop within the thymus from bone marrow-derived progenitors. They are also sometimes known as the primary lymphoid organs. is tolerance that is established in lymphocytes developing in central lymphoid organs. Cf. peripheral tolerance. are large, rapidly dividing cells found in germinal centers, and are the cells in which somatic hypermutation is believed to occur. Antibody-secreting and memory B cells derive from these cells. are the small B cells in germinal centers that derive from centroblasts. They may mature into antibody-secreting plasma cells or memory B cells, or may undergo apoptosis, depending on their receptor's interaction with antigen. is caused by a defect in a protein involved in intracellular vesicle fusion. Phagocytic cell function is affected as lysosomes fail to fuse properly with phagosomes and there is impaired killing of ingested bacteria. are small chemoattractant proteins that stimulate the migration and activation of cells, especially phagocytic cells and lymphocytes. They have a central role in inflammatory responses. Most lymphoid tumors, and many other tumors, bear that mark points of breakage and rejoining of different chromosomes. These chromosomal breaks are particularly frequent in lymphomas and leukemias. is an immunodeficiency disease in which multiple granulomas form as a result of defective elimination of bacteria by phagocytic cells. It is caused by defects in the NADPH oxidase system of enzymes that generate the superoxide radical involved in bacterial killing. () are B-cell tumors that are found in the blood. The great majority express CD5 and unmutated V genes and are therefore thought to arise from B-1 cells. The cell-surface receptor called is found on many immature hematopoietic cells. It is a receptor for CSF. The () is a peptide of variable length cleaved from the class II invariant chain by proteases. It remains associated with the MHC class II molecule in an unstable form until it is removed by the HLA-DM protein. (): see MHC class II transactivator. : see isotype switching. : see isotypes. The of complement activation is the pathway activated by Cl binding either directly to bacterial surfaces or to antibody, that serves as a means of flagging the bacteria as foreign. See also alternative pathway; mannan-binding lectin. is the elimination of immature lymphocytes on binding to self antigens to produce tolerance to self, as required by the clonal selection theory. Clonal deletion is the main mechanism of central tolerance and can also occur in peripheral tolerance. is the proliferation of antigen-specific lymphocytes in response to antigenic stimulation and precedes their differentiation into effector cells. It is an essential step in adaptive immunity, allowing rare antigen-specific cells to increase in number so that they can effectively combat the pathogen that elicited the response. The is a central paradigm of adaptive immunity. It states that adaptive immune responses derive from individual antigen-specific lymphocytes that are self-tolerant. These specific lymphocytes proliferate in response to antigen and differentiate into antigen-specific effector cells that eliminate the eliciting pathogen, and memory cells to sustain immunity. The theory was formulated by Sir Macfarlane Burnet and in earlier forms by Niels Jerne and David Talmage. A is a population of cells all derived from a single progenitor cell. A is a continuously growing line of T cells derived from a single progenitor cell. Cloned T-cell lines must be stimulated with antigen periodically to maintain growth. They are useful for studying T-cell specificity, growth, and effector functions. A feature unique to individual cells or members of a clone is said to be . Thus, a monoclonal antibody that reacts with the receptor on a cloned T-cell line is said to be a clonotypic antibody and to recognize its clonotype or the clonotypic receptor of that cell. See also idiotype; idiotypic. () are groups of monoclonal antibodies that identify the same cell-surface molecule. The cell-surface molecule is designated CD followed by a number (e.g. CD1, CD2, etc.). The is a proteolytic cascade of plasma enzymes that triggers blood clotting when blood vessels are damaged. The expression of a gene is said to be when both alleles at one locus are expressed in roughly equal amounts in heterozygotes. Most genes show this property, including the highly polymorphic MHC genes. A is formed by the imprecise joining of a V gene segment to a (D)J gene segment in immunoglobulin or T-cell receptor genes. : see immunoprecipitation analysis. : see congenic. are a structurally related family of calcium-dependent sugar-binding proteins or lectins containing collagen-like sequences. An example is mannan-binding lectin. Antigen receptors manifest two distinct types of generated by the combination of separate units of genetic information. Receptor gene segments are joined in many different combinations to generate diverse receptor chains, and then two different receptor chains (heavy and light in immunoglobulins; 0, and P or y and 6 in T-cell receptors) are combined to make the antigenrecognition site. The (γ_C) is a transmembrane polypeptide chain (CD132) that is common to a subgroup of class I cytokine receptors. It plays a key role in the intracellular signaling mediated by these receptors as shown by gene knockout. are stem cells that give rise to all lymphocytes. They are derived from pluripotent hematopoietic stem cells. is a relatively common deficiency in antibody production whose pathogenesis is not yet understood. There is a strong association with genes mapping within the MHC. are serological assays in which unknowns are detected and quantitated by their ability to inhibit the binding of a labeled known ligand to its specific antibody. This is also referred to as a competitive inhibition assay. When known sources of antibody or antigen are used as competitive inhibitors of antigen-antibody interactions, this assay is referred to as a . The system is a set of plasma proteins that act together to attack extracellular forms of pathogens. can occur spontaneously on certain pathogens or by antibody binding to the pathogen. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes and can also kill certain pathogens directly. () are cell-surface proteins on various cells that recognize and bind complement proteins that have bound an antigen such as a pathogen. Complement receptors on phagocytes allow them to identify pathogens coated with complement proteins for uptake and destruction. Complement receptors include CR1, CR2, CR3, CR4, and the receptor for Clq. The () of immunoglobulins and T-cell receptors are the parts of these molecules that determine their specificity and make contact with specific ligand. The CDRs are the most variable part of the molecule, and contribute to the diversity of these molecules. There are three such regions (CDR1, CDR2, and CDR3) in each V domain. In , it is possible to use optics to produce images at very high resolution by having two origins of fluorescent light that come together only at one plane of a thicker section. , or discontinuous spitopes, on a protein antigen are formed from several separate regions in the primary sequence of a protein brought together by protein folding. Antibodies that bind conformational epitopes bind only native folded proteins. strains of mice are genetically identical at all loci except one. Each strain is generated by the repetitive back-crossing of mice carrying the desired trait onto a strain that provides the genetic background for the set of congenic strains. The most important congenic strains in immunology are the congenic strains, developed by George Snell, that differ from each other at the MHC. are vaccines made from capsular polysaccharides bound to proteins of known immunogenicity, such as tetanus toxoid. The () of an immunoglobulin or T-cell receptor is that part of the molecule that is relatively constant in amino acid sequence between different molecules. In an antibody molecule the constant regions of each chain are composed of one or more C domains. The constant region of an antibody determines its particular effector function. Cf. variable region. A is a form of delayed-type hypersensitivity in which T cells respond to antigens that are introduced by contact with the skin. Poison ivy hypersensitivity is a contact hypersensitivity reaction due to T-cell responses to the chemical antigen pentadecacatechol in poison ivy leaves. , or linear epitopes, are antigenic determinants on proteins that are contiguous in the amino acid sequence and therefore do not require the protein to be folded into its native conformation for antibody to bind. The epitopes detected by T cells are continuous. A is an enzymatic activity that converts a complement protein into its reactive form by cleaving it. Generation of the C3 convertase is the pivotal event in complement activation. The is a test for antibody binding to red blood cells. Red blood cells that are coated with antibody are agglutinated if they are exposed to an anti-immunoglobulin antibody. The Coombs test is important in detecting the nonagglutinating antibodies against red blood cells produced by Rh incompatibility in pregnancy. Two binding sites are said to demonstrate in binding to their ligand when the binding of ligand to one site enhances the binding of ligand to the second site. A is a cell-surface protein that increases the sensitivity of the antigen receptor to antigen by binding to associated ligands and participating in signaling for activation. CD4 and CD8 are MHC-binding co-receptors on T cells, whereas CD19 is part of a complex that makes up a co-receptor on B cells. : see B-cell corona. are a family of drugs related to steroids that are naturally produced in the adrenal cortex, such as cortisone. Corticosteroids can kill lymphocytes, especially developing thymocytes, inducing apoptotic cell death. They are useful anti-inflammatory, anti-lymphoid tumor, and immunosuppressive agents. The proliferation of lymphocytes requires both antigen binding and the receipt of a . Co-stimulatory signals are delivered to T cells by the , B7.1 and B7.2, related molecules that are expressed on the surface of the cell presenting antigen, and which bind the T-cell surface molecule CD28. B cells may receive co-stimulatory signals from common pathogen components such as LPS, from complement fragments, or from CD40 ligand expressed on the surface of an activated antigenspecific helper T cell. is the common name of the disease produced by vaccinia virus, used by Edward Jenner in the successful vaccination against smallpox, which is caused by the related variola virus. : see complement receptors. () is one of several receptors on cells for various components of complement. It is used to remove immune complexes from the plasma. () is part of the B-cell co-receptor complex along with CD19 and CD81. It binds to antigens that have various breakdown products of C3, especially C3d, bound to them and, by cross-linking to the B-cell receptor, enhances sensitivity to antigen by at least a hundredfold. It is also used by the Epstein-Barr virus to invade B cells and produce the symptoms of infectious mononucleosis. () is a P2 integrin that functions both as an adhesion molecule and as a complement receptor. It binds iC3b, and stimulates phagocytosis. () is a P2 integrin that binds iC3b and stimulates phagocytosis. is an acute-phase protein that binds to phosphorylcholine, which is a constituent of the C-polysaccharide of the bacterium Streptococcus pneumoniae, hence its name. Many other bacteria also have surface phosphorylcholine that is accessible to C-reactive protein, so the protein can bind many different bacteria and opsonize them for uptake by phagocytes. C-reactive protein does not bind to mammalian tissues. is used in blood typing and histocompatibility testing to determine whether donor and recipient have antibodies against each other's cells that might interfere with successful transfusion or grafting. A is the binding of antibody to an antigen not used to elicit that antibody. Thus, if antibody raised against antigen A also binds antigen B, it is said to cross-react with antigen B. The term is used generically to describe the reactivity of antibodies or T cells with antigens other than the eliciting antigen. The protein known as or is constitutively active in lymphocytes and has the function of phosphorylating the C-terminal tyrosine of Src-family tyrosine kinases, thus inactivating them. is the high-affinity receptor for B7 molecules on T cells. () is a cell-surface molecule that is involved in lymphocyte horning to the skin in humans. is a malignant growth of T cells that home to the skin. is a DNA alkylating agent that is used as an immunosuppressive drug. It acts by killing rapidly dividing cells, including lymphocytes proliferating in response to antigen. is a powerful immunosuppressive drug that inhibits signaling from the T-cell receptor, preventing T-cell activation and effector function. It binds to cyclophilin, and this complex binds to and inactivates the serine/threonine phosphatase calcineurin. : see antigen capture. are cellular receptors for cytokines. Binding of the cytokine to the cytokine receptor induces new activities in the cell, such as growth, differentiation, or death. are proteins made by cells that affect the behavior of other cells. Cytokines made by lymphocytes are often called lymphokines or interleukins (abbreviated IL), but the generic term cytokine is used in this book and most of the literature. Cytokines act on specific cytokine receptors on the cells that they affect. See also chemokines. T cells that can kill other cells are called . Most cytotoxic T cells are MHC class I-restricted CD8 T cells, but CD4 T cells can also kill in some cases. Cytotoxic T cells are important in host defense against cytosolic pathogens. are proteins made by cytotoxic T cells that participate in the destruction of target cells. Perforins and granzymes are the major defined cytotoxins. In the context of immunoglobulins, is the type of heavy chain in IgD. , or , are short DNA sequences that join the V and J gene segments in rearranged immunoglobulin heavy-chain genes and in T-cell receptor β and δ chain genes. See gene segments. : see germinal centers. were originally defined in proteins encoded by genes involved in programmed cell death or apoptosis, and are now known to be involved in protein-protein interactions. The ( or ) is a cell-surface molecule that protects cells from lysis by complement. Its absence causes the disease paroxysmal nocturnal hemoglobinuria. are partial retroviral genomes integrated into host cell DNA and carried as host genes. There are a great many defective endogenous retroviruses in the mouse genome. , or type IV hypersensitivity, is a form of cell-mediated immunity elicited by antigen in the skin and is mediated by CD4 TH1 cells. It is called delayed-type hypersensitivity because the reaction appears hours to days after antigen is injected. Cf. immediate hypersensitivity. , also known as interdigitating reticular cells, are found in T-cell areas of lymphoid tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses. Nonlymphoid tissues also contain dendritic cells, but these are not able to stimulate T-cell responses until they are activated and migrate to lymphoid tissues. The dendritic cell derives from bone marrow precursors. It is distinct from the follicular dendritic cell that presents antigen to B cells. (), are a specialized class of γ:δ T cells found in the skin of mice and some other species, but not humans. All dETCs have the same γ:δ T-cell receptor; their function is unknown. is a procedure in which an allergic individual is exposed to increasing doses of allergen in hopes of inhibiting their allergic reactions. It probably involves shifting the balance between CD4 T_H1 and T_H2 cells and thus changing the antibody produced from IgE to IgG. : see epitope