(BQ) Part 2 book USMLE road map - Immunology presents the following contents: B cell differentiation and function, T cell differentiation and function, regulation of immune responses, immune tissue injury, protective immunity and vaccines, immune deficiency states, autotolerance and autoimmunity, transplantation.
6193ch09.qxd_mg 2/6/06 01:01 PM Page 104 C CH HA AP PT TE ER R 9 B CELL D I F F E R E N T I AT I O N AND FUNCTION N I The development of a diverse, self-tolerant population of antigen-specific B cells is central to creating an adaptive immune system A The initial events of lymphopoiesis occur in the fetal liver and bone marrow and not require exposure to foreign antigens Hematopoietic stem cells (HSC), which express CD34, are pluripotent and can become any of the blood cell lineages (eg, erythroid, lymphoid, myeloid) Lineage commitment is determined by the hematopoietic inductive microenvironment, which includes stromal cell ligands and growth factors (Chapter 12) Interleukin-7 (IL-7) is an important growth factor for B and T lymphocyte development Lymphocyte lineage commitment is indicated by the formation of the lymphoid progenitor cell Commitment to the B lymphocyte lineage occurs at the progenitor B (pro-B) cell stage (Table 9–1) a Most pro-B cells express CD19 as all subsequent cells of the B cell lineage b Recombination activating genes and (Rag1, Rag2) and terminal deoxynucleotidyltransferase (TdT) are expressed in preparation for immunoglobulin (Ig) locus rearrangements c The Ig H chain locus is rearranged by VDJ recombination, but H chain polypeptides are not expressed The pro-B cell differentiates into a precursor-B (pre-B) cell, which expresses a pre-B cell receptor (BCR) a The pre-BCR consists of a membrane µ chain, an invariant surrogate L chain, and Igα and Igβ polypeptides b Signaling through the pre-BCR induces allelic exclusion at the Ig H locus and rearrangement of the κ locus The pre-B cell differentiates into an immature B cell expressing an authentic BCR a The BCR complex consists of membrane µ chains, κ or λ light chains, and the Igα and Igβ polypeptides b Immature B cells exit the bone marrow and complete their differentiation into mature B cells in the periphery c Most immature B cells die in the periphery unless they encounter antigen 104 6193ch09.qxd_mg 2/6/06 01:01 PM Page 105 N Chapter 9: B Cell Differentiation and Function 105 Table 9–1 Stages of antigen-independent B cell differentiation.a HSC Pro-B Pre-B Immature B Mature B Igα, Igβ − + + + + Rag1, − + + + − TdT − + + − − Surrogate L chain − + + − − Membrane µ chain − − + + + − + Membrane δ chain Membrane κ or λ chain − − − + + Btk kinase − + + + + Positive selection - − + + − Negative selection − − − + − a HSC, hematopoietic stem cells; Ig, immunoglobulin; Rag1, Rag2, recombination activating genes and 2; Tdt, terminal deoxynucleotidyltransferase; Btk, Bruton’s tyrosine kinase Mature B cells express two forms of the BCR, membrane IgM and membrane IgD (Chapter 4) a B-1 B cells are among the first peripheral B cells and are found predominantly in the peritoneal and pleural cavities b B-1 B cells produce natural antibodies thought to be induced by microbial flora c B-1 B cells have a limited BCR repertoire (1) Most B-1 B cells produce low-affinity IgM antibodies specific for polysaccharide antigens (2) The BCRs of B-1 B cells contain relatively conserved V regions B Selection occurs at several differentiation checkpoints and determines the peripheral B cell repertoire Positive selection rescues bone marrow B cells from apoptosis (“death by neglect”) (Table 