Insects and other invertebrates have only innate immunity. This system is triggered by receptors that bind sequences of sugars, lipids, amino acids, or nucleic acids that are common on bacteria and other microorganisms, but are not found in eukaryotic cells. These receptors, in turn, activate various defense mechanisms. The receptors are coded in the germ line, and their fundamental structure is not modified by exposure to antigen. The activated defenses include, in various species, release of interferons, phagocytosis, production of antibacterial peptides, activation of the complement system, and several proteolytic cascades. Even plants release antibacterial peptides in response to infection. This primitive immune system is also important in vertebrates, particularly in the early response to infection. However, in vertebrates, innate immunity is also complemented by adaptive or acquired immunity, a system in which T and B lymphocytes are activated by specific antigens. T cells bear receptors related to antibody molecules, but which remain cell-bound. When these receptors encounter their cognate antigen, the T cell is stimulated to proliferate and produce cytokines that orchestrate the immune response, including that of B cells. Activated B lymphocytes form clones that produce secreted antibodies, which attack foreign proteins. After the invasion is repelled, small numbers of lymphocytes persist as memory cells so that a second exposure to the same antigen provokes a prompt and magnified immune attack. The genetic event that led to acquired immunity occurred 450 million years ago in the ancestors of jawed vertebrates and was probably insertion of a transposon into the genome in a way that made possible the generation of the immense repertoire of T cell receptors and antibodies that can be produced by the body.
In vertebrates, including humans, innate immunity provides the first line of defense against infections, but it also triggers the slower but more specific acquired immune response (Figure 3–4). In vertebrates, natural and acquired immune mechanisms also attack tumors and tissue transplanted from other animals.
Once activated, immune cells communicate by means of cytokines and chemokines. They kill viruses, bacteria, and other foreign cells by secreting other cytokines and activating the complement system.
CLINICAL BOX 3–1 Disorders of Phagocytic Function
More than 15 primary defects in neutrophil function have been described, along with at least 30 other conditions in which there is a secondary depression of the function of neutrophils. Patients with these diseases are prone to infections that are relatively mild when only the neutrophil system is involved, but which can be severe when the monocyte-tissue macrophage system is also involved. In one syndrome (neutrophil hypomotility), actin in the neutrophils does not polymerize normally, and the neutrophils move slowly. In another, there is a congenital deficiency of leukocyte integrins. In a more serious disease (chronic granulomatous disease), there is a failure to generate O2– in both neutrophils and monocytes and consequent inability to kill many phagocytosed bacteria. In severe congenital glucose-6-phosphate dehydrogenase deficiency, there are multiple infections because of failure to generate the NADPH necessary for O2– production. In congenital myeloperoxidase deficiency, microbial killing power is reduced because hypochlorous acid is not formed. THERAPEUTIC HIGHLIGHTS
The cornerstones of treatment in disorders of phagocytic function include scrupulous efforts to avoid exposure to infectious agents, and antibiotic and antifungal prophylaxis. Antimicrobial therapies must also be implemented aggressively if infections occur. Sometimes, surgery is needed to excise and/or drain abscesses and relieve obstructions. Hematopoietic stem cell transplantation may offer the hope of a definitive cure for severe conditions, such as chronic granulomatous disease. Sufferers of this condition have a significantly reduced life expectancy due to recurrent infections and their complications, and so the risks of bone marrow transplantation may be deemed acceptable. Gene therapy, on the other hand, remains a distant goal.
How bacteria, viruses, and tumors trigger innate immunity and initiate the acquired immune response. Arrows indicate mediators/cytokines that act on the target cell shown and/or pathways of differentiation. APC, antigen-presenting cell; M, monocyte; N, neutrophil; TH1 and TH2, type 1 and type 2 helper T cells, respectively.