spreading. () is most commonly released from inositol phospholipids by the action of phospholipase C-β. Diacylglycerol production is stimulated by the ligation of many receptors and it acts as an intracellular signaling molecule, activating cytosolic protein kinase C, which further propagates the signal. is the movement of blood cells, particularly leukocytes, from the blood across blood vessel walls into tissues. The proposes that qualitatively different antigens might mediate the positive and negative selection of T cells in the thymus. Cf. avidity hypothesis. are proteins detected on some cells by means of specific antibodies. Many differentiation antigens have important functional roles characteristic of the differentiated phenotypes of the cell on which they are expressed, such as cell-surface immunoglobulin on B cells. is a recessive genetic immunodeficiency disease in which there is a failure to develop thymic epithelium, and is associated with absent parathyroid glands and large vessel anomalies. It seems to be due to a developmental defect in neural crest cells. The uses anti-immunoglobulin to agglutinate red blood cells as a way of detecting whether they are coated with antibody in vivo due to autoimmunity or maternal anti-fetal immune responses (see Coombs test; indirect Coombs test). : see conformational epitopes. are created by placing a different DNA on a small part of a microchip, and using them to assess RNA expression in normal or malignant cells. When vaccinating with plasmid DNA, it was seen that an adaptive immune response to the encoded protein occurred, leading to the term . This lead to the realization that bacterial DNA, which is loaded with unmethylated CpG dinucleotides, was adjuvant for this type of vaccination. The genetic defect in scid mice, which cannot rearrange their T- or B-cell receptor genes and have a severe combined immunodeficiency phenotype, is in the enzyme . This enzyme is part of a complex of proteins that bind to the hairpin ends of doublestranded breaks in DNA, and its catalytic subunit is critical for VDJ recombinationD In tissue grafting experiments, the grafted tissues come from a and are placed in a recipient or host. are immature T cells within the thymus that lack expression of the two co-receptors, CD4 and CD8. In a normal thymus, these represent about 5% of thymocytes. are an intermediate stage in T-cell development in the thymus and are characterized by expression of both the CD4 and the CD8 co-receptor proteins. They represent the majority (80%) of thymocytes. The term is used for any lymph node that is downstream of a site of infection and thus receives antigens and microbes from the site via the lymphatic system. Draining lymph nodes often enlarge enormously during an immune response and can be palpated; they were originally called swollen glands. In the context of immunoglobulins, (epsilon) is the heavy chain of IgE. The or early nonadaptive responses are a series of host defense responses that are triggered by infectious agents early in infection. They are distinct from innate immunity because there is an inductive phase, and from adaptive immunity in that they do not operate by clonal selection of rare antigen-specific lymphocytes. : see pro-B cell. The common skin disease is seen mainly in children; its etiology is poorly understood. In immunology, is the swelling caused by the entry of fluid and cells from the blood into the tissues, which is one of the cardinal features of the process of inflammation. can mediate the removal of pathogens from the body without the need for further differentiation, as distinct from naive lymphocytes, which must proliferate and differentiate before they can mediate effector functions, and memory cells, which must differentiate and often proliferate before they become effector cells. They are also called armed effector cells in this book, to indicate that they can be triggered to effector function by antigen binding alone. are those processes by which pathogens are destroyed and cleared from the body. Innate and adaptive immune responses use most of the same effector mechanisms to eliminate pathogens. Lymphocytes leave a lymph node through the . is the movement of molecules in a charged field. In immunology, many forms of electrophoresis are used to separate molecules, especially protein molecules, to determine their charge, size, and subunit composition. : see enzyme-linked immunosorbent assay. is an adaptation of ELISA in which cells are placed over antibodies or antigens attached to a plastic surface. The antigen or antibody traps the cells' secreted products, which can then be detected using an enzyme-coupled antibody that cleaves a colorless substrate to make a localized colored spot. () are mouse embryonic cells that will grow continuously in culture and that retain the ability to contribute to all cell lineages. ES cells can be genetically manipulated in tissue culture and then inserted into mouse blastocysts to generate mutant lines of mice; most often, genes are deleted in ES cells by homologous recombination and the mutant ES cells are then used to generate gene knockout mice. They have also been used to clone sheep, and could soon be used to replace body parts in humans. have thick carbohydrate coats that protect them from phagocytosis. Encapsulated bacteria can cause extracellular infections and are effectively engulfed and destroyed by phagocytes only if they are first coated with antibody and complement produced in an adaptive immune response. Cytokines that can induce a rise in body temperature are called , as distinct from exogenous substances such as endotoxin from gram-negative bacteria that induce fever by triggering endogenous pyrogen synthesis and release. Antigen taken up by phagocytosis generally enters the , the acidified vesicles present in cells. Protein antigens entering by this route are presented by MHC class II molecules. are bacterial toxins that are released only when the bacterial cell is damaged, as opposed to exotoxins, which are secreted bacterial toxins. The most important endotoxin is the lipopolysaccharide of gram-negative bacteria, which is a potent inducer of cytokine synthesis and the proximal cause of endotoxic shock. Within genomic DNA, there are specific sequences that act as cellspecific of RNA transcription. The () is a serological assay in which bound antigen or antibody is detected by a linked enzyme that converts a colorless substrate into a colored product. The ELISA assay is widely used in biology and medicine as well as in immunology. are white blood cells thought to be important chiefly in defense against parasitic infections; they are activated by the lymphocytes of the adaptive immune response. The level of eosinophils in the blood is normally quite low. It can increase markedly in several situations, such as atopy, resulting in eosinophilia, an abnormally large number of eosinophils in the blood. and are CC chemokines that act specifically on eosinophils. An is a site on an antigen recognized by an antibody or an antigen receptor; epitopes are also called antigenic determinants. A T-cell epitope is a short peptide derived from a protein antigen. It binds to an MHC molecule and is recognized by a particular T cell. B-cell epitopes are antigenic determinants recognized by B cells and are typically discontinuous in the primary structure. describes the fact that responses to autoantigens tend to become more diverse as the response persists. This is also called determinant spreading or antigen spreading. The () is a herpesvirus that selectively infects human B cells by binding to complement receptor 2 (CR2, also known as CD21). It causes infectious mononucleosis and establishes a lifelong latent infection in B cells that is controlled by T cells. Some B cells latently infected with EBV will proliferate in vitro to form lymphoblastoid cell lines. The affinity of an antibody for its antigen can be determined by , a technique in which antibody in a dialysis bag is exposed to varying amounts of a small antigen able to diffuse across the dialysis membrane. The amount of antigen inside and outside the bag at the equilibrium diffusion state is determined by the amount and affinity of the antibody in the bag. are human T cells that will bind to treated red blood cells from sheep; the many red blood cells bound to each T cell give it the appearance of a rosette and increase its buoyant density so that the T cells can be isolated by gradient centrifugation. E-rosetting is often used for isolating human T cells. is a chaperone molecule involved in loading peptide onto MHC class I molecules in the endoplasmic reticulum. is a severe form of Rh hemolytic disease in which maternal anti-Rh antibody enters the fetus and produces a hemolytic anemia so severe that the fetus has mainly immature erythroblasts in the peripheral blood. : see selectins. () is an inflammatory disease of the central nervous system that develops after mice are immunized with neural antigens in a strong adjuvant. The movement of cells or fluid from within blood vessels to the surrounding tissues is called . IgG antibody molecules can be cleaved into three fragments by the enzyme papain. Two of these are identical s, so called because they are the Fragment with specific antigen binding. The Fab fragment consists of the light chain and the N-terminal half of the heavy chain held together by an interchain disulfide bond. Another protease, pepsin, cuts in the same general region of the antibody molecule as papain but on the carboxy-terminal side of the disulfide bonds. This produces the F(ab')2 fragment, in which the two arms of the antibody molecule remain linked. See also Fc fragment. : see fluorescence-activated cell sorter. , , , , and are all components of the alternative pathway of complement activation. Factor B plays a role very similar to that of C2b in the classical pathway. Factor D is a serine protease that cleaves factor B. Factor H is an inhibitory protein with a role similar to decay-accelerating factor. Factor I is a protease that breaks down various components of the alternative pathway. Factor P, or properdin, is a positive regulatory component of the alternative pathway. It stabilizes the C3 convertase of the alternative pathway on the surface of bacterial cells. is a hypersensitivity disease caused by the interaction of IgG antibodies with large amounts of an inhaled allergen in the alveolar wall of the lung, causing alveolar wall inflammation and compromising gas exchange. is a member of the TNF receptor family; it is expressed on certain cells and makes them susceptible to killing by cells expressing , a cell-surface member of the TNF family of proteins. Binding of Fas ligand to Fas triggers apoptosis in the Fas-bearing cell. IgG antibody molecules can be cleaved into three fragments by the enzyme papain. One of these is the , so-called for Fragment crystallizable. The Fc fragment consists of the C-terminal halves of the two heavy chains disulfide-bonded to each other by the residual hinge region. See also Fab fragments. are receptors for the Fc portion of immunoglobulin isotypes. They include the Fcγ and Fcε receptors. The high-affinity () on the surface of mast cells and basophils binds free IgE. When antigen binds this IgE and crosslinks FcεRI, it causes mast-cell activation. , including , , and , are cell-surface receptors that bind the Fc portion of IgG molecules. Most Fcγ receptors bind only aggregated IgG, allowing them to discriminate bound antibody from free IgG. They are expressed on phagocytes, B lymphocytes, NK cells, and follicular dendritic cells. They have a key role in humoral immunity, linking antibody binding to effector cell functions. When tissue or organ grafts are placed in an unmatched recipient, they are rejected by a , which is an immune response by the host against foreign antigens in the graft. Cf. second set rejection. : see tacrolimus. Individual cells can be characterized and separated in a machine called a () that measures cell size, granularity, and fluorescence due to bound fluorescent antibodies as single cells pass in a stream past photodetectors. The analysis of single cells in this way is called flow cytometry and the instruments that carry out the measurements and/or sort cells are called flow cytometers or cell sorters. Peripheral lymphoid tissues, such as lymph nodes and Peyer's patches, contain large areas of B cells called , which are organized around follicular dendritic cells. A is a type of B-cell lymphoma that tends to grow in the follicles of lymphoid tissues. The of lymphoid follicles are cells of uncertain origin. They are characterized by long branching processes that make intimate contact with many different B cells. They have Fc receptors that are not internalized by receptor-mediated endocytosis and thus hold antigen:antibody complexes on the surface for long periods. These cells are crucial in selecting antigen-binding B cells during antibody responses. The V domains of immunoglobulins and T-cell receptors contain relatively invariant that provide a protein scaffold for the hypervariable regions that make contact with antigen. are single-celled and multicellular eukaryotic organisms, including the yeasts and molds, that can cause a variety of diseases. Immunity to fungi is complex and involves both humoral and cellmediated responses. : see single-chain Fv. : see tyrosine kinase. In the context of immunoglobulins, is the heavy chain of IgG. are intracellular proteins that bind GTP and convert it to GDP in the process of cell signal transduction. There are two kinds of G protein, the heterotrimeric (α, β, γ) receptor-associated G proteins, and the small G proteins, such as Ras and Raf, that act downstream of many transmembrane signaling events. : see . Most T lymphocytes have α:β heterodimeric T-cell receptors, but some bear a distinct composed of different antigenrecognition chains, γ and δ, assembled in a γ:δ heterodimer. Cells bearing these receptors are called and their specificity and function are not yet clear. Plasma proteins can be separated on the basis of electrophoretic mobility into albumin and the α, β, and γ globulins. Most antibodies migrate in electrophoresis as (or ), and patients who lack antibodies are said to have agammaglobulinemia. : see . In birds and rabbits, immunoglobulin receptor diversity is generated mainly by , in which homologous inactive V gene segments exchange short sequences with an active, rearranged V-region gene. is jargon for gene disruption by homologous recombination. The V domains of the polypeptide chains of antigen receptors are encoded in sets of that must first undergo somatic recombination to form a complete V-domain exon. There are three types of gene segment: V gene segments that encode the first 95 amino acids, D gene segments that encode about 5 amino acids, and J gene segments that form the last 10-15 amino acids of the V region. There are multiple copies of each type of gene segment in the germline DNA, but only one is expressed for each type of receptor chain in a receptor-bearing lymphocyte. A gene can be specifically disrupted by a technique known as or gene knockout. Usually this involves homologous recombination in embryonic stem cells followed by the preparation of chimeric mice by injection of these cells into the blastoeyst. is the correction of a genetic defect by the introduction of a normal gene into bone marrow or other cell types. It is also known as somatic gene therapy because it does not affect the germline genes of the individual. is a novel technique for inducing adaptive immune responses. Plasmid DNA encoding a protein of interest is injected into muscle; for unknown reasons, it is expressed and elicits antibody and T-cell responses to the protein encoded by the DNA. Mice that are raised in the complete absence of intestinal and other flora are called or mice. Such mice have very depleted immune systems, but they can respond virtually normally to any specific