9–2) a Positive selection occurs at the pre-B and immature B cell stages b Selection requires signaling through the pre-BCR or BCR c The pre-BCR signals differentiation to the immature B cell stage and the BCR promotes differentiation into mature B cells d Positive selection through the BCR probably involves low affinity binding to self-ligands 6193ch09.qxd_mg 2/6/06 01:01 PM Page 106 N 106 USMLE Road Map: Immunology Table 9–2 Positive and negative selection of developing B cells.a Positive Selection Negative Selection Stage of B cell development Pre-B cell Immature B cell Immature B cell Receptors Pre-BCR BCR BCR Ligands Unknown Self antigens Events triggered by selection Allelic exclusion of H locus Proliferation of pre-B cells κ locus rearrangement Apoptosis BCR editing Secondary κ locus rearrangement Outcome Advancement to immature B cell stage Elimination of autoreactive B cell clones Replacement of autoreactive BCRs Monoclonal expression of µ chain BCR expression a BCR, B cell receptor X-LINKED AGAMMAGLOBULINEMIA • X-linked agammaglobulinemia (XLA) is a congenital immune deficiency characterized by the lack of peripheral B cells • Agammaglobulinemia becomes apparent only after maternal IgG disappears during the first year of life • XLA patients have a mutation in the gene coding for Bruton’s tyrosine kinase (Btk) • Btk is first required for signaling by the pre-BCR at the pre-B cell stage and mediates positive selection • A similar phenotype exists in patients with H locus deletions that prevent functional µ chain synthesis and pre-BCR expression Negative selection mediates removal of autoreactive B cell clones a Negative selection establishes self-tolerance b Negative selection occurs at the immature B cell stage and is mediated by high-affinity BCR binding of self antigens c Negative selection can signal either apoptosis or anergy within B cells d Negative selection can stimulate BCR editing (1) The cell undergoes a second light chain locus rearrangement CLINICAL CORRELATION 6193ch09.qxd_mg 2/6/06 01:01 PM Page 107 N Chapter 9: B Cell Differentiation and Function 107 (2) The second rearrangement replaces the L chain of the self-reactive BCR (3) The B cell undergoes another round of selection based on its new BCR II In the periphery, antigen induces further differentiation of mature B cells into antibody-producing plasma cells and memory cells A Antigen enters the spleen, lymph nodes, and submucosal lymphoid follicles via the blood, the lymph, or by transport across the mucosal epithelium, respectively B A single antigen-reactive B cell can give rise to thousands of daughter cells through 10–-12 cell doublings C Activated B cells differentiate into sessile plasma cells that live for only a few days Differential RNA processing ensures that plasma cells synthesize secreted, rather than membrane, Igs (Chapter 4) The progeny of a single B cell can synthesize up to 1012 antibody molecules D Antigen-specific, long-lived memory B cells also arise during B cell clonal expansion in lymph node germinal centers Follicular dendritic cells promote memory B cell development by retaining antigens over long periods of time Germinal center development is T cell dependent Memory B cells undergo Ig isotype switching Memory B cells mediate secondary responses characterized by the following: a A requirement for less antigen to induce the response b A shorter lag period before antibody is detected c Higher average affinity of the antibodies produced d The presence of additional Ig isotypes E Affinity maturation accompanies memory B cell development Affinity