Cytokines are hormone-like molecules that act—generally in a paracrine fashion—to regulate immune responses. They are secreted not only by lymphocytes and macrophages but by endothelial cells, neurons, glial cells, and other types of cells. Most of the cytokines were initially named for their actions, for example, B cell–differentiating factor, or B cell–stimulating factor 2. However, the nomenclature has since been rationalized by international agreement to that of the interleukins. For example, the name of B cell–differentiating factor was changed to interleukin-4. A number of cytokines selected for their biologic and clinical relevance are listed in Table 3–2, but it would be beyond the scope of this text to list all cytokines, which now number more than 100.
TABLE 3–2Examples of cytokines and their clinical relevance. ||Download (.pdf) TABLE 3–2 Examples of cytokines and their clinical relevance.
|Cytokine ||Cellular Sources ||Major Activities ||Clinical Relevance |
|Interleukin-1 ||Macrophages ||Activation of T cells and macrophages; promotion of inflammation ||Implicated in the pathogenesis of septic shock, rheumatoid arthritis, and atherosclerosis |
|Interleukin-2 ||Type 1 (TH1) helper T cells ||Activation of lymphocytes, natural killer cells, and macrophages ||Used to induce lymphokine-activated killer cells; used in the treatment of metastatic renal cell carcinoma, melanoma, and various other tumors |
|Interleukin-4 ||Type 2 (TH2) helper T cells, mast cells, basophils, and eosinophils ||Activation of lymphocytes, monocytes, and IgE class switching ||As a result of its ability to stimulate IgE production, plays a part in mast-cell sensitization and thus in allergy and in defense against nematode infections |
|Interleukin-5 ||Type 2 (TH2) helper T cells, mast cells, and eosinophils ||Differentiation of eosinophils ||Monoclonal antibody against interleukin-5 used to inhibit the antigen-induced late-phase eosinophilia in animal models of allergy |
|Interleukin-6 ||Type 2 (TH2) helper T cells and macrophages ||Activation of lymphocytes; differentiation of B cells; stimulation of the production of acute-phase proteins ||Overproduced in Castleman disease; acts as an autocrine growth factor in myeloma and in mesangial proliferative glomerulonephritis |
|Interleukin-8 ||T cells and macrophages ||Chemotaxis of neutrophils, basophils, and T cells ||Levels are increased in diseases accompanied by neutrophilia, making it a potentially useful marker of disease activity |
|Interleukin-11 ||Bone marrow stromal cells ||Stimulation of the production of acute-phase proteins ||Used to reduce chemotherapy-induced thrombocytopenia |
|Interleukin-12 ||Macrophages and B cells ||Stimulation of the production of inter-feron γ by type 1 (TH1) helper T cells and by natural killer cells; induction of type 1 (TH1) helper T cells ||May be useful as an adjuvant for vaccines |
|Interleukin-17 ||T cells ||Promotion of inflammatory cell chemotaxis and inflammation ||Implicated in many immune/autoimmune diseases such as rheumatoid arthritis, asthma, and psoriasis |
|Tumor necrosis factor-α ||Macrophages, natural killer cells, T cells, B cells, and mast cells ||Promotion of inflammation ||Treatment with antibodies against tumor necrosis factor-α beneficial in rheumatoid arthritis and Crohn disease |
|Lymphotoxin (tumor necrosis factor-β) ||Type 1 (TH1) helper T cells and B cells ||Promotion of inflammation ||Implicated in the pathogenesis of multiple sclerosis and insulin-dependent diabetes mellitus |
|Transforming growth factor-β ||T cells, macrophages, B cells, and mast cells ||Immunosuppression ||May be useful therapeutic agent in multiple sclerosis and myasthenia gravis |
|Granulocyte-macrophage colony-stimulating factor ||T cells, macrophages, natural killer cells, and B cells ||Promotion of the growth of granulocytes and monocytes ||Used to reduce neutropenia after chemotherapy for tumors and in ganciclovir-treated patients with AIDS; used to stimulate cell production after hematopoietic stem cell transplantation |
|Interferon-α ||Virally infected cells ||Induction of resistance of cells to viral infection ||Used to treat AIDS-related Kaposi sarcoma, melanoma, chronic hepatitis B infection, and chronic hepatitis C infection |