antigen, provided it is mixed with a strong adjuvant. in secondary lymphoid tissues are sites of intense B-cell proliferation, selection, maturation, and death during antibody responses. Germinal centers form around follicular dendritic cell networks when activated B cells migrate into lymphoid follicles. They can be divided by morphology into the dark zone, which is rich in proliferating B lymphocytes, and a light zone, which contains FDCs and centrocytes. Immunoglobulin and T-cell receptor genes are said to be in the in the DNA of germ cells and in all somatic cells in which somatic recombination has, not occurred. The of antigen receptors is due to the inheritance of multiple gene segments that encode V domains; such diversity is distinguished from the diversity that is generated during gene rearrangement or after receptor gene expression, which is somatically generated. One theory of antibody diversity, the , proposed that each antibody was encoded in a separate germline gene. This is now known not to happen in people, mice, and most other organisms, but appears to happen in Elasmobranchs, which have rearranged genes in the germline. is a mucinlike molecule found on the high endothelial venuies of lymphoid tissues. It is an important ligand for the L-selectin molecule expressed on naive lymphocytes, directing these cells to leave the blood and enter the lymphoid tissues. : see . is an autoimmune disease in which autoantibodies against basement membrane or type IV collagen are produced and cause extensive vasculitis. It is rapidly fatal. Tissue and organ grafts between genetically distinct individuals almost always elicit an adaptive immune response that causes , the destruction of the grafted tissue by attacking lymphocytes. When mature T lymphocytes are injected into a nonidentical immunoincompetent recipient, they can attack the recipient, causing a () reaction; in human patients, mature T cells in allogeneic bone marrow grafts can cause (). : see . () is a cytokine involved in the growth and differentiation of myeloid and monocytic lineage cells, including dendritic cells, monocytes and tissue macrophages, and cells of the granulocyte lineage. A is a site of chronic inflammation usually triggered by persistent infectious agents such as mycobacteria or by a nondegradable foreign body. Granulomas have a central area of macrophages, often fused into multinucleate giant cells, surrounded by T lymphocytes. are serine proteases produced by cytotoxic T cells and are involved in inducing apoptosis in the target cell. is an autoimmune disease in which antibodies against the thyroid-stimulating hormone receptor cause overproduction of thyroid hormone and thus hyperthyroidism. The () are proteins that can remove the bound GDP from small G proteins; this allows GTP to bind and activate the G protein. The () are lymphoid tissues closely associated with the gastrointestinal tract, including the palatine tonsils, Peyer's patches, and intraepithelial lymphocytes. The GALT has a distinctive biology related to its exposure to antigens from food and normal intestinal microbial flora. or , are known as major histocompatibility antigens when they encode molecules that present foreign peptides to T cells and as minor H antigens when they present polymorphic self peptides to T cells. See also histocompatibility. The major histocompatibility complex of the mouse is called (for ). Haplotypes are designated by a lower-case superscript, as in H-2b. A is a linked set of genes associated with one haploid genome. The term is used mainly in connection with the linked genes of the major histocompatibility complex, which are usually inherited as one haplotype from each parent. Some MHC haplotypes are overrepresented in the population, a phenomenon known as linkage disequilibrium. are molecules that can bind antibody but cannot by themselves elicit an adaptive immune response. Haptens must be chemically linked to protein carriers to elicit antibody and T-cell responses. is an autoimmune disease characterized by persistent high levels of antibody against thyroid-specific antigens. These antibodies recruit NK cells to the tissue, leading to damage and inflammation. All immunoglobulin molecules have two types of chain, a () of 50-70 kDa and a light chain of 25 kDa. The basic immunoglobulin unit consists of two identical heavy chains and two identical light chains. Heavy chains come in a variety of heavy-chain classes or isotypes, each of which confers a distinctive functional activity on the antibody molecule. are CD4 T cells that can help B cells make antibody in response to antigenic challenge. The most efficient helper T cells are also known as T_H2 cells, which make the cytokines IL-4 and IL-5. Some experts refer to all CD4 T cells, regardless of function, as helper T cells; we do not accept this usage because function can be determined only in cellular assays, and some CD4 T cells kill the cells they interact with. A is any substance that causes red blood cells to agglutinate, a process known as . The hemagglutinins in human blood are antibodies that recognize the ABO blood group antigens. Influenza and some other viruses have hemagglutinin molecules that bind to glycoproteins on host cells to initiate the infectious process. is the generation of the cellular elements of blood, including the red blood cells, leukocytes, and platelets. These cells all originate from pluripotent whose differentiated progeny divide under the influence of . A is any developmental series of cells that derives from hematopoietic stem cells and results in the production of mature blood cells. : see erythroblastosis fetalis. Recombination signal sequences (RSS) flanking gene segments consist of a seven-nucleotide and a nine-nucleotide nonamer of conserved sequence, separated by 12 or 23 nucleotides. RSSs form the target for the site-specific RAG-1:RAG-2 recombinase that joins the gene segments. is the clinical name for a genetic deficiency of the Cl inhibitor of the complement system. In the absence of Cl inhibitor, spontaneous activation of the complement system can cause diffuse fluid leakage from blood vessels, the most serious consequence of which is epiglottal swelling leading to suffocation. Individuals for a particular gene have two different alleles of that gene. An excellent model for membranous glomerulonephritis is , a disease induced by injecting animals with tubular epithelial tissue. () are specialized venules found in lymphoid tissues. Lymphocytes migrate from blood into lymphoid tissues by attaching to and migrating across the of these vessels. Tolerance to injected protein antigens occurs at low or high doses of antigen. Tolerance induced by the injection of high doses of antigen is called , whereas tolerance produced with low doses of antigen is called low-zone tolerance. The of antibody molecules is a flexible domain that joins the Fab arms to the Fc piece. The flexibility of the hinge region in IgG and IgA molecules allows the Fab arms to adopt a wide range of angles, permitting binding to epitopes spaced variable distances apart. is a vasoactive amine stored in mast cell granules. Histamine released by antigen binding to IgE molecules on mast cells causes dilation of local blood vessels and smooth muscle contraction, producing some of the symptoms of immediate hypersensitivity reactions. Antihistamines are drugs that counter histamine action. is literally the ability of tissues (Greek: histos) to get along with each other. It is used in immunology to describe the genetic systems that determine the rejection of tissue and organ grafts resulting from immunological recognition of histocompatibility (H) antigens. : see H-2. : see human immunodeficiency virus. , the acronym for Human Leukocyte Antigen, is the genetic designation for the human MHC. Individual loci are designated by upper-case letters, as in HLA-A, and alleles are designated by numbers, as in HLA-A*0201. The invariant molecule in humans is involved in loading peptides onto MHC class II molecules. It is encoded in the MHC within a set of genes resembling MHC class II genes. A homologous protein in mice is called H-2M. is an immune system tumor characterized by large cells called Reed-Sternberg cells, which derive from mutated B-lineage cells. It exists in at least two polar forms, Hodgkin's lymphoma and nodular sclerosis. is a generic term describing the status of physiological normality. In the case of lymphocytes, homeostasis refers to an uninfected individual who has normal numbers of lymphocytes. Cellular genes can be disrupted by with copies of the gene into which erroneous sequences have been inserted. When these exogenous DNA fragments are introduced into cells, they recombine selectively with the cellular gene through remaining regions of sequence homology, replacing the functional gene with a nonfunctional copy. () is another name for the allograft rejection reaction. The term is used mainly in relation to bone marrow transplantation. The () is the causative agent of the acquired immune deficiency syndrome (AIDS). HIV is a retrovirus of the lentivirus family that selectively infects macrophages and CD4 T cells, leading to their slow depletion, which eventually results in immunodeficiency. : see HLA is a term used to describe the genetic engineering of mouse hypervariable loops of a desired specificity into otherwise human antibodies. The DNA encoding hypervariable loops of mouse monoclonal antibodies or V regions selected in phage display libraries is inserted into the framework regions of human immunoglobulin genes. This allows the production of antibodies of a desired specificity that do not cause an immune response in humans treated with them. is the antibody-mediated specific immunity made in a . Humoral immunity can be transferred to unimmunized recipients by using immune serum containing specific antibody. Monoclonal antibodies are most commonly produced from . These are hybrid cell lines formed by fusing a specific antibodyproducing B lymphocyte with a myeloma cell that is selected for its ability to grow in tissue culture and for an absence of immunoglobulin chain synthesis. of an allogenic tissue graft is an immediate reaction caused by natural preformed antibodies that react against antigens on the graft. The antibodies bind to endothelium and trigger the blood clotting cascade, leading to an engorged, ischemic graft and rapid loss of the organ. is an abnormal state in which there are extremely large numbers of eosinophils in the blood. Repetitive immunization to achieve a heightened state of immunity is called . Immune responses to innocuous antigens that lead to symptomatic reactions upon reexposure are called . These can cause if they occur repetitively. This state of heightened reactivity to antigen is called . Hypersensitivity reactions are classified by mechanism: type I hypersensitivity reactions involve IgE antibody triggering of mast cells; type II hypersensitivity reactions involve IgG antibodies against cellsurface or matrix antigens; type III hypersensitivity reactions involve antigen:antibody complexes; and type IV hypersensitivity reactions are T cell-mediated. The () of immunoglobulin and T-cell receptor V domains are small regions that make contact with the antigen and differ extensively from one receptor to the next. Cf. framework regions. The inactive complement fragment is produced by cleavage of C3b and is the first step in C3b inactivation. The (intercellular adhesion molecules) are cell-surface ligands for the leukocyte integrins and are crucial in the binding of lymphocytes and other leukocytes to certain cells, including antigenpresenting cells and endothelial cells. They are members of the immunoglobulin superfamily. is the most prominent ligand for the integrin CD11a:CD18 or LFA-1. It is rapidly inducible on endothelial cells by infection, and plays a major role in local inflammatory responses. is constitutively expressed at relatively low levels by endothelium. is expressed only on leukocytes and is thought to play an important part in adhesion between T cells and antigen-presenting cells, particularly dendritic cells. All antibody molecules belong to a family of plasma proteins called (). Membrane-bound immunoglobulin serves as the specific antigen receptor on B lymphocytes. are small fragments of membrane coated with immune complexes that fragment off the processes of follicular dendritic cells in lymphoid follicles early in a secondary or subsequent antibody response. is a CD28-related protein that is induced on activated T cells and can enhance T-cell responses. It binds a ligand known as LICOS, which is distinct from the B7 molecules. Each immunoglobulin molecule has the potential of binding a variety of antibodies directed at its unique features or . An idiotype is made up of a series of from idiotype epitopes. Lymphocyte antigen receptors can recognize one another through idiotope - anti-idiotope interactions, forming an of receptors that may be important for the generation and maintenance of the receptor repertoire. The proposed components of idiotype networks exist, but their functional significance is uncertain. : see interferons. : standard abbreviation for . Different immunoglobulin isotypes are called IgM, IgD, IgG, IgA, and IgE. , : see B-cell antigen receptor. is the class of immunoglobulin characterized by α heavy chains. IgA antibodies are secreted mainly by mucosal lymphoid tissues. is the class of immunoglobulin characterized by δ heavy chains. It appears as surface immunoglobulin on mature naive B cells but its function is unknown. is the class of immunoglobulin characterized by ε-heavy chains. It is involved in allergic reactions. is the class of immunoglobulin characterized γ heavy chains. It is the most abundant class of immunoglobulin found in the plasma. is the class of immunoglobulin characterized by μ heavy chains. It is the first immunoglobulin to appear on the surface of B cells and the first to be secreted. : see interleukins. are B cells that have rearranged a heavy- and a light-chain V-region gene and express surface IgM, but have not yet matured sufficiently to express surface IgD as well. Tissues throughout the body contain , which only leave the tissues in response to an inflammatory mediator or an infection. See also dendritic cells. During allergic reactions, there are normally two phases: the first happens almost immediately and is called the . Hypersensitivity reactions that occur within minutes of exposure to antigen are called ; such reactions are antibody mediated. Cf. delayed-type hypersensitivity. When late amounts of antigen are injected into the blood, they are initially removed slowly by normal catabolic processes that also degrade plasma proteins. However, if the antigen elicits an antibody response, then antigen is removed at an accelerated rate as antigen:antibody complexes, a process known as . The binding of antibody to a soluble antigen forms an . Large immune complexes form when sufficient antibody is available to cross-link the antigen; these are readily cleared by the reticuloendothelial system of cells bearing Fc and complement receptors. Small, soluble immune complexes that form when antigen is in excess can be deposited in and damage small blood vessels. is a term used to describe the polarization of an immune response to one dominated by TH1 or TH2 by the injection of antigen. is a general term encompassing various alterations in an immune response. The is the response made by the host to defend itself against a pathogen. () are genetic polymorphisms that control the intensity of the immune response to a particular antigen. Virtually all Ir phenotypes are due to the differential binding of peptide fragments of antigen to MHC molecules, especially MHC class II molecules. The term is little used now. An is usually, but not always, due to failure to bind an immunogenic peptide, so that no T-cell response is observed. It has been proposed that most tumors that arise are