maturation is an increase in the average affinity of an antibody response over time Affinity maturation is T cell dependent Affinity maturation requires somatic hypermutation of Ig V region genes a Proliferating B cell clones bear mutations in the complementarity determining regions of their BCRs b The average affinities of the antibodies these cells produce increase by 10- to 100-fold c Cells that express mutated, high-affinity BCRs are positively selected by antigen for additional cycles of proliferation III Antigen-induced activation of B cells is mediated through the BCR, coreceptors, and cytokine receptors (Figure 9–1) A The BCRs on mature naive B cells are membrane IgM and IgD B Memory B cells utilize membrane IgG, IgA, or IgE as their BCRs C Each of these BCRs signals through Igα and Igβ and intermediates that are similar to those used by the T cell receptor (TCR) (Chapter 6) (Table 9–3) D Signaling is initiated by clustering of the BCR complex Polyvalent antigens with repeating identical determinants can activate B cells without coreceptor signals Most native protein antigens contain univalent epitopes that not mediate BCR cross-linking 6193ch09.qxd_mg 2/6/06 01:01 PM Page 108 N 108 USMLE Road Map: Immunology Ag MHC II B cell TH cell Binding Ag to BCR G0 phase CD40 CD28 B7 Ag presentation by B cell CD40L (CD154) CD40 G1 phase B cell-Th cell contact: • TCR-MHC class II • Coreceptors: B7, CD40 Cytokines Cytokine receptor expression S phase Activated B cells Cytokine signaling: IL-2, IL-4, IL-5, IL-6 G1 M G1 S G2 M S Mitosis G2 Proliferating B cells Figure 9–1 Cooperative signaling for B cell activation by antigen Ag, antigen; BCR, B cell receptor; TCR, T cell receptor; MHC, major histocompatibility complex; IL, interleukin 6193ch09.qxd_mg 2/6/06 01:01 PM Page 109 N Chapter 9: B Cell Differentiation and Function 109 Table 9–3 Analogous components of the TCR and BCR signaling pathways.a Signaling Event or Intermediate TCR Associated BCR Associated Effects Clustering of receptors TCRαβ or TCRγδ in the membrane with CD3 peptides BCR with Igα and Igβ Concentrate subsequent signaling mediators Phosphorylation of ITAMs Phosphorylation of CD3 ITAMs by Lck Phosphorylation of Igα and Igβ ITAMs by Src kinases Binding sites for downstream adaptor proteins and kinases Effector kinase recruitment and activation ZAP-70 Syk Phosphorylates downstream adapters and kinases Phospholipase activation PLCγ PLCγ PIP2 hydrolysis IP3 and DAG Ca2+ mobilization PKC activation Ca2+ mobilization PKC activation Calcineurin activation Calcineurin activation NFAT dephosphorylation NFAT dephosphorylation Transcriptional activation through NFAT PKC activation of IκB kinase IκB phosphorylation IκB phosphorylation Transcriptional activation through NFκB Rac, Ras activation of MAP kinases Fos/Jun phosphorylation Fos/Jun phosphorylation Transcriptional activation through NFκB TCR, T cell receptor; BCR, B cell receptor; Ig, immunoglobulin; ITAM, immunotyrosine activation motif; ZAP-70, ζ-associated protein-70 kDa; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-biphosphate; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; MAP, mitogen-activated protein a Igα and Igβ transmit BCR signals across the cell membrane a The cytoplasmic domains of Igα and Igβ contain immunotyrosine activation motifs (ITAM)(Figure 9–2) b Src family kinases phosphorylate ITAM tyrosine residues The tyrosine kinase Syk is recruited to the phosphorylated ITAMs, becomes phosphorylated, and phosphorylates downstream adapter proteins (eg, BLNK) and latent kinases a Btk kinase is recruited to BLNK