|Interferon-β ||Virally infected cells ||Induction of resistance of cells to viral infection ||Used to reduce the frequency and severity of relapses in multiple sclerosis |
|Interferon-γ ||Type 1 (TH1) helper T cells and natural killer cells ||Activation of macrophages; inhibition of type 2 (TH2) helper T cells ||Used to enhance the killing of phagocytosed bacteria in chronic granulomatous disease |
Many of the receptors for cytokines and hematopoietic growth factors (see above), as well as the receptors for prolactin (see Chapter 22), and growth hormone (see Chapter 18) are members of a cytokine-receptor superfamily that has three subfamilies (Figure 3–5). The members of subfamily 1, which includes the receptors for IL-4 and IL-7, are homodimers. The members of subfamily 2, which includes the receptors for IL-3, IL-5, and IL-6, are heterodimers. The receptor for IL-2 (and several other cytokines) consists of a heterodimer plus an unrelated protein, the so-called Tac antigen. The other members of subfamily 3 have the same γ chain as IL-2R. The extracellular domain of the homodimer and heterodimer subunits all contain four conserved cysteine residues plus a conserved Trp-Ser-X-Trp-Ser domain, and although the intracellular portions do not contain tyrosine kinase catalytic domains, they activate cytoplasmic tyrosine kinases when ligand binds to the receptors.
Members of an important cytokine receptor superfamily, showing shared structural elements. Note that all subunits except the α subunit in subfamily 3 have four conserved cysteine residues (C) and a Trp-Ser-X-Trp-Ser motif (X). Many subunits also contain a critical regulatory domain in their cytoplasmic portions (R). CNTF, ciliary neurotrophic factor; Epo, erythropoietin; GH, growth hormone; LIF, leukemia inhibitory factor; OSM, oncostatin M; PRL, prolactin.
The effects of the principal cytokines are listed in Table 3–2. Some of them have systemic as well as local paracrine effects. For example, IL-1, IL-6, and tumor necrosis factor-α cause fever, and IL-1 increases slow-wave sleep and reduces appetite.
Another superfamily of cytokines is the chemokine family. Chemokines are substances that attract neutrophils (see previous text) and other white blood cells to areas of inflammation or immune response. Over 40 have now been identified, and it is clear that they also play a role in the regulation of cell growth and angiogenesis. The chemokine receptors are G-protein–coupled receptors that cause, among other things, extension of pseudopodia with migration of the cell toward the source of the chemokine.
The cell-killing effects of innate and acquired immunity are mediated in part by a system of more than 30 plasma proteins originally named the complement system because they “complemented” the effects of antibodies. Three different pathways or enzyme cascades activate the system: the classic pathway, triggered by immune complexes; the mannose-binding lectin pathway, triggered when this lectin binds mannose groups in bacteria; and the alternative or properdin pathway, triggered by contact with various viruses, bacteria, fungi, and tumor cells. The proteins that are produced have three functions: they help kill invading organisms by opsonization, chemotaxis, and eventual lysis of the cells; they serve in part as a bridge from innate to acquired immunity by activating B cells and aiding immune memory; and they help dispose of waste products after apoptosis. Cell lysis, one of the principal ways the complement system kills cells, is brought about by inserting proteins called perforins into their cell membranes. These create holes, which permit free flow of ions and thus disruption of membrane polarity.
The cells that mediate innate immunity include neutrophils, macrophages, and NK cells. All these cells respond to molecular patterns produced by bacteria and to other substances characteristic of viruses, tumor, and transplant cells. Many cells that are not professional immunocytes may nevertheless also contribute to innate immune responses, such as endothelial and epithelial cells. The activated cells produce their effects via the release of cytokines, as well as, in some cases, complement and other systems.