detected and eliminated by mediated by lymphocytes specific for tumor antigens. There is little evidence for the efficacy of this proposed process, but it remains an important concept in tumor immunology. The is the name used to describe the tissues, cells, and molecules involved in adaptive immunity, or sometimes the totality of host defense mechanisms. is the ability to resist infection. is the deliberate provocation of an adaptive immune response by introducing antigen into the body. See also active immunization; passive immunization. is the study of the biological basis for host defense against infection. is a common technique in which proteins separated by gel electrophoresis are blotted onto a nitrocellulose membrane and revealed by the binding of specific labeled antibodies. are a group of inherited or acquired disorders in which some aspect or aspects of host defense are absent or functionally defective. is the detection of antigen or antibody by the formation of an antigen:antibody precipitate in a clear agar gel. is a technique in which antigens are first separated by their electrophoretic mobility and are then detected and identified by immunodiffusion. is a technique for detecting molecule using antibodies labeled with fluorescent dyes. The bound fluorescent antibody can be detected by microscopy, or by flow cytome" depending on the application being used. uses anti-immunoglobulin antibodies labeled with fluorescent dyes to detect the binding of a specific unlabeled antibody. There are three ways of detecting molecules in tissues: that reveals the presence of any molecule against which you have a specific antibody; , in which one links an enzyme that produces a change in a molecule that is visible under the microscope; and , in which different sized gold particles are linked to antibodies and detected as bound gold particles. Any molecule that can elicit an adaptive immune response on injection into a person or animal is called an . In practice, only proteins are fully because only proteins can be recognized by T lymphocytes. was originally the analysis of genetic traits by means of antibodies against genetically polymorphic molecules such as blood group antigens or MHC proteins. Immunogenetics now refers to the genetic analysis, by any technique, of molecules important in immunology. : see IgA. : see IgD. Many proteins are partly or entirely composed of protein domains known as or because the were first described in antibody molecules. Immunoglobulin domains are characteristic of proteins of the immunoglobulin superfamily, which includes antibodies, T-cell receptors, MHC molecules, and many other proteins described in this book. The immunoglobulin domain consists of a sandwich of two β sheets held together by a disulfide bond and called the . There are two main types of immunoglobulin domain: C domains and V domains. Domains less closely related to the canonical Ig domains are sometimes also called . : see IgG. : see IgE. : see IgM. The , also known as the antibody repertoire, is the total variety of immunoglobulin molecules in the body of an individual. Many proteins involved in antigen recognition and cell-cell interaction in the immune system and other biological systems are members of a protein family called the , or , because their shared structural features were first defined in immunoglobulin molecules. All members of the immunoglobulin superfamily have at least one immunoglobulin or immunoglobulin-like domain. The detection of antigens in tissues by means of visible products produced by the degradation of a colorless substrate by antibodylinked enzymes is called . This technique has the advantage that it can be combined with other stains to be viewed in the light microscope, whereas immunofluorescence microscopy requires a special dark-field or UV microscope. describes a form of self tolerance in which reactive lymphocytes and their target antigen are both detectable within an individual, yet no autoimmune attack occurs. Most autoimmune diseases probably reflect the loss of other lymphocytes known as regulatory or suppressor T cells. When an antigen is encountered more than once, the adaptive immune response to each subsequent encounter is speedier and more effective, a crucial feature of protective immunity known as . Immunological memory is specific for a particular antigen and is long-lived. Allogeneic tissue placed in certain sites in the body, such as the brain, does not elicit graft rejection. Such sites are called . Immunological privilege results from the effects of both physical barriers to cell and antigen migration, and soluble immunosuppressive mediators such as certain cytokines. is the study of all aspects of host defense against infection and of adverse consequences of immune responses. are proteins with peptidyl-prolyl cis-trans isomerase activity that bind the immunosuppressive drugs cyclosporin A, tacrolimus, and rapamycin. Soluble proteins, or membrane proteins solubilized in detergents, can be labeled and then detected by using specific antibodies. The immunoprecipitated labeled protein is usually detected by SDS-PAGE followed by autoradiography. When proteins that do not react directly with the antibody used are nevertheless precipitated, they are said to co-immunoprecipitate. The T and B cell antigen receptors are associated with transmembrane molecules with () in their cytoplasmic domains. These tyrosine-containing motifs are sites of tyrosine phosphorylation and of association with tyrosine kinases and other phosphotyrosine-binding moieties involved in receptor signaling. Related motifs with opposing effects are (), which recruit phosphatases to the receptor site that remove the phosphate groups added by tyrosine kinases. The ability of the immune system to sense and regulate its own responses is called . Compounds that inhibit adaptive immune responses are called . They are used mainly in the treatment of graft rejection and severe autoimmune disease. are antibodies that are chemically coupled to toxic proteins usually derived from plants or microbes. The antibody targets the toxin moiety to the required cells. Immunotoxins are being tested as anticancer agents and as immunosuppressive drugs. The is a variation of the direct Coombs test in which an unknown serum is tested for antibodies against normal red blood cells by first mixing the two and then washing out the serum from the red blood cells and reacting them with anti-immunoglobulin antibody. If antibody in the unknown serum binds to the red blood cells, agglutination by anti-immunoglobulin occurs. : see immunofluorescence. Macrophages and many other cells have an , or , that is induced by many different stimuli to activate NO synthesis. This is a major mechanism of host resistance to intracellular infection in mice, and probably in humans as well. , or glandular fever, is the common form of infection with the Epstein-Barr virus. It consists of fever, malaise, and swollen lymph nodes. is a general term for the local accumulation of fluid, plasma proteins, and white blood cells that is initiated by physical injury, infection, or a local immune response. This is also known as an . Acute inflammation is the term used to describe early and often transient episodes, whereas chronic inflammation occurs when the infection persists or during autoimmune diseases. Many different forms of inflammation are seen in different diseases. The cells that invade tissues undergoing inflammatory responses are often called or an . : see hemagglutinin. The early phases of the host response to infection depend on in which a variety of innate resistance mechanisms recognize and respond to the presence of a pathogen. Innate immunity is present in all individuals at all times, does not increase with repeated exposure to a given pathogen, and discriminates between a group of related pathogens. When inositol phospholipid is cleaved by phospholipase C-γ, it yields () and diacylglycerol. Inositol trisphosphate releases calcium ions from intracellular stores in the endoplasmic reticulum. In (), the β cells of the pancreatic islets of Langerhans are destroyed so that no insulin is produced. The disease is believed to result from an autoimmune attack on the P cells. are heterodimeric cell-surface proteins involved in cell-cell and cell-matrix interactions. They are important in adhesive interactions between lymphocytes and antigen-presenting cells and in lymphocyte and leukocyte migration into tissues. The , or very late antigens (VLA), are a family of integrins with shared β1 chains and different α chains that mediate adhesion to other cells and to extracellular matrix proteins. : see ICAMs. : see dendritic cells. are cytokines that can induce cells to resist viral replication. () and () are produced by leukocytes and fibroblasts, respectively, as well as by other cells, whereas ( is a product of CD4 T_H1 cells, CD8 T cells, and NK cells. IFN-γ has as its primary action the activation of macrophages. , abbreviated , is a generic term for cytokines produced by leukocytes. We use the more general term cytokine in this book, but the term interleukin is used in the naming of specific cytokines such as IL-2. () is the cytokine that is most central to the development of an adaptive immune response. Staining for cytokines in cells that produce them can be achieved by permiablizing the cell and reacting it with a labelled fluorescent anticytokine antibody. This procedure is called . Injections can be administered by a number of routes: (intradermal)-entering the skin or dermis; - entering below the skin or dermis; - entering the muscle; - by way of the nose; and - entering a vein. : see dendritic cells. The major histocompatibility complex (MHC) class II proteins are assembled in the endoplasmic reticulum with the (Ii), which is involved in shielding the MHC class II molecules from binding peptides and in delivering them to cellular vesicles. There Ii is degraded, leaving the MHC class II molecules able to bind peptide fragments of antigen. are of antigen held within a lipid matrix that acts as an adjuvant and enables the antigen to be taken up into the cytoplasm after fusion of the lipid with the plasma membrane. is an electrophoretic technique in which proteins migrate in a pH gradient until they reach the place in the gradient at which their net charge is neutral-their isoelectric point. Uncharged proteins no longer migrate; thus each protein is focused at its isoelectric point. The first antibodies produced in a humoral immune response are IgM, but activated B cells subsequently undergo or class switching to secrete antibodies of different isotypes: IgG, IgA, and IgE. Isotype switching does not affect antibody specificity significantly, but alters the effector functions that an antibody can engage. Isotype switching occurs by recombination involving the deletion of DNA between the rearranged V region and the selected C-region exon at so-called S regions. Immunoglobulins are made in several distinct or classes- IgM, IgG, IgD, IgA, and IgE-each of which has a distinct heavy-chain C region encoded by a distinct C-region gene. The isotype of an antibody determines the effector mechanisms that it can engage on binding antigen. The different heavy-chain C regions are encoded in exons 3' to the V(D)J rearrangement site. This allows the same antibody heavy-chain V region to link up with different heavy-chain C-region isotypes as a result of somatic recombination. describes the use of one or other of the lightchain isotypes, κ or λ, by a given B cell or antibody. The , or , are found some distance 5' to the C genes in immunoglobulin and T-cell receptor loci. A V and in the case of IgH chains, TCRβ chains and TCRδ chains, a D gene segment must also rearrange to a J gene segment to form a complete V-region exon. Cytokine receptors signal via ()-tyrosine kinases that are activated by the aggregation of cytokine receptors. These kinases phosphorylate proteins known as STATS, for Signal Transducers and Activators of Transcription. STATs are normally found in the cytosol, but move to the nucleus on phosphorylation and activate a variety of genes. is the diversity present in antigen-specific receptors that is created during the process of joining V, D, and J gone segments. In the context of immunoglobulins, is one of the two classes of lightchain. () are cell-surface receptors on NK cells or cytotoxic T cells; they are receptors that can activate killing by these cells. is a commonly used term for cytotoxic T cell. The is an enzymatic cascade of plasma proteins that is triggered by tissue damage to produce several inflammatory mediators, including the vasoactive peptide bradykinin. The cell-surface receptor , present on developing B cells and other developing white blood cells, binds to the stem cell factor on bone marrow stromal cells. Kit has protein tyrosine kinase activity. are phagocytes lining the hepatic sinusoids; they remove debris and dying cells from the blood, but are not known to elicit immune responses. In the context of immunoglobulins, . is one of the two is one of the two classes of light-chain. : see pre-B-cell receptor. : see light chain. are phagocytic dendritic cells found in the epidermis. They can migrate from the epidermis to regional lymph nodes via the afferent lymphatics. In the lymph node they differentiate into dendritic cells. The have a cell-surface , which is lost on the transition to small pre-B cells, in which light-chain gene rearrangement occurs. : see linker of activation in T cells. The is the stage in B-cell development in which VH to DJH joining occurs. Some viruses can enter a call but not replicate, a state known as . Latency can be established in various ways; when the virus is reactivated and replicates, it can produce disease. In type I immediate hypersensitivity reactions, the persists and is resistant to treatment with antihistamine. The tyrosine kinase associates most strongly with the cytoplasmic tails of CD4 and CD8. It plays a central role in signal transduction and activation of the T-cell receptor. : see lymphocyte choriomeningitis virus. are a group of retroviruses that include the human immunodeficiency virus, HIV-1. They cause disease after a long incubation period and can take years to become apparent. is caused by Mycobacterium leprae and occurs in a variety of forms. There are two polar forms: , which is characterized by abundant replication of leprosy bacilli and abundant antibody production without cell-mediated immunity; and , in which few organisms are seen in the tissues, there is little or no antibody, but cell-mediated immunity is very active. The other forms of leprosy are intermediate between the polar forms. is the unrestrained proliferation of a malignant white blood cell characterized by very high numbers of the malignant cells in the blood. Leukemias can be lymphocytic, myelocytic, or monocytic. is a general term for a white blood cell. Leukocytes include lymphocytes, polymorphonuclear leukocytes, and monocytes. is an immunodeficiency disease in which the common P chain of the leukocyte integrins is not produced. This mainly affects the ability of leukocytes to enter sites of infection with extracellular pathogens, so that infections cannot be effectively eradicated. : see CD45. The or , are cell adhesion molecules initially defined with monoclonal antibodies: is a β2 integrin; is a member of the immunoglobulin superfamily, as is , now called CD58. LFA-1 is particularly important in T-call adhesion to endothelial cells and antigen-presenting cells. : see leukocyte functional antigens. is the presence of increased numbers of leukocytes in the blood. It is commonly seen in acute infection. are lipid mediators of inflammation that are derived from arachidonic acid. They are produced by macrophages and other cells. : see leukocyte functional antigens. is the ligand for ICOS, a CD28-related protein that is induced on activated T cells and can enhance T-cell responses. LICOS is produced