and activates phospholipase C␥ (PLC␥) (1) PLCγ hydrolyzes the membrane phospholipid phosphatidylinositol 4,5biphosphate (PIP2) to form inositol triphosphate (IP3) and diacylglycerol (DAG) (2) IP3 mobilizes intracellular Ca2+ and activates calcineurin (3) Calcineurin activates the transcription factor NFAT by dephosphorylation 6193ch09.qxd_mg 2/6/06 01:01 PM Page 110 N 110 USMLE Road Map: Immunology Fyn Blk Lyn P P P P Syk P P P SOS P PLCγ activation PLCγ BLNK P Grb2 Btk GTP/GDP exchange on Ras, Rac Increased cytosolic Ca2+ Diacylglycerol (DAG) Ras•GTP Rac•GTP Ca2+-dependent enzymes PKC ERK, JNK NFAT NFκB AP-1 Figure 9–2 B cell receptor (BCR) signaling PLC, phospholipase C; GTP, guanosine triphosphate; GDP, guanosine diphosphate; PKC, protein kinase C (4) Protein kinase C is activated by DAG, which indirectly induces the degradation of IB, the inhibitor of NFB (5) The transcription factor NFκB is activated b The guanosine triphosphate/guanosine diphosphate (GTP/GDP) exchange proteins Rac and Ras are activated (1) Rac and Ras activate mitogen-activated protein (MAP) family kinases (2) The MAP kinases activate the AP-1 family of transcription factors (eg, Fos and Jun) by phosphorylation NFAT, NFκB, and AP-1 translocate to the nucleus and initiate gene transcription by binding to their respective enhancers The transcription of Ig, coreceptor, and cytokine receptor genes is initiated or increased E Coreceptors enhance signals delivered through the BCR (Table 9–4) Contact with T helper cells is required for coreceptor signaling 6193ch09.qxd_mg 2/6/06 01:01 PM Page 111 N Chapter 9: B Cell Differentiation and Function 111 Table 9–4 Important receptors and coreceptors on B cells.a Receptor or Coreceptor Ligand Biological Response Pre-BCR BCR Unknown Self antigens Positive selection of pre-B cells Positive and negative selection of immature B cells Activation of peripheral mature B cells Foreign antigens CR2 C3d Coactivation of mature B cells Enhancement of BCR signaling CD40 CD154 (CD40L) Coactivation of mature B cells Enhancement of BCR signaling IL-2R IL-2 Growth of activated B cells IL-4R IL-4 Switching to IgE IL-5R IL-5 Switching to IgA IL-6R IL-6 Differentiation of cycling B cells Increased Ig synthesis CCR7 CCL7 Chemotaxis of germinal center B cells a BCR, B cell receptor; IL, interleukin; Ig, immunoglobulin a The chemokine CCL7 mediates chemoattraction of B cells to the outer edge of germinal centers where they bind Th cells b Contact-dependent signaling is promoted by major histocompatibility complex (MHC) class II, on B cells, which is bound by the TCR c T cell contact-dependent signaling promotes B cell proliferation, increases MHC class II expression, induces coreceptor, cytokine receptor, and chemokine receptor expression, promotes affinity maturation, and induces Ig class switching CD154 (CD40 ligand or CD40L) on CD4+ Th cells coactivates B cells by binding to CD40 a CD40 signals B cells to switch Ig class by H chain gene locus rearrangement b Mutations in the CD154 gene can block T cell-induced Ig class switching in B cells (hyper-IgM syndrome type 1) Complement activation during innate and adaptive immune responses can generate the B cell coreceptor ligand C3d (Figure 8–5) a C3d can covalently bind to antigens b C3d–antigen complexes cross-link the BCR with CR2, which is composed of the CD19 and CD21 peptides 6193ch09.qxd_mg 2/6/06 01:01 PM Page 112 N 112 USMLE Road Map: Immunology c Src kinases associated with CR2 promote BCR signaling through phosphorylation SWITCH RECOMBINASE DEFICIENCY CLINICAL CORRELATION • Ig class switching