Innate immunity in Drosophila centers around a receptor protein named toll, which binds fungal antigens and triggers activation of genes coding for antifungal proteins. An expanding list of toll-like receptors (TLRs) has now been identified in humans and other vertebrates. One of these, TLR4, binds bacterial lipopolysaccharide and a protein called CD14, and this initiates intracellular events that activate transcription of genes for a variety of proteins involved in innate immune responses. This is important because bacterial lipopolysaccharide produced by gram-negative organisms is the cause of septic shock. TLR2 mediates the response to microbial lipoproteins, TLR6 cooperates with TLR2 in recognizing certain peptidoglycans, TLR5 recognizes a molecule known as flagellin in bacterial flagellae, and TLR9 recognizes bacterial DNA. TLRs are referred to as pattern recognition receptors (PRRs) because they recognize and respond to the molecular patterns expressed by pathogens. Other PRRs may be intracellular, such as the so-called NOD proteins. One NOD protein, NOD2, has received attention as the product of a candidate gene leading to the intestinal inflammatory condition, Crohn disease (Clinical Box 3–2).
As noted previously, the key to acquired immunity is the ability of lymphocytes to produce antibodies (in the case of B cells) or cell-surface receptors (in the case of T cells) that are specific for one of the many millions of foreign agents that may invade the body. The antigens stimulating production of T cell receptors or antibodies are usually proteins and polypeptides, but antibodies can also be formed against nucleic acids and lipids if these are presented as nucleoproteins and lipoproteins. Antibodies to small molecules can also be produced experimentally if the molecules are bound to protein. Acquired immunity has two components: humoral immunity and cellular immunity. Humoral immunity is mediated by circulating immunoglobulin antibodies in the γ-globulin fraction of the plasma proteins. Immunoglobulins are produced by differentiated forms of B lymphocytes known as plasma cells, and they activate the complement system and attack and neutralize antigens. Humoral immunity is a major defense against bacterial infections. Cellular immunity is mediated by T lymphocytes. It is responsible for delayed allergic reactions and rejection of transplants of foreign tissue. Cytotoxic T cells attack and destroy cells bearing the antigen that activated them. They kill by inserting perforins (see above) and by initiating apoptosis. Cellular immunity constitutes a major defense against infections due to viruses, fungi, and a few bacteria such as the tubercle bacillus. It also helps defend against tumors.
CLINICAL BOX 3–2 Crohn Disease
Crohn disease is a chronic, relapsing, and remitting disease that involves transmural inflammation of the intestine that can occur at any point along the length of the gastrointestinal tract but most commonly is confined to the distal small intestine and colon. Patients with this condition suffer from changes in bowel habits, bloody diarrhea, severe abdominal pain, weight loss, and malnutrition. Evidence is accumulating that the disease reflects a failure to downregulate inflammatory responses to the normal gut commensal microbiota. In genetically susceptible individuals, mutations in genes controlling innate immune responses (eg, NOD2) or regulators of acquired immunity appear to predispose to disease when individuals are exposed to appropriate environmental factors, which can include a change in the microbiota or stress. THERAPEUTIC HIGHLIGHTS
During flares of Crohn disease, the mainstay of treatment remains high-dose corticosteroids to suppress inflammation nonspecifically. Surgery is often required to treat complications such as strictures, fistulas, and abscesses. Some patients with severe disease also benefit from ongoing treatment with immunosuppressive drugs, or from treatment with antibodies targeted against tumor necrosis factor-α. Probiotics, therapeutic microorganisms designed to restore a “healthy” microbiota, may have some role in prophylaxis. The pathogenesis of Crohn disease, as well as the related inflammatory bowel disease, ulcerative colitis, remains the subject of intense investigation, and therapies that target specific facets of the inflammatory cascade that may be selectively implicated in individual patients with differing genetic backgrounds are under development.