on activated dendritic cells, monocytes, and B cells. The immunoglobulin () is the smaller of the two types of polypeptide chain that make up all immunoglobulins. It consists of one V and one C domain, and is disulfide-bonded to the heavy chain. There are two classes of light chain, known as κ and λ. : see germinal centers. : see continuous epitopes. Alleles at linked loci within the major histocompatibility complex are said to be in if they are inherited together more frequently than predicted from their individual frequencies. Epitopes recognized by B cells and helper T cells must be physically linked for the helper T cell to activate the B cell. This is called . The adaptor protein known as () is a cytoplasmic protein with several tyrosines that become phosphorylated by the tyrosine kinase ZAP-70. It becomes associated with membrane lipid rafts and coordinates downstream signaling events in T-cell activation. : see high-zone tolerance. A molecule of bacterial lipopolysaccharide (LPS) has first to be bound by the () before it can interact with CD14, an LPS:LBP-binding protein on cells such as macrophages. is an adhesion molecule of the selectin family found on lymphocytes. L-selectin binds to CD34 and GlyCAM-1 on high endothelial venules to initiate the migration of naive lymphocytes into lymphoid tissue. Also called CD62L. is a chronic infection with Borrelia burgdorferi, a spirochete that can evade the immune response. is the extracellular fluid that accumulates in tissues and is carried by lymphatic vessels back through the lymphatic system to the thoracic duct and into the blood. are a type of peripheral or secondary lymphoid organ. They are found in many locations throughout the body where lymphatic vessels converge, and are sites where adaptive immune responses are initiated. Antigen-presenting cells and antigen delivered by the lymphatic vessels from a site of infection are displayed to the many recirculating lymphocytes that migrate through the lymph nodes. Some of these lymphocytes will recognize the antigen and respond to it, triggering an adaptive immune response. The is the system of lymphoid channels and tissues that drains extracellular fluid from the periphery via the thoracic duct to the blood. It includes the lymph nodes, Peyer's patches, and other organized lymphoid elements apart from the spleen, which communicates directly with the blood. , or , are thin-walled vessels that carry lymph through the lymphatic system. A is a lymphocyte that has enlarged and increased its rate of RNA and protein synthesis. All adaptive immune responses are mediated by . Lymphocytes are a class of white blood cells that bear variable cellsurface receptors for antigen. These receptors are encoded in rearranging gene segments. There are two main classes of lymphocyte-B lymphocytes (B cells) and T lymphocytes (T cells)-which mediate humoral and cell-mediated immunity, respectively. Small lymphocytes have little cytoplasm and condensed nuclear chromatin; on antigen recognition, the cell enlarges to form a lymphoblast and then proliferates and differentiates into an antigenspecific effector cell. : see leukocyte functional antigens. The is the totality of the highly variable antigen receptors carried by B and T lymphocytes. () is a virus that causes a nonbacterial meningitis in mice and occasionally in humans. It is used extensively in experimental studies. Dendritic cells can arise from myeloid cells, in which case they are called myeloid dendritic cells, or from lymphoid tissues, in which case they are called . Functional differences exist between these two lineages. are organized tissues characterized by very large numbers of lymphocytes interacting with a nonlymphoid stroma. The central or primary lymphoid organs, where lymphocytes are generated, are the thymus and bone marrow. The main peripheral or secondary lymphoid organs, in which adaptive immune responses are initiated, are the lymph nodes, spleen, and mucosal-associated lymphoid tissues such as tonsils and Peyer's patches. are cytokines produced by lymphocytes. are tumors of lymphocytes that grow in lymphoid and other tissues but do not enter the blood in large numbers. There are many types of lymphoma, which represent the transformation of various developmental stages of B or T lymphocytes. is the differentiation of lymphoid cells from a common lymphoid progenitor. () is also known as tumor necrosis factor-β (TNF-β), a cytokine secreted by inflammatory CD4T cells that is directly cytotoxic for some cells. : see tyrosine kinase. are acidified organelles that contain many degradative hydrolytic enzymes. Material taken up into endosomes is eventually delivered to lysosomes. containing perforin and granzymes are a defining characteristic of armed effector cytotoxic cells. In the context of immunoglobulins, is the heavy chain of IgM. Antigens and pathogens enter the body from the intestines through cells called microfold or , which are specialized for this function. They are found over the gut-associated lymphoid tissue, or GALT. They may provide a route of infection for HIV. is another name for the leukocyte integrin CD11b:CD18 (or complement receptor 2 (CR2)). describes plasma proteins that are globulins of high molecular weight, including immunoglobulin M (IgM) and α2-macroglobulin. Resting macrophages will not destroy certain intracellular bacteria unless the macrophage is activated by a T cell. is important in controlling infection and also causes damage to neighbouring tissues. The is highly specific for certain carbohydrates that occur on the surface of some pathogens but not on host cells. are large mononuclear phagocytic cells important in innate immunity, in early non-adaptive phases of host defense, as antigen-presenting cells, and as effector cells in humoral and cellmediated immunity. They are migratory cells deriving from bone marrow precursors and are found in most tissues of the body. They have a crucial role in host defense. Dendritic cells are unique in being able to carry out , a process in which large amounts of extracellular fluid are taken up in single vesicles. This is one means of antigen uptake. is the mucosal cell adhesion molecule-1 or mucosal addressin that is recognized by the lymphocyte surface proteins L-selectin and VLA-4, allowing specific homing of lymphocytes to mucosal tissues. Eosinophils can be triggered to release their , which can then act on mast cells to cause their degranulation. The () is a cluster of genes on human chromosome 6 or mouse chromosome 17. It encodes a set of membrane glycoproteins called the MHC molecules. The MHC class I molecules present peptides generated in the cytosol to CD8 T cells, and the MHC class II molecules present peptides degraded in intracellular vesicles to CD4 T cells. The MHC also encodes proteins involved in antigen processing and other aspects of host defense. The MHC is the most polymorphic gene cluster in the human genome, having large numbers of alleles at several different loci. Because this polymorphism is usually detected by using antibodies or specific T cells, the MHC molecules are often called major histocompatibility antigens. : see mucosal-associated lymphoid tissue. The (), also called mannose-binding protein, is an acute-phase protein that binds to mannose residues. It can opsonize pathogens bearing mannose on their surfaces and can activate the complement system via the () an important part of innate immunity. The follicular is a rim of B lymphocytes that surrounds lymphoid follicles. The precise nature and role of mantle zone lymphocytes have not yet been determined. : see mitogen-activated protein kinases. The of the lymphoid tissue of the spleen lies at the border of the white pulp. It contains a unique population of B cells, the , which do not circulate and are distinguished by a distinct set of surface proteins. The components of the MB-lectin pathway of complement activation include two serine proteases, and , that bind to mannan-binding lectin and play the same role in cleaving C4 as do Cl r and Cl s in the classical pathway. are large cells found in connective tissues throughout the body, most abundantly in the submucosal tissues and the dermis. They contain large granules that store a variety of mediator molecules including the vasoactive amine histamine. Mast cells have high-affinity Fcε receptors (FCεRI) that allow them to bind IgE monomers. Antigenbinding to this IgE triggers mast-cell degranulation and mast-cell activation, producing a local or systemic immediate hypersensitivity reaction. Mast cells have a crucial role in allergic reactions. indicates an overproduction of mast cells. are B cells that have acquired surface IgM and IgD and have become able to respond to antigen. ; : see mannan-binding lectin. The is generally the central or collecting point of an organ. The thymic medulla is the central area of each thymic lobe, rich in bone marrow-derived antigen-presenting cells and the cells of a distinctive medullary epithelium. The medulla of the lymph node is a site of macrophage and plasma cell concentration through which the lymph flows on its way to the efferent lymphatics. (MOP or CD46) is a host-cell membrane protein that acts in conjunction with factor I to cleave C3b to its inactive derivative iC3b and thus prevent convertase formation. B cells carry on their surfaces many molecules of () of a single specificity, which acts as the receptor for antigen. The is made up of the terminal complement components, which assemble to generate a membrane-spanning hydrophilic pore, damaging the membrane. is a disease of the kidneys characterized by proteinuria and heavy deposits of antibody and complement. are the lymphocytes that mediate immunological memory. They are more sensitive to antigen than are naive lymphocytes and respond rapidly on reexposure to the antigen that originally induced them. Both and have been defined. ; ; : see major histocompatibility complex. The molecules encoded within the MHC are not highly polymorphic like the MHC class I and MHC class II molecules, and present a restricted set of antigens. The () is a site in the cell where MHC class II molecules accumulate, encounter HLA-DM, and bind antigenic peptides, before migrating to the surface of the cell. The protein that activates the transcription of MHC class II genes, the (), is one of several defective genes in the disease bare lymphocyte syndrome, in which MHC class II molecules are lacking on all cells. Various specialized strains of mice are used to explore the role of MHC polymorphism in vivo. These are called , meaning that the mice differ only at the MHC complex, , meaning that the mice have a crossover within the MHC, or , meaning that they are mutant at one or more loci. MHC genes are inherited in most cases as an , the set of genes in a haploid genome inherited from one parent. Thus, if the parents are designated as ab and cd, then the offspring are most likely to be ac, ad, bc, or bd. is the general name given to the highly polymorphic glycoproteins encoded by MHC class I and MHC class II genes, which are involved in the presentation of peptide antigens to T cells. They are also known as histocompatibility antigens. The development of held together by fluorescent streptavidin, which has four binding sites for the biotin attached to the tail of the MHC molecule, has made it possible to stain specific T cells in any species. , or , refers to the fact that a given T cell will recognize a peptide antigen only when it is bound to a particular MHC molecule. Normally, as T cells are stimulated only in the presence of self MHC molecules, antigen is recognized only as peptides bound to self MHC molecules. are MHC class I-like molecules that are expressed in the gut under conditions of stress and are encoded within the class I region of the human MHC. They are not found in mice. : see M cells. are microscopic organisms, unicellular except for some fungi, that include bacteria, yeasts and other fungi, and protozoa, all of which can cause human disease. : see membrane immunoglobulin. Anti-carbohydrate antibodies can bind either the ends or the middles of polysaccharide chains; the latter antibodies are called . : see MHC class II compartment. () are peptides of polymorphic cellular proteins bound to MHC molecules that can lead to graft rejection when they are recognized by T cells. : see MIs antigens. () are kinases that become phosphorylated and activated on cellular stimulation by a variety of ligands, and lead to new gene expression by phosphorylating key transcription factors. When lymphocytes from two unrelated individuals are cultured together, the T cells proliferate in response to the allogeneic MHC molecules on the cells of the other donor. This is used in testing for histocompatibility. are non-MHC antigens that provoke strong primary mixed lymphocyte responses. They are encoded by , which are endogenous mammary tumor viruses integrated in the mouse genome. Mls antigens are encoded in the 3' long terminal repeat of the integrated virus and act as superantigens. They stimulate a large number of T lymphocytes by binding to the Vβ domain of all T-cell receptors bearing the Vβ for which the superantigen is specific. : see mouse mammary tumor virus. It has been proposed that infectious agents could provoke autoimmunity by , the induction of antibodies and T cells that react against the pathogen but also cross-react with self antigens. are produced by a single clone of B lymphocytes. Monoclonal antibodies are usually produced by making hybrid antibody-forming cells from a fusion of nonsecreting myeloma cells with immune spleen cells. are white blood cells with a bean-shaped nucleus; they are precursors of macrophages. Some antibodies recognize all allelic forms of a polymorphic molecule such as an MHC class I protein; these antibodies are thus said to recognize a epitope. An individual lymphocyte carries antigen receptors of a single antigen specificity and thus has the property of in response to antigen. () is a retrovirus that encodes a viral superantigen; integrated copies of related viruses encode the endogenous superantigens known as Mis antigens. are highly glycosylated cell-surface proteins. Mucinlike molecules are bound by L-selectin in lymphocyte homing. All of the body's internal epithelial organs are lined with epithelium that is coated with mucus, and are therefore called . This system is the site of entry for virtually all antigens, and is protected by a unique set of lymphoid organs. The () comprises all lymphoid cells in epithelia and in the lamina propria lying below the body's mucosal surfaces. The main sites of mucosal-associated lymphoid tissues are the gut-associated lymphoid tissues (GALT), and the bronchial-associated lymphoid tissues (BALT). is a tumor of plasma cells, almost always first detected as multiple foci in bone marrow. Myeloma cells produce a monoclonal immunoglobulin, called a myeloma protein, that is detectable in the patient's plasma. is a neurological disease characterized by focal demyelination in the central nervous system, lymphocytic infiltration in the brain, and a chronic progressive course. It is caused by an autoimmune response to various antigens found in the myelin sheath. is an autoimmune disease in which autoantibodies against the acetylcholine receptor on skeletal muscle cells cause a block in neuromuscular junctions, leading to progressive weakness and eventually death. Dendritic cells can arise from myeloid cells, in which case they are called , or from lymphoid tissues, in which case they are called lymphoid dendritic cells. Functional differences exist between these two lineages. are cells in bone marrow that give rise to the granulocytes and macrophages of the immune system. are immunoglobulins secreted by myeloma tumors and are found in the patient's plasma. is the production of monocytes and polymorphonuclear leukocytes in bone marrow. are lymphocytes that have never encountered their specific antigen and