involves a DNA recombination event mediated by the recombinase activation-induced cytidine deaminase (AID) • Mutations in the AID gene have been described and result in impaired antigen-induced isotype switching, somatic hypermutation in B cells, and affinity maturation of the antibody response • The resulting phenotype, designated hyper-IgM syndrome type 2, resembles the X-linked CD154 deficiency known as hyper-IgM syndrome type F Cytokines produced by T helper cells promote B cell activation Interleukin (IL)-2, IL-4, and IL-5 promote B cell proliferation IL-6 enhances the differentiation of activated B cells into antibody-producing plasma cells IL-2, IL-4, and IL-6 promote antibody synthesis by activated B cells and plasma cells Several cytokines promote Ig class switching a Switch cytokines promote specific switch recombinase interactions with specific switch sites within the Ig H gene locus (Chapter 4) b IL-4 and IL-13 promote switching to IgE c Interferon (IFN)-γ promotes switching to IgG1 and IgG3 d IL-5 and transforming growth factor-β (TGF-β) induce switching to IgA ANTICYTOKINE THERAPIES FOR CONTROLLING B CELL ACTIVATION • Monoclonal antibodies capable of neutralizing cytokines or blocking their receptors have potential for the treatment of allergic or neoplastic diseases involving B cells • For example, atopic allergies could theoretically be treated by blocking B cell switching to IgE synthesis with anti-IL-4 or anti-IL-13 • Another application undergoing clinical trials is the use of anti-IL-6 or anti-IL-6 receptor antibodies to inhibit the growth and Ig production of myeloma cells IV Foreign polysaccharides, glycolipids, and nucleic acids induce antibody production without the need for T cell help A These T-independent (TI) antigens contain repeating epitopes that cross-link multiple BCRs on a single B cell B Some TI antigens (eg, bacterial LPS) also coactivate B cells through Toll-like receptors (Chapter 1) C Some TI antigens [eg, lipopolysaccharide (LPS)] can activate complement and coactivate B cells through CR2 D Because TI antigens are not presented by antigen-presenting cells (APCs), they not activate CD4+ Th cells E The responses to TI antigens differ from responses to foreign proteins There is little Ig class switching in TI antibody responses; IgM and IgG2 antibodies predominate A limited repertoire of antibody-mediated effector functions results CLINICAL CORRELATION 6193ch09.qxd_mg 2/6/06 01:01 PM Page 113 N Chapter 9: B Cell Differentiation and Function 113 Memory B cell populations are not formed and affinity maturation through somatic hypermutation does not occur High-titered antibody responses are not seen on secondary challenge SELECTIVE IGG2 DEFICIENCY CLINICAL CORRELATION • IgG2 is a common subclass of antibody produced in response to T-independent antigens in humans • Antibody responses to protein antigens are predominantly of the IgG1 subclass • Children with selective IgG2 subclass deficiency have difficulty clearing bacteria that express polysaccharide capsules (eg, Streptococcus pneumoniae and Haemophilus influenzae) • The increased survival of encapsulated bacteria in IgG2-deficient patients suggests that other (sub)classes of Igs not provide sufficient host defense against these organisms V Antibody responses at mucosal surfaces are mediated by a specialized set of B cells that synthesizes IgA antibodies A Most of the IgA in the body is synthesized in the small intestine B IgA-secreting plasma cells are most abundant within the lamina propria of the submucosum and produce g of Ig per day C The secretory form