The number of different antigens recognized by lymphocytes in the body is extremely large. The repertoire develops initially without exposure to the antigen. Stem cells differentiate into many million different T and B lymphocytes, each with the ability to respond to a particular antigen. When the antigen first enters the body, it can bind directly to the appropriate receptors on B cells. However, a full antibody response requires that the B cells contact helper T cells. In the case of T cells, the antigen is taken up by an antigen-presenting cell (APC) and partially digested. A peptide fragment of it is presented to the appropriate receptors on T cells. In either case, the cells are stimulated to divide, forming clones of cells that respond to this antigen (clonal selection). Effector cells are also subject to negative selection, during which lymphocyte precursors that are reactive with self-antigens are normally deleted. This results in immune tolerance. It is this latter process that presumably goes awry in autoimmune diseases, where the body reacts to and destroys cells expressing normal proteins, with accompanying inflammation that may lead to tissue destruction.
APCs include specialized cells called dendritic cells in the lymph nodes and spleen and the Langerhans dendritic cells in the skin. Macrophages and B cells themselves, and likely many other cell types, can also function as APCs. For example, in the intestine, the epithelial cells that line the tract are likely important in presenting antigens derived from commensal bacteria. In APCs, polypeptide products of antigen digestion are coupled to the HLA protein products of the major histocompatibility complex (MHC) genes and presented on the surface of the cell.
The genes of the MHC, which are located on the short arm of human chromosome 6, encode glycoproteins that are divided into two classes on the basis of structure and function. Class I antigens are composed of a 45-kDa heavy chain associated noncovalently with β2-microglobulin encoded by a gene outside the MHC (Figure 3–6). They are found on all nucleated cells. Class II antigens are heterodimers made up of a 29- to– 34-kDa α chain associated noncovalently with a 25- to 28-kDa β chain. They are present in “professional” APCs, including B cells, and in activated T cells.
Schematic structure of a class I MHC protein bound to an antigen fragment, based on the structure of the human histocompatibility antigen HLA-A2. The antigen-binding pocket is at the top and is formed by the α1 and α2 parts of the molecule. The α3 portion and the associated β2-microglobulin (β2m) are close to the membrane. MHC, major histocompatibility complex. Reproduced with permission from Bjorkman PJ, et al: Structure of the human histocompatibility antigen HLA-A2, Nature 1987; Oct 8–14; 329(6139):506–512
The class I MHC proteins (MHC-I proteins) are coupled primarily to peptide fragments generated from proteins synthesized within cells. Peptides to which the host is not tolerant (eg, those from mutant or viral proteins) are recognized by T cells. The digestion of these proteins occurs in complexes of proteolytic enzymes known as proteasomes, and the peptide fragments bind to MHC proteins in the endoplasmic reticulum. The class II MHC proteins (MHC-II proteins) are concerned primarily with peptide products of extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested in the late endosomes.
The MHC protein–peptide complexes on the surface of the APCs bind to appropriate T cells. Therefore, receptors on the T cells must recognize a very wide variety of complexes. Most of the receptors on circulating T cells are made up of two polypeptide units designated α and β. They form heterodimers that recognize the MHC proteins and the antigen fragments with which they are combined (Figure 3–7). These cells are called αβ T cells. On the other hand, about 10% of circulating T cells have two different polypeptides designated γ and δ in their receptors, and they are called γδ T cells. These T cells are prominent in the mucosa of the gastrointestinal tract, and there is evidence that they form a link between the innate and acquired immune systems by way of the cytokines they secrete (Figure 3–3).
Interaction between antigen-presenting cell (top) and αβ T lymphocyte (bottom). The MHC proteins (in this case, MHC-I) and their peptide antigen fragment bind to the α and β units that combine to form the T cell receptor. Some experts refer to this set of protein–protein interactions as the “immune synapse.” MHC, major histocompatibility complex.
CD8 occurs on the surface of cytotoxic T cells that bind MHC-I proteins, and CD4 occurs on the surface of helper T cells that bind MHC-II proteins (Figure 3–8). The CD8 and CD4 proteins facilitate the binding of the MHC proteins to the T cell receptors, and they also foster lymphocyte development. The activated CD8 cytotoxic T cells kill their targets directly, whereas the activated CD4 helper T cells secrete cytokines that activate other lymphocytes.