thus have never responded to it, as distinct from memory or effector lymphocytes. All lymphocytes leaving the central lymphoid organs are naive lymphocytes, those from the thymus being naive T cells and those from bone marrow being naive B cells. () are large granular, non-T, non-B lymphocytes, which kill certain tumor cells. NK cells are important in innate immunity to viruses and other intracellular pathogens, as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). is the death of cells or tissues due to chemical or physical injury, as opposed to apoptosis, which is a biologically programmed form of cell death. Necrosis leaves extensive cellular debris that needs to be removed by phagocytes, whereas apoptosis does not. During intrathymic development, thymocytes that recognize self are deleted from the repertoire, a process known as . Autoreactive B cells undergo a similar process in bone marrow. Antibodies that can inhibit the infectivity of a virus or the toxicity of a toxin molecule are said to them. Such antibodies are known as and the process of inactivation as . describes the situation in which there are fewer neutrophils in the blood than normal. , also known as , are the major class of white blood cell in human peripheral blood. They have a multilobed nucleus and neutrophilic granules. Neutrophils are phagocytes and have an important role in engulfing and killing extracellular pathogens. : see nuclear factor of activated T cells. The transcription factor called is made up of two chains of 50 kDa and 65 kDa. It is found under normal circumstances in the cytosol, where it is bound to a third chain called IκB, which is an inhibitor of NFκB transcription. cells are a small subset of T cells that express the NK1.1 marker, a molecule normally found on NK cells. NK1.1 T cells also express α:β T-cell receptors of limited diversity and either the coreceptor molecule CD4 or no co-receptor. They are enriched in the liver, and produce cytokines shortly after stimulation. : see natural killer cells. : see Hodgkin's disease. are inserted into the junctions between gene segments of T-cell receptor and immunoglobulin heavy-chain V-region genes during gene segment joining. These N-regions are not encoded in either gene segment, but are inserted by the enzyme terminal deoxynucleotidyl transferase (TdT). They markedly increase the diversity of these receptors. Recombination signal sequences (RSS) flanking gene segments consist of a seven-nucleotide heptamer and a nine-nucleotide of conserved sequence, separated by 12 or 23 nucleotides. RSSs form the target for the site-specific recombinase that joins the gene segments in antigen receptor gene rearrangement. When T- and B-cell receptor gene segments rearrange, they often form that cannot encode a protein because the coding sequences are in the wrong translational reading frame. : see N-nucleotides. The transcription factor called () is a complex of a protein called NFATC, as it is held in the cytosol by serine/threonine phosphorylation, and the Fos/Jun dimer known as AP-1. It moves from the cytosol to the nucleus on cleavage of the phosphate residues by calcineurin, a serine/threonine protein phosphatase. The mutation of mice produces hairlessness and defective formation of the thymic stroma, so that nude mice, which are homozygous for this mutation, have no mature T cells. When a person's work induces allergy, this is called . are genes involved in regulating cell growth. When these genes are defective in structure or expression, they can cause cells to grow continuously to form a tumor. An is a microorganism that causes disease only in individuals with compromised host defense mechanisms, as occurs in AIDS. is the alteration of the surface of a pathogen or other particle so that it can be ingested by phagocytes. Antibody and complement opsonize extracellular bacteria for destruction by neutrophils and macrophages. The feeding of foreign antigens leads typically to a state of specific and active unresponsiveness, a phenomenon known as . An autoimmune disease that targets a specific organ is said to be . describes the tendency of humans to make antibody responses to those epitopes shared between the original strain of a virus and subsequent related viruses, while ignoring other highly immunogenic epitopes on the second and subsequent viruses. Lymphocyte subpopulations can be isolated by on petri dishes coated with monoclonal antibodies against cell-surface markers, to which the lymphocytes bind. The , or , is the T-cell area of lymph nodes, lying just below the follicular cortex, which is primarily composed of B cells. are organisms that obtain sustenance from a live host. In medical practice, the term is restricted to worms and protozoa, the subject matter of parasitology. () is a disease in which complement regulatory proteins are defective, so that complement activation leads to episodes of spontaneous hemolysis. : see altered peptide ligands. is a technique for detecting antibody in which red blood cells are coated with antigen and the antibody is detected by agglutination of the coated red blood cells. The injection of antibody or immune serum into a naive recipient is called . Cf. active immunization. , or , are microorganisms that can cause disease when they infect a host. is the scientific study of disease. The term pathology is also used to describe detectable damage to tissues. The term () is used to define receptors that bind to (). are receptors of the innate immune system that recognize common molecular patterns on pathogen surfaces. The cell-adhesion molecule () is found both on lymphocytes and at endothelial cell junctions. It is believed that CD31-CD31 interactions enable leukocytes to leave blood vessels and enter tissues. is the chemical substance in the leaves of the poison ivy plant that causes the cell-mediated immunity associated with hypersensitivity to poison ivy. are a family of acute-phase proteins formed of five identical subunits, to which C-reactive protein and serum amyloid protein belong. is a protein that can polymerize to form the membrane pores that are an important part of the killing mechanism in cell-mediated cytotoxicity. Perforin is produced by cytotoxic T cells and NK cells and is stored in granules that are released by the cell when it contacts a specific target cell. The () is part of the inner region of the white pulp of the spleen, and contains mainly T cells. are lymphocytes and monocytes isolated from peripheral blood, usually by Ficoll-Hypaque™ density centrifugation. or are the lymph nodes, spleen, and mucosal-associated lymphoid tissues, in which immune responses are induced, as opposed to the central lymphoid organs, in which lymphocytes develop. is tolerance acquired by mature lymphocytes in the peripheral tissues, as opposed to central tolerance, which is acquired by immature lymphocytes during their development. are aggregates of lymphocytes along the small intestine, especially the ileum. Antibody-like phage can be produced by cloning immunoglobulin V-region genes in filamentous phage, which thus express antigen-binding domains on their surfaces, forming a . Antigenbinding phage can be replicated in bacteria and used like antibodies. This technique can be used to develop novel antibodies of any specificity. is the internalization of particulate matter by cells. Usually, the or are macrophages or neutrophils, and the particles are bacteria that are taken up and destroyed. The ingested material is contained in a vesicle called a , which then fuses with one or more lysosomes to form a . The lysosomal enzymes are important in pathogen destruction and degradation to small molecules. () is a membrane-associated phospholipid that is cleaved by phospholipase C-y to give the signaling molecules diacylglycerol and inositol trisphosphate. is a key enzyme in signal transduction. It is activated by protein tyrosine kinases that are themselves activated by receptor ligation, and activated phospholipase C-γ cleaves inositol phospholipid into inositol trisphosphate and diacylglycerol. is the fluid component of blood containing water, electrolytes, and the plasma proteins. are terminally differentiated B lymphocytes and are the main antibody-secreting cells of the body. They are found in the medulla of the lymph nodes, in splenic red pulp, and in bone marrow. A is a B call in a lymph node that already shows some features of a plasma cell. () is a lipid mediator that activates the blood clotting cascade and several other components of the innate immune system. are small cell fragments found in the blood that are crucial for blood clotting. They are formed from megakaryocytes. are nucleotides found in junctions between gene segments of the rearranged V-region genes of antigen receptors. They are an inverse repeat of the sequence at the end of the adjacent gene segment, being generated from a hairpin intermediate during recombination, and hence are called palindromic or P-nucleotides. is a plant whose leaves contain pentadecacatechol, a potent contact sensitizing agent and a frequent cause of contact hypersensitivity. Antigen activates specific lymphocytes, whereas all mitogens, by definition, activate most or all lymphocytes, a process known as because it involves multiple clones of diverse specificity. Such mitogens are known as . The major histocompatibility complex is both , containing several loci encoding proteins of identical function, and polymorphic, having multiple alleles at each locus. The receptor binds polymeric immunoglobulins, especially IgA, at the basolateral membrane of epithelia and transports them across the cell, where they are released from the apical surface. This transcytosis transfers IgA from its site of synthesis to its site of action at epithelial surfaces. The or uses high temperature and unique thermostable enzymes to replicate DNA. It has revolutionized molecular biology. literally means existing in a variety of different shapes. Genetic polymorphism is variability at a gene locus in which the variants occur at a frequency of greater than 1%. The major histocompatibility complex is the most polymorphic gene cluster known in humans. are white blood cells with multilobed nuclei and cytoplasmic granules. There are three types of polymorpho-nuclear leukocyte: the neutrophils with granules that stain with neutral dyes, the eosinophils with granules that stain with eosin, and the basophils with granules that stain with basic dyes. Some antibodies show , the ability to bind to many different antigens. This is also known as . Only those developing T cells whose receptors can recognize antigens presented by self MHC molecules can mature in the thymus, a process known as . All other developing T cells die before reaching maturity. Expression of the , or , is a critical event in B-cell development. Expression of this receptor, which is a complex of at least five proteins, causes the pre-B cell to enter the call cycle, to turn off the RAG genes, to degrade the RAG proteins, and to expand by several cell divisions. Then the signal ceases, and the pre-B cell is ready to rearrange its light chains. During B-cell development, are cells that have rearranged their heavy-chain genes but not their light-chain genes. The was the first quantitative technique for measuring antibody production. The amount of antibody is determined from the amount of precipitate obtained with a fixed amount of antigen. The precipitin reaction also can be used to define antigen valence and zones of antibody or antigen excess in mixtures of antigen and antibody. is a synthetic steroid with potent anti-inflammatory and immunosuppressive activity used in treating acute graft rejection, autoimmune disease, and lymphoid tumors. In T-cell development, TCR β chains expressed by CD44^lowCD25₊ thymocytes pair with a surrogate α chain called pTα (pre-T-cell α) to form a that exits the endoplasmic reticulum via the Golgi as a complex with the CD3 molecules. During T-dependent antibody responses, a of B-cell activation forms in the vicinity of the margin between T and B cell areas of lymphoid tissue. Here, the T and B cells interact and B cells can differentiate directly into antibody-forming cells or migrate to lymphoid follicles for further proliferation and differentiation. Lymphoid tissues contain lymphoid follicles made up of follicular dendritic cells and B lymphocytes. The contain resting B lymphocytes and are the site at which germinal centers form when they are entered by activated B cells, forming secondary follicles. The is the adaptive immune response to an initial exposure to antigen. , also known as priming, generates both the primary immune response and immunological memory. The binding of antibody molecules to antigen is called a , as distinct from secondary interactions in which binding is detected by some associated change such as the precipitation of soluble antigen or agglutination of particulate antigen. : see central lymphoid organ. of antigen-specific naive lymphocytes occurs when antigen is presented to them in an immunogenic form; the primed cells will differentiate either into armed effector cells or into memory cells that can respond in second and subsequent immune responses. During B-cell development, are cells that have displayed B-cell surface marker proteins but have not yet completed heavychain gene rearrangement. They are divided into early pro-B cells and late pro-B cells. Any lymphocyte receptor chain can be rearranged in either of two ways, productive and nonproductive. are in the correct reading frame for the receptor chain in question. are the more differentiated progeny of stem cells that give rise to distinct subsets of mature blood cells and lack the capacity for self-renewal possed by true stem cells. : see apoptosis. : see factor P. , like leukotrienes, are lipid products of the metabolism of arachidonic acid that have a variety of effects on a variety of tissues, including activities as inflammatory mediators. Cytosolic proteins are degraded by a large catalytic multisubunit protease called a . It is thought that peptides that are presented by MHC class I molecules are generated by the action of proteasomes, and two interferon-inducible subunits of some proteasomes are encoded in the MHC. (CD59) is a cell-surface protein that protects host cells from being damaged by complement. It inhibits the formation of the membrane-attack complex by preventing the binding of C8 and C9 to the C5b,6,7 complex. is the resistance to specific infection that follows infection or vaccination. is a membrane component of Staphylococcus aureus that binds to the Fc region of IgG and is thought to protect the bacteria from IgG antibodies by inhibiting their interactions with complement and Fc receptors. It is useful for purifying IgG antibodies. () is a family of serine/threonine kinases that are activated by diacylglycerol and calcium as a result of signaling via many different receptors. add phosphate groups to proteins, and remove these phosphate groups. Enzymes that add phosphate groups to tyrosine residues are called . These enzymes have crucial roles in signal transduction and regulation of cell growth. Their activity is regulated by a second set of molecules called that remove the phosphate from the tyrosine residues. are cellular genes that regulate growth control. When mutated or aberrantly expressed, they can contribute to the malignant transformation of cells, leading to cancer. Cf. oncogenes. A is the DNA form of a retrovirus when it is integrated into the host cell genome, where it can remain transcriptionally inactive for long periods of time. : see selecting. : see pre-T-cell receptor. The and D proteins are members of the pentraxin family that play various roles in the acute-phase response. () is an enzyme defect that results in severe combined immunodeficiency. This enzyme is important in purine metabolism, and its deficiency causes the accumulation of purine nucleosides, which are toxic for developing T