of IgA is the central mediator of mucosal humoral immunity Secretory IgA is dimeric and contains J chain and secretory component (SC)(Chapter 3) a The α, κ, λ, and J chains of dimeric IgA are produced by mucosal B cells b Secretory component is synthesized by the intestinal epithelial cell Secretory component mediates transepithelial transport of IgA a On the basolateral surface of epithelial cells, a precursor of SC called polyIg receptor is expressed (Figure 9–3) b The poly-Ig receptor binds the polymeric Igs (IgA and IgM) c The loaded receptor is internalized into endosomes, which are translocated to the apical cell surface Lamina propria Lamina propria Lumen Mucosal epithelial cell J chain IgA-producing plasma cell Poly-Ig receptor with bound IgA Dimeric IgA Endocytosed complex of IgA and Poly-Ig receptor Figure 9–3 Transport of dimeric immunoglobulin A (IgA) by poly-Ig receptor Secretory IgA Proteolytic cleavage 6193ch17.qxd_mg 2/6/06 01:23 PM Page 216 6193APP.qxd_cc 2/6/06 01:25 PM Page 217 Appendix I CD markers and their functions.a CD Marker Principal Functions CD1 Presentation of glycolipids to NKT cells CD3 Signaling chains of the TCR CD4 Coreceptor for MHC class II-restricted T cells CD8 Coreceptor for MHC class I-restricted T cells CD11 α chain of the β2 integrin family CD14 Nonsignaling component of the LPS receptor CD18 β chain of the β2 integrin family CD19 Signal transducer on B cells CD20 Chain of the CR2 coreceptor CD21 Chain of the CR2 coreceptor CD25 α chain of the IL-2 receptor CD28 Coreceptor on T cells that binds B7 CD34 Marker on hematopoietic stem cells CD40 Coreceptor on B cells CD45 Tyrosine phosphatase of T and B cells CD55 Membrane decay accelerating factor CD59 Membrane regulator of MAC assembly CD80 B7-1 coreceptor on APCs CD154 Ligand on T cells for CD40 a NKT, natural killer T; TCR, T cell receptor; MHC, major histocompatibility complex; LPS, lipopolysaccharide; IL, interleukin; MAC, membrane attack complex; APC, antigenpresenting cell 6193APP.qxd_cc 2/6/06 01:25 PM Page 218 Appendix II Cytokines.a Cytokine Principal Functions IL-1 α, β Similar to TNF-α; fever, leukocyte adhesion, lymphocyte costimulation IL-2 T, B, and NK cell proliferation IL-3 Proliferation of progenitor cells; growth factor for mast cells IL-4 Differentiation of Th2 cells and B cells; Ig class switching to IgE IL-5 Differentiation of B cells and eosinophils; Ig class switching to IgA IL-6 Hematopoiesis, acute phase response IL-7 Progenitor B and T cell growth IL-8 Chemotaxis of neutrophils IL-10 Inhibits the Th1 pathway IL-12 Coactivator of the Th1 pathway; induces IFN-γ production IL-13 Ig class switching to IgE IL-15 NK cell growth IL-18 Coactivator for IFN-γ production TGF-β Antiinflammatory; promotes wound healing; chemotaxis; Ig class switching to IgA TNF-α Proinflammatory; neutrophil and endothelial cell activation; proapoptotic IFN-α,β Inhibits viral replication; primes macrophages IFN-γ Macrophage activation; inhibition of Th2 pathway CSF-M Growth and differentiation of monocyte/macrophage lineage CSF-G Growth and differentiation of granulocytes CSF-GM Growth and differentiation of myeloid lineage cells a IL, interleukin; TNF, tumor necrosis factor; NK, natural killer; Ig, immunoglobulin; IFN, interferon; TGF, transforming growth factor; CSF, colony-stimulating factor; M, macrophage; G, granulocyte See also Table 12-3 for a list of important chemokines 6193Indx.qxd_cc 2/6/06 01:29 PM Page 219 INDEX Note: Page numbers followed by f or t indicate figures or tables, respectively ABO blood group system antigens and antibodies, 35, 35f, 