Diagrammatic summary of the structure of CD4 and CD8, and their relation to MHC-I and MHC-II proteins. Note that CD4 is a single protein, whereas CD8 is a heterodimer. MHC, major histocompatibility complex.
The T cell receptors are surrounded by adhesion molecules and proteins that bind to complementary proteins in the APC when the two cells transiently join to form the “immunologic synapse” that permits T cell activation to occur (Figure 3–7). It is now generally accepted that two signals are necessary to produce activation. One is produced by the binding of the digested antigen to the T cell receptor. The other is produced by the joining of the surrounding proteins in the “synapse.” If the first signal occurs but the second does not, the T cell is inactivated and becomes unresponsive.
As noted above, B cells can bind antigens directly, but they must contact helper T cells to produce full activation and antibody formation. It is the TH2 subtype that is mainly involved. Helper T cells develop along the TH2 lineage in response to IL-4 (see below). On the other hand, IL-12 promotes the TH1 phenotype. IL-2 acts in an autocrine fashion to cause activated T cells to proliferate. The role of various cytokines in B cell and T cell activation is summarized in Figure 3–9.
Summary of acquired immunity. (1) An antigen-presenting cell (depicted here as a macrophage, but other cell types, including dendritic cells, are important) ingests and partially digests an antigen, then presents part of the antigen along with MHC peptides (in this case, MHC II peptides on the cell surface). (2) An “immune synapse” forms with a naive CD4 T cell, which is activated to produce IL-2. (3) IL-2 acts in an autocrine fashion to cause the cell to multiply, forming a clone. (4) The activated CD4 cell may promote B cell activation and the proliferation of plasma cells that produce antibodies or it may activate a cytotoxic CD8 cell. The CD8 cell can also be activated by forming a synapse with an MCH I antigen-presenting cell. MHC, major histocompatibility complex. (Reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 6th ed. New York, NY: McGraw-Hill; 2010.)
The activated B cells proliferate and transform into memory B cells (see above) and plasma cells. The plasma cells secrete large quantities of antibodies into the general circulation. The antibodies circulate in the globulin fraction of the plasma and, like antibodies elsewhere, are called immunoglobulins. The immunoglobulins are actually the secreted form of antigen-binding receptors on the B cell membrane.
Circulating antibodies protect their host by binding to and neutralizing some protein toxins, by blocking the attachment of some viruses and bacteria to cells, by opsonizing bacteria (see above), and by activating complement. Five general types of immunoglobulin antibodies are produced by plasma cells. The basic component of each is a symmetric unit containing four polypeptide chains (Figure 3–10). The two long chains are called heavy chains, whereas the two short chains are called light chains. There are two types of light chains, k and λ, and nine types of heavy chains. The chains are joined by disulfide bridges that permit mobility, and there are intrachain disulfide bridges as well. In addition, the heavy chains are flexible in a region called the hinge. Each heavy chain has a variable (V) segment in which the amino acid sequence is highly variable, a diversity (D) segment in which the amino acid segment is also highly variable, a joining (J) segment in which the sequence is moderately variable, and a constant (C) segment in which the sequence is constant. Each light chain has a V, J, and C segment. The V segments form part of the antigen-binding sites (Fab portion of the molecule [Figure 3–10]). The Fc portion of the molecule is the effector portion, which mediates the reactions initiated by antibodies.
Typical immunoglobulin G molecule. Fab, portion of the molecule that is concerned with antigen binding; Fc, effector portion of the molecule. The constant regions are pink and purple, and the variable regions are orange. The constant segment of the heavy chain is subdivided into CH1, CH2, and CH3. SS lines indicate intersegmental disulfide bonds. On the right side, the C labels are omitted to show regions JH, D, and JL.