cells, causing the immune deficiency. is the mixture of cell debris and dead neutrophils that is present in wounds and abscesses infected with extracellular encapsulated bacteria. Bacteria with large capsules are difficult for phagocytes to ingest. Such encapsulated bacteria often produce pus at the site of infection, and are thus called . Pyogenic organisms used to kill many young people. Now, pyogenic infections are largely limited to the elderly. The states that gene segments of immunoglobulin or T-cell receptors can be joined only if one has a recognition signal sequence with a 12 base pair spacer, and the other has a 23 base pair spacer. : see small G proteins. are mice that have been heavily irradiated and then reconstituted with bone marrow cells of a different strain of mouse, so that the lymphocytes differ genetically from the environment in which they develop. Such chimeric mice have been important in studying lymphocyte development. Antigen-antibody interaction can be studied by () in which antigen or antibody is labeled with radioactivity. An unlabeled antigen or antibody is attached to a solid support such as a plastic surface, and the fraction of the labeled antibody or antigen retained on the surface is determined in order to measure binding. : see small G proteins. The recombination activating genes and encode the proteins RAG-1 and RAG-2, which are critical to receptor gene rearrangement. Mice lacking either of these genes cannot form receptors and thus have no lymphocytes. , or sirolimus, is an immunosuppressive drug that blocks cytokine action. : see small G proteins. Antigen receptor expression requires gene segment in developing lymphocytes. The expressed V-region sequences are compos* of rearranged gene segments. The replacement of a light chain of a self-reactive antigen receptor on immature B cells with a light chain that does not confer autoreactivity is known as . This has also been shown with heavy chains. The antigen receptors of lymphocytes are associated with , mainly of the Src family, which bind to receptor tails via their SH2 domains. is the internalization into endosomes of molecules bound to cell-surface receptors. Antigens bound to B-cell receptors are internalized by this process. A encodes a protein that is needed for the human or animal to develop to adulthood; when both copies are defective, the human or animal dies in utero or early after birth. In any situation in which cells or tissues are transplanted, they come from a donor and are placed in a or host. : see RAG-1 and RAG-2. () are short stretches of DNA that flank the gene segments that are rearranged to generate a V-region exon. They always consist of a conserved heptamer and nonamer separated by 12 or 23 base pairs. Gene segments are only joined if one is flanked by an RSS containing a 12 base pair spacer and the other is flanked by an RSS containing a 23 bass pair spacer-the 12/23 rule of gene segment joining. The nonlymphoid area of the spleen in which red blood cells are broken down is called the . are large malignant B cells that are found in Hodgkin's disease. or can inhibit T-cell responses. When neutrophils and macrophages take up opsonized particles, this triggers a metabolic change in the cell called the . It leads to the production of a number of mediators. The virus known as virus (RSV) is a human pathogen that is a common cause of severe chest infection in young children, often associated with wheezing, as well as in immunocompromised patients and patients with AIDS. The protein is the product of the rev gene of the human immunodeficiency virus (HIV). The Rev protein promotes the passage of viral RNA from nucleus to cytoplasm during HIV replication. The enzyme is an essential component of retroviruses, as it translates the RNA genome into DNA before integration into host cell DNA. Reverse transcriptase also enables RNA sequences to be converted into complementary DNA (cDNA), and so to be cloned, and thus is an essential reagent in molecular biology. The () is used to amplify RNA sequences. The enzyme reverse transcriptase is used to convert an RNA sequence into a CDNA sequence, which is then amplified by PCR. The (Rh) is a red cell membrane antigen that is also detectable on the red blood cells of rhesus monkeys. Anti-Rh antibodies do not agglutinate human red blood calls, so antibody to Rh antigen must be detected by using a Coombs test. is caused by antibodies elicited by infection with some Streptococcus species. These antibodies cross-react with kidney, joint, and heart antigens. is a common inflammatory joint disease that is probably due to an autoimmune response. The disease is accompanied by the production of , an IgM anti-IgG antibody that can also be produced in normal immune responses. The technique of uses antibody bound to a surface to trap a protein by binding to one of its epitopes. The trapped protein is then detected by an enzyme-linked antibody specific for a different epitope on the protein's surface. This gives the assay a high degree of specificity. is a mathematical analysis of equilibrium binding that allows the affinity and valence of a receptor-ligand interaction to be determined. on macrophages and other cells bind to numerous ligands and remove them from the blood. The Kupffer cells in the liver are particularly rich in scavenger receptors. , scid: see . is the common abbreviation for polyacrylamide gel electrophoresis (PAGE) of proteins dissolved in the detergent sodium dodecyl sulfate (SDS). This technique is widely used to characterize proteins, especially after labeling and immunoprecipitation. A is the antibody response induced by a second or booster injection of antigen-a . The secondary response starts sooner after antigen injection, reaches higher levels, is of higher affinity than the primary response, and is dominated by IgG antibodies. Therefore, the response to each immunization is increasingly intense, so the secondary, tertiary, and subsequent responses are of increasing magnitude. When the recipient of a first tissue or organ graft has rejected that graft, a second graft from the same donor is rejected more rapidly and vigorously in what is called a . The co-stimulatory signal required for lymphocyte activation is often called a , with the first signal coming from the binding of antigen by the antigen receptor. Both signals are required for the activation of most lymphocytes. : see primary interactions. The attached to IgA antibodies in body secretions is a fragment of the poly-Ig receptor left attached to the IgA after transport across epithelial cells. A cell is said to be by antigen when its receptors bind that antigen. If the cell starts to proliferate as a result, this is called clonal selection, and the cell founds a clone; if the cell is killed as a result of binding antigen, this is called negative selection or clonal deletion. are a family of cell-surface adhesion molecules of leukocytes and endothelial cells that bind to sugar moieties on specific glycoproteins with mucinlike features. Antigens in the body of an individual are by convention called . Lymphocytes are screened during their immature stages for reactivity with self antigens, and those that do respond undergo apoptosis. Tolerance is the failure to respond to an antigen; when that antigen is borne by self tissues, tolerance is called . See also . Allergic reactions require prior immunization, called , by the allergen that elicits the acute response. Allergic reactions occur only in individuals. is infection of the bloodstream. This is a very serious and frequently fatal condition. Infection of the blood with gram-negative bacteria triggers through the release of the cytokine TNF-α. A is a pattern of nucleotides or amino acids shared by different genes or proteins that often have related functions. Sequence motifs observed in peptides that bind a particular MHC glycoprotein are based on the requirements for particular amino acids to achieve binding to that MHC molecule. is the phase of an infection when antibodies against the infecting agent are first detectable in the blood. is the use of antibodies to detect and measure antigens using , so called because these assays were originally carried out with serum, the fluid component of clotted blood, from immunized individuals. Mast cells in mice store the small soluble mediator in their granules. Different strains of bacteria and other pathogens can sometimes be distinguished by their , the ability of an immune serum to agglutinate or lyse some strains of bacteria and not others. are a large family of protease inhibitors. is the fluid component of clotted blood. occurs when foreign serum or serum proteins are injected into a person. It is caused by the formation of immune complexes between the injected protein and the antibodies formed against it. It is characterized by fever, arthraigias, and nephritis. () is an immune deficiency disease in which neither antibody nor T-cell responses are made. It is usually the result of T-cell deficiencies. The scid mutation causes severe combined immune deficiency in mice. : see . A is formed by the precise joining of recognition signal sequences in the process of somatic recombination that generates T-cell receptor and immunoglobulin genes. (): see . describes the general process by which cells perceive changes in their environment. In lymphocytes, the most important changes are those occurring during infection that generate antigens that stimulate the cells of the immune system to bring about an adaptive immune response. A fragment, comprising a V region of a heavy chain linked by a stretch of synthetic peptide to a V region of a light chain, can be made by genetic engineering. During T-cell maturation in the thymus, mature T cells are detected by the expression of either the CD4 or the CD8 co-receptor and are therefore called . is the drug name that has been adopted for the chemical rapamycin; the two terms are used interchangeably in the literature. The chemokine known as is produced by lymphatic vessels and attracts dendritic cells. are monomeric G proteins such as Ras, that act as intracellular signaling molecules downstream of many transmembrane signaling events. They bind GTP in their active form, and hydrolyze it to GDP to become inactive. : see large pre-B cells. is an infectious disease, caused by the virus variola, that once killed at least 10% of infected people. It has now been eradicated by vaccination. When immunologists discovered that antibodies were variable, they entertained various theories, including the that postulated that the genes for immunoglobulin were constant, and that they diversified in somatic cells. This turned out to be partly true, as somatic hypermutation is now well established. However, other theories were needed to explain other features of antibody diversity, including somatic gene rearrangement and isotype switching. : see gene therapy. During B-cell responses to antigen, the V-region DNA sequence undergoes , resulting in the generation of variant immunoglobulins, some of which bind antigen with a higher affinity. This allows the affinity of the antibody response to increase. These mutations affect only somatic cells, and are not inherited through germline transmission. During lymphocyte development, receptor gene segments undergo to generate intact V-region exons that encode the V region of each immunoglobulin and T-cell receptor chain. These events occur only in somatic cells; the changes are not inherited. : see 12/23 rule. The of an antibody determines its ability to distinguish the immunogen from other antigens. One uses to define certain types of DNA gene segments that give a repetitive spacing of three nucleotides, or one codon. The is an organ in the upper left side of the peritoneal cavity containing a red pulp, involved in removing senescent blood cells, and a white pulp of lymphoid cells that respond to antigens delivered to the spleen by the blood. The are receptor-associated protein tyrosine kinases. They have several domains, called Src-homology 1, 2, and 3. The SH1 domain contains the active site of the kinase, the SH2 domain can bind to phosphotyrosine residues, and the SH3 domain is involved in interactions with proline-rich regions in other proteins. () cause food poisoning and also stimulate many T cells by binding to MHC class II molecules and the Vp domain of certain T-cell receptors; the staphylococcal enterotoxins are thus superantigens. : see Janus kinases. () is a transmembrane protein on bone marrow stromal cells that binds to c-Kit, a signaling receptor carried on developing B cells and other developing white blood cells. The development of B lymphocytes and T lymphocytes occurs in association with , which provide various soluble and cell-bound signals to the developing lymphocyte. Antigens can be injected into the layer to induce an adaptive immune response. See also intracutaneous. are molecules that stimulate a subset of T cells by binding to MHC class II molecules and Vβ domains of T-cell receptors, stimulating the activation of T cells expressing particular Vβ gene segments. The staphylococcal enterotoxins are one of the sources of superantigens. : see regulatory T cells. The membrane-bound immunoglobulin that acts as the antigen receptor on B cells is often known as (). The is made up of two molecules called VpreB and λ5. Together, this chain can pair with an in-frame heavy chain, move to the cell surface, and signal for pre-B-cell growth. When isotype switching occurs, the active heavy-chain V-region exon undergoes somatic recombination with a 3' constant-region gene at a of DNA. These DNA joints do not need to occur at precise sites, because they occur in intronic DNA. Thus, all switch recombinations are productive. : see tyrosine kinase. When one eye is damaged, there is often an autoimmune response that damages the other eye, a syndrome known as . A is a graft between two genetically identical individuals. It is accepted as self. is the most dangerous form of immediate hypersensitivity reaction. It involves antigen in the bloodstream triggering mast cells all over the body. The activation of these mast cells causes widespread vasodilation, tissue fluid accumulation, epigiottal swelling, and often death. () is an autoimmune disease in which autoantibodies against DNA, RNA, and proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially of the kidney. , or , are a subset of lymphocytes defined by their development in the thymus and by heterodimeric receptors associated with the proteins of the CD3 complex. Most T cells have α:β heterodimeric receptors but γ:δ T cells have a γ:δ heterodimeric receptor. () is a member of the TNF-receptor family and is one of two major receptors for BLYS. It is found on B cells, dendritic cells, and T cells and is probably the important receptor for receiving signals from BLYS. , or FK506, is an immunosuppressive polypeptide drug that inactivates T cells by inhibiting signal transduction from the T-cell receptor. Tacrolimus and cyclosporin A are the most commonly used immunosuppressive drugs in organ transplantation. and (transporters associated with antigen processing) are ATP-binding cassette proteins involved in transporting short peptides from the cytosol into the lumen of the endoplasmic reticulum, where they associate with MHC class I molecules. , or the , is a key molecule in the assembly of MHC class I molecules; a cell deficient in this protein has only unstable MHC class I molecules on the cell surface. The functions of effector T cells are always assayed by the changes that they produce in antigen-bearing . These cells can be B cells, which are activated to produce antibody; macrophages, which are activated to kill bacteria or tumor cells; or labeled cells that are killed by cytotoxic T cells. The protein is a product of the tat gene of HIV. It is produced when latently infected cells are activated, and it binds to a transcriptional enhancer in the long terminal repeat of the