36t transplantation across incompatibilities, 209 Acquired immune deficiency syndrome (AIDS), 187, 188t Acquired immunity See Adaptive immunity Activation-induced cytidine deaminase (AID), 112, 181t Active immunization, 14 ADA (adenosine deaminase), 182, 182t Adaptive immunity clonal selection theory, 19–20, 20f definition, 1, 14 features, 14 vs innate immunity, 15t lymphocyte functions See Lymphocytes lymphoid tissues and organs, 16–19 primary vs secondary response, 14–16, 15f response regulation, 10–11, 130–133 Addison’s disease, 199t Adenosine deaminase (ADA), 182, 182t Affinity, 52, 68 Agammaglobulinemia, 106, 178 Agar gel immunodiffusion, 56, 57f AID (activation-induced cytidine deaminase), 112, 181t AIDS (acquired immune deficiency syndrome), 187, 188t ALG (antilymphocyte globulin), 212t, 213 Allelic exclusion, 44–45 Allergic rhinitis, 157 Allergy(ies) atopic See Atopic allergy clinical manifestations and allergen sources, 150, 150t definition, 149 food, 149, 159 prophylaxis, 157–158 treatment, 157–159, 158t Allografts, 204 See also Rejection ALPS (autoimmune lymphoproliferative syndrome), 122 Altered peptide ligands, 79–80 Anaphylactoid shock, 149 Anaphylactoid syndrome, 160 Anaphylaxis, 149, 156 Anemia, 144, 198 Anti-IgE, 158t Antibody(ies) See also Immunoglobulin(s) affinity, 52 avidity, 52 deficiencies, 177t, 178–179, 178t in immune response to microbes, 167t natural, 34–35 reactions with antigens, 52–59, 53t, 54t See also Immunoassays Antibody-mediated therapies, 37 Anticytokine therapies, 112 Antigen(s) in differentiation of B cells, 107, 108f, 109–112 presentation pathways, 84–87, 84t, 85f properties, 28–29 reaction with antibodies, 52–59, 53t, 54t See also Immunoassays recognition by B cells and T cells, 29t T-independent, 112–113 Antigen-presenting cell (APC) in adaptive immune response regulation, 22, 84–87, 130 T cell receptor stimulation, 68, 68t, 124t Antigen receptor complexes, 21–24, 22f, 23f Antigenic drift, 169 Antigenic shift, 169 Antigenicity, 28 Antihistamines, 158t, 159 Antilymphocyte globulin (ALG), 212t, 213 Antithymocyte globulin (ATG), 212t, 213 AP-1, 70, 110 APC See Antigen-presenting cell APS (autoimmune polyendocrine syndrome), 195 Asthma, allergic, 157 ATG (antithymocyte globulin), 212t, 213 Atopic allergy characteristics, 149 diagnosis, 157 pathogenic mechanisms, 133, 152–157 prophylaxis, 157–159 treatment, 157–159, 158t Autografts, 204 Autoimmune diseases See also Autoimmunity criteria, 194 diagnosis, 194–195 epidemiology, 199t infection and, 198 organ-specific, 195 219 pathogenic mechanisms antireceptor autoantibodies, 196, 197t cell-mediated, 197t, 200–201 cytotoxic immune tissue injury, 196–198, 197t immune complex-mediated, 197t, 198–200 systemic, 195 treatment, 200t Witebsky’s postulates, 194 Autoimmune hemolytic anemia, 28, 196–198, 197t, 200t Autoimmune lymphoproliferative syndrome (ALPS), 122 Autoimmune orchitis, vasectomy and, 194 Autoimmune polyendocrine syndrome (APS), 195 Autoimmunity See also Autoimmune diseases complement deficiencies and, 100, 187 mechanisms, 133, 193 Autotolerance, 192–193 Avidity, 52 Azathioprine, 212t, 213 B7, 68t, 108f B cell(s) anticytokine therapies for controlling activation, 112 antigen-induced activation, 107, 108f, 109–112 coreceptors, 110–111, 111t See also B cell receptor(s) deficiency, 168t, 178t, 179, 182, 182t differentiation, 104–107, 105t, 106t inhibition of activation, 131, 132f selection, 105–106, 106t T cell activation and, 108f, 112, 124t B cell receptor(s) (BCR) Ig expression, 46–49, 47f ligands and biological responses, 111t signaling pathways, 107, 108f, 109–112, 109t, 110f vs T cell receptor, 21, 65 Bacteria, in immunocompromised patients, 168t Bacteria, intracellular, 166t, 167 Bare lymphocyte syndrome type (BLS-1) clinical presentation, 84 pathogenic mechanisms, 84, 122, 180, 181t 6193Indx.qxd_cc 2/6/06 01:29 PM Page 220 N 220 Index Bare lymphocyte syndrome type (BLS-2) clinical presentation and treatment, 84, 177t differential diagnosis, 122 pathogenic mechanisms, 84, 122, 181, 181t BCR See B cell receptor(s) Bence-Jones proteins, 36 β2- agonists, 158t β2- microglobulin, 78–79, 78f, 82f, 84t Biclonal myeloma, 46 Bispecific antibodies, 37 Blood transfusions, 35, 159, 206t BLS-1 See Bare lymphocyte syndrome type BLS-2 See Bare lymphocyte syndrome type Bruton’s tyrosine kinase, 105t, 106, 179 Calcineurin, 69, 109t Candidiasis, oral, 120–121, 168t CD markers, 24t, 25, 217 CD3 deficiency, 64, 180, 181t CD4+CD25+ regulatory T (Treg) cells See Regulatory T (Treg) cells Cell adhesion molecules, 123, 183 CGD See Chronic granulomatous disease Chediak-Higashi syndrome genetic defect, 126, 184 pathogenic mechanisms, 184, 184t Chemokines functions, 144–145, 144t, 218 properties, 141 Chronic granulomatous disease (CGD), 5–6, 184t, 185 Clonal anergy, 192 Clonal deletion, 192 Clonal selection theory, 19–20, 21f, 49t Cluster of differentiation (CD) scheme See CD markers Colony-stimulating factor for granulocytes (CSF-G), 16, 218 Common γ chain (γc), 182, 182t Common variable immune deficiency, 188 Complement receptors (CR), 98, 98t, 99f Complement system activation alternative pathway, 92t, 93f, 94–95 classical pathway, 91–93, 92t, 93f control, 95–96 core elements, 92f lectin pathway, 92t, 93–94, 93f terminal steps, 95, 95f components and complexes, 97–99, 97t deficiencies autoimmunity and, 100, 187 common infections with, 99–100, 168t, 186, 186t primary, 99–100, 185–186, 186t treatment, 187 in disease pathogenesis, 99–100 functions, 91 inflammatory effects, 2t, 10 innate immune effects, 2t, 9–10 receptors, 98, 98t, 99f regulation, 95–96, 96t Conjugate vaccines, 34, 171, 172t Contact dermatitis, 161 Convertases, 91, 92t Coombs test, 28, 55, 197 Coreceptors, in B cell activation, 110–111, 111t Coreceptors, in T cell activation, 123 Corneal transplants, 206 Corticosteroids, 158t, 159, 212t, 213 CR See Complement receptors Crohn’s disease epidemiology, 199t pathogenic mechanisms, 151–152, 197t treatment, 200t Cross-match, 55, 208 Cross-reactivity, 52–53, 53t, 204, 205f Cryoglobulinemia, 36 CSF-G (colony-stimulating factor for granulocytes), 16, 218 CTL See Cytotoxic T lymphocyte Cyclic neutropenia, 16, 17t, 183 Cyclosporine, 70, 212t, 213 Cytokine(s) See also Chemokines; Interferon(s); Appendix II in adaptive immune response, 142–143, 157 in allograft rejection, 208 in amplification of biological response, 138, 139f in control of adaptive immune responses, 130 in danger signaling response, 8, 9t, 140–141 functions, 137–138 in hematopoiesis, 143–144, 143f in innate immune response, 2t, 139–142, 140t proinflammatory effects, 140–141, 140t receptors See Cytokine receptors redundant effects, 137, 138t in response to infection, 134, 167–168 Cytokine receptors, 107, 123, 145–146, 145t Cytotoxic T lymphocyte (CTL) in allograft rejection, 207f, 208 in immune response to infectious agent, 166t, 167t, 168 properties, 72–73, 73t, 74f Daclizumab, 212t, 213 Danger signaling, 7–8, 9t, 10–11 Decay accelerating factor (DAF), 95, 96t, 97 Defensins, 4, Dendritic cells, 124t Desensitization, 158 Diabetes mellitus type I epidemiology, 199t pathogenic mechanisms, 197t, 200–201 treatment, 200t Diacylglyceride (DAG), 69, 110