Two of the classes of immunoglobulins contain additional polypeptide components (Table 3–3). In IgM, five of the basic immunoglobulin units join around a polypeptide called the J chain to form a pentamer. In IgA, the secretory immunoglobulin, the immunoglobulin units form dimers and trimers around a J chain and a polypeptide that comes from epithelial cells, the secretory component (SC).
TABLE 3–3Human immunoglobulins.a ||Download (.pdf) TABLE 3–3 Human immunoglobulins.a
|Immunoglobulin ||Function ||Heavy Chain ||Additional Chain ||Structure ||Plasma Concentration (mg/dL) |
|IgG ||Complement activation ||γ1, γ2, γ3, γ4 || ||Monomer ||1000 |
|IgA ||Localized protection in external secretions (tears, intestinal secretions, etc) ||α1, α2 ||J, SC ||Monomer; dimer with J or SC chain; trimer with J chain ||200 |
|IgM ||Complement activation ||μ ||J ||Pentamer with J chain ||120 |
|IgD ||Antigen recognition by B cells ||δ || ||Monomer ||3 |
|IgE ||Reagin activity; releases histamine from basophils and mast cells ||ε || ||Monomer ||0.05 |
In the intestine, bacterial and viral antigens are taken up by M cells (see Chapter 26) and passed on to underlying aggregates of lymphoid tissue (Peyer patches), where they activate naive T cells. These lymphocytes then form B cells that infiltrate mucosa of the gastrointestinal, respiratory, genitourinary, and female reproductive tracts and the breast. There they secrete large amounts of IgA when exposed again to the antigen that initially stimulated them. The epithelial cells produce the SC, which acts as a receptor for, and binds to, IgA. The resulting secretory immunoglobulin passes through the epithelial cell and is secreted by exocytosis. This system of secretory immunity is an important and effective defense mechanism at all mucosal surfaces. It also accounts for the immune protection that is conferred by the breastfeeding of infants whose immune systems are otherwise immature because IgA is secreted into the breast milk.
GENETIC BASIS OF DIVERSITY IN THE IMMUNE SYSTEM
The genetic mechanism for the production of the immensely large number of different configurations of immunoglobulins produced by human B cells, as well as T cell receptors, is a fascinating biologic problem. Diversity is brought about in part by the fact that in immunoglobulin molecules there are two kinds of light chains and nine kinds of heavy chains. As noted previously, there are areas of great variability (hypervariable regions) in each chain. The variable portion of the heavy chains consists of the V, D, and J segments. In the gene family responsible for this region, there are several hundred different coding regions for the V segment, about 20 for the D segment, and four for the J segment. During B cell development, one V coding region, one D coding region, and one J coding region are selected at random and recombined to form the gene that produces that particular variable portion. A similar variable recombination takes place in the coding regions responsible for the two variable segments (V and J) in the light chain. In addition, the J segments are variable because the gene segments join in an imprecise and variable fashion (junctional site diversity) and nucleotides are sometimes added (junctional insertion diversity). It has been calculated that these mechanisms permit the production of about 1015 different immunoglobulin molecules. Additional variability is added by somatic mutation.
Similar gene rearrangement and joining mechanisms operate to produce the diversity in T cell receptors. In humans, the α subunit has a V region encoded by 1 of about 50 different genes and a J region encoded by 1 of another 50 different genes. The β subunits have a V region encoded by 1 of about 50 genes, a D region encoded by 1 of 2 genes, and a J region encoded by 1 of 13 genes. These variable regions permit the generation of up to an estimated 1015 different T cell receptors (Clinical Box 3–3 and Clinical Box 3–4).
More than 300 primary immunodeficiency states are now known to arise from defects in these various stages of B and T lymphocyte maturation (Clinical Box 3–5). A few important ones are shown in Figure 3–11.
Sites of congenital blockade of B and T lymphocyte maturation in various primary immunodeficiency states. SCID, severe combined immune deficiency.