provirus, increasing the transcription of the proviral genome. : see T-cell receptor. A is derived from a single progenitor T cell. See also cloned T-cell line. are formed by fusing an antigen-specific, activated T cell with a T-cell lymphoma. The hybrid cells bear the receptor of the specific T-cell parent and grow in culture like the lymphoma. are cultures of T cells grown by repeated cycles of stimulation, usually with antigen and antigen-presenting cells. When single T cells from these lines are propagated, they can give rise to T-cell clones or cloned T-cell lines. The () consists of a disulfide-linked heterodimer of the highly variable α and β chains expressed at the cell membrane as a complex with the invariant CD3 chains. T cells carrying this type of receptor are often called α:β T cells. An alternative receptor made up of variable γ and δ chains is expressed with CD3 on a subset of T cells. Both of these receptors are expressed with a disulfide-linked homodimer of ζ chains. The in lymphoid tissues are enriched in T cells and are distinct from the B-cell zones and the stromal elements. Activation of the lymphocyte antigen receptors is linked to activation of PLC-γ through members of the family of src-like tyrosine kinases. Other Tec kinases are Btk in B cells, which is mutated in the human immunodeficiency disease X-linked agammaglobulinemia (XLA), and Itk in T lymphocytes. The complement system can be activated directly or by antibody, but both pathways converge with the activation of the , which may assemble to form the membraneattack complex. The enzyme () inserts nontemplated or N-nucleotides into the junctions between gene segments in T-cell receptor and immunoglobulin V-region genes. The N-nucleotides contribute greatly to junctional diversity in V regions. When the same antigen is injected a third time, the response elicited is called a and the injection a . are a subset of CD4 T cells that are characterized by the cytokines they produce. They are mainly involved in activating macrophages, and are sometimes called inflammatory CD4 T cells. are a subset of CD4 T cells that are characterized by the cytokines they produce. They are mainly involved in stimulating B cells to produce antibody, and are often called helper CD4 T cells. The term has been used to describe unique cells that produce mainly transforming growth factor-β in response to antigen; they develop predominantly in the mucosal immune response to antigens that are presented orally. The lymph from most of the body, except the head, neck, and right arm, is gathered in a large lymphatic vessel, the , which runs parallel to the aorta through the thorax and drains into the left subclavian vein. The thoracic duct thus returns the lymphatic fluid and lymphocytes back into the peripheral blood circulation. Surgical removal of the thymus is called . The is the tissue from which the thymic stroma develops during embryogenesis. The is the outer region of each thymic lobule in which thymic progenitor cells proliferate, rearrange their T-cell receptor genes, and undergo thymic selection, especially positive selection on . The consists of epithelial cells and connective tissue that form the essential microenvironment for T-cell development. are lymphoid cells found in the thymus. They consist mainly of developing T cells, although a few thymocytes have achieved functional maturity. The , the site of T-cell development, is a lymphoepithelial organ in the upper part of the middle of the chest, just behind the breastbone. Some antigens elicit responses only in individuals that have T cells; they are called or . Other antigens can elicit antibody production in the absence of T cells and are called or . There are two types of TI antigen: the , which have intrinsic B-cell activating activity, and the , which seem to activate B cells by having multiple identical epitopes that cross-link the B-cell receptor. T cell and T lymphocyte are short designations for , the lymphocyte population that fails to develop in the absence of a functioning thymus. One uses to examine processes in biology, that are anywhere from cell migration (fast) to a flower blossoming (slow). During the process of germinal center formation, cells called appear. These are phagocytic cells engulfing apoptotic B cells, which are produced in large numbers during the height of the germinal center response. All dendritic cells arise from hematopoietic progenitors that migrate to various locations all over the body. Here, they are referred to as Transplantation of organs or such as skin grafts is used medically to repair organ or tissue deficits. Some autoimmune diseases attack particular tissues, such as the β cell in the islets of Langerhans in autoimmune diabetes mellitus; such diseases are called . The of an antiserum is a measure of its concentration of specific antibodies based on serial dilution to an end point, such as a certain level of color change in an ELISA assay. : see Toll-like receptors. : see T cells. : see lymphotoxin; tumor necrosis factor-α. There are several members of the () family. Some lead to apoptosis of the cell on which they are expressed (TNFR-I, II, Fas), while others lead to activation (CD40, 4-1BB). All of them signal as trimeric proteins. is the failure to respond to an antigen; the immune system is said to be to self antigens. Tolerance to self antigens is an essential feature of the immune system; when tolerance is lost, the immune system can destroy self tissues, as happens in autoimmune disease. The is an ancient signaling pathway that activates the transcription factor NFκB by degrading its inhibitor IκB. All members of the Toll family of receptors so far discovered have been homologous to the original Toll in Drosophila. They have been named () followed by a number, as in or . The palatine that lie on either side of the pharynx are large aggregates of lymphoid cells organized as part of the mucosal- or gut-associated immune system. is a systemic toxic reaction caused by the massive production of cytokines by CD4 T cells activated by the bacterial superantigen (), which is secreted by Staphylococcus aureus. Inactivated toxins called are no longer toxic but retain their immunogenicity so that they can be used for immunization. : see regulatory T cells. The family of proteins known as TNF receptor-associated factors, or , consists of at least six members that bind to various TNF family receptors or TNFRS. They share a domain known as a TRAF domain, and have a crucial role as signal transducers between upstream members of the TNFR family and downstream transcription factors. The active transport of molecules across epithelial cells is called . Transcytosis of IgA molecules involves transport across intestinal epithelial cells in vesicles that originate on the basolateral surface and fuse with the apical surface in contact with the intestinal lumen. The insertion of small pieces of DNA into cells is called . If the DNA is expressed without integrating into host call DNA, this is called a transient transfection; if the DNA integrates into host cell DNA, then it replicates whenever host cell DNA is replicated, producing a stable transfection. Foreign genes can be placed in the mouse genome by . This generates that are used to study the function of the inserted gene, or transgene, and the regulation of its expression. Some cancers have chromosomal , in which a piece of one chromosome is abnormally linked to another chromosome. The grafting of organs or tissues from one individual to another is called . The or grafts can be rejected by the immune system unless the host is tolerant to the graft antigens or immunosuppressive drugs are used to prevent rejection. : see TAP1 and TAP2. The is a clinical test in which a purified protein derivative (PPD) of Mycobacterium tuberculosis, the causative agent of tuberculosis, is injected subcutaneously. PPD elicits a delayedtype hypersensitivity reaction in individuals who have had tuberculosis or have been immunized against it. : see leprosy. is the study of host defenses against tumors, usually studied by tumor transplantation. () is a cytokine produced by macrophages and T cells that has multiple functions in the immune response. It is the defining member of the TNF family of cytokines. These cytokines function as cell-associated or secreted proteins that interact with receptors of the () family, which in turn communicates with the interior of the cell via components known as TRAFs (tumor necrosis factor receptorassociated factors). (): see lymphotoxin. Tumors transplanted into syngeneic recipients can grow progressively or can be rejected through T-cell recognition of () or . TSTA are peptides of mutant or overexpressed cellular proteins bound to MHC class I molecules on the tumor cell surface. The (TdT-dependent dUTP-biotin nick end labeling) identifies apoptotic cells in situ by the characteristic fragmentation of their DNA. Biotin-tagged DUTP added to the free 3' ends of the DNA fragments by the enzyme TdT can be detected by immunohistochemical staining with enzyme-linked streptavidin. In , proteins are separated by isoelectric focusing in one dimension, followed by SDS-PAGE on a slab gel at right-angles to the first dimension. This can separate and identify large numbers of distinct proteins. Hypersensitivity reactions are classified by mechanism: involve IgE antibody triggering of mast cells; involve IgG antibodies against cell surface or matrix antigens; involve antigen:antibody complexes; and are T cell-mediated. A is an enzyme that specifically phosphorylates tyrosine residues in proteins. They are critical in T- and B-cell activation. The kinases that are critical for B-cell activation are Blk, Fyn, Lyn, and Syk. The tyrosine kinases that are critical for T-cell activation are called Lck, Fyn, and ZAP-70. is the technical term for hives, which are red, itchy skin welts usually brought on by an allergic reaction. The variable region of the polypeptide chains of an immunoglobulin or T-cell receptor is composed of a single N-terminal . Paired V domains form the antigen-binding sites of immunoglobulins and T-cell receptors. The first 95 amino acids or so of immunoglobulin or T-cell receptor V domains are encoded in inherited . There are multiple different V gene segments in the germline genome. To produce a complete exon encoding a V domain, one V gene segment must be rearranged to join up with a J or a rearranged DJ gene segment. is the deliberate induction of adaptive immunity to a pathogen by injecting a , a dead or attenuated (nonpathogenic) form of the pathogen. The first effective vaccine was , a cowpox virus that causes a limited infection in humans that leads to immunity to the human smallpox virus. The of an antibody or antigen is the number of different molecules that it can combine with at one time. The of a protein is a measure of the difference between the amino acid sequences of different variants of that protein. The most variable proteins known are antibodies and T-cell receptors. : see Wu and Kabat plot. : see V gene segments. The () of an immunoglobulin or T-cell receptor is formed of the amino-terminal domains of its component polypeptide chains. These are called the variable domains (V domains) and are the most variable parts of the molecule. They contain the antigen-binding sites. are molecules on endothelial cells to which leukocyte adhesion molecules bind. They have a key role in selective homing of leukocytes to particular sites in the body. : see adaptor proteins. The enzyme that joins the gene segments of B-cell and T-cell receptor genes is called the . It is made up of several enzymes, but most important are the products of the recombinaseactivating genes RAG-1 and RAG-2 whose protein products RAG-1 and RAG-2 are expressed in developing lymphocytes and make up the only known lymphoid-specific components of the V(D)J recombinase. The process of is found exclusively in lymphocytes in vertebrates, and allows the recombination of different gene segments into sequences encoding complete protein chains of immunoglobulins and T-cell receptors. The () are members of the Pi family of integrins involved in cell-cell and cell-matrix interactions. Some VLAs are important in leukocyte and lymphocyte migration. are small membrane-bounded compartments within the cytosol. Many viruses that are produced by mammalian cells are enclosed in a of host cell membrane lipid and proteins bound to the viral core by viral envelope proteins. are complete virus particles, the form in which viruses spread from cell to cell or from one individual to another. are pathogens composed of a nucleic acid genome enclosed in a protein coat. They can replicate only in a living cell, as they do not possess the metabolic machinery for independent life. : see pre-B-cell receptor. Antibodies against the neutrophil granule proteinase-3 are formed in , an autoimmune disease in which there is severe necrotizing vasculitis. The presence of anti-neutrophil cytoplasmic antigen, or ANCA, helps in the diagnosis of this disease. are granules within endothelial cells that contain P-selectin. Activation of the endothelial cell by mediators such as histamine and C5a leads to rapid translocation of P-selectin to the cell surface. In , a mixture of proteins is separated, usually by gel electrophoresis and transferred by blotting to a nitrocellulose membrane; labeled antibodies are then used as probes to detect specific proteins. When small amounts of allergen are injected into the dermis of an allergic individual, a is observed. This consists of a raised area of skin containing fluid and a spreading, red, itchy circular reaction. The discrete areas of lymphoid tissue in the spleen are known as the . The is characterized by defects in the cytoskeleton of cells due to a mutation in the protein WASP. Patients with this disease are highly susceptible to pyogenic bacteria. A , or variability plot, is generated from the amino acid sequences of related proteins by plotting the variability of the sequence against amino acid residue number. Variability is the number of different amino acids observed at a position divided by the frequency of the most common amino acid. Animals of different species are . The use of , organs from a different species, is being explored as a solution to the severe shortage of human organs for transplantation. The main problem with xenografting is the presence of natural antibodies against xenograft antigens; attempts are being made to modify these reactions by creating transgenic animals. Mice with mutations in the btk gene have a deficiency in making antibodies, especially in primary responses. These mice are called , for X-linked immunodeficiency, the mouse equivalent of X-linked agammaglobulinemia, the human form of this disease. () is a genetic disorder in which B-cell development is arrested at the pre-B-cell stage and no mature B cells or antibodies are formed. The disease is due to a defect in the gene encoding the protein tyrosine kinase btk. is a disease in which little or no IgG, IgE, or IgA antibody is produced and even IgM responses are deficient, but serum IgM levels are normal to high. It is due to a defect in the gene encoding the CD40 ligand or CD154. is a rare immunodeficiency that results from mutations in a gene named SH2-domain containing gene 1A (SH2DlA). Boys with this deficiency typically develop overwhelming EBV infection during childhood, and sometimes lymphomas. () is a disease in which T-cell development fails at an early intrathymic stage and no production of mature T cells or T-cell dependent antibody occurs. It is due to a defect in a gene that encodes the y, chain that is a component of the receptors for several different cytokines. The protein called is found in T cells and is a relative of Syk in B cells. It contains two SH2 domains that, when bound to the phosphorylated ζ chain, leads to activation of kinase activity. The main cellular substrate of ZAP-70 is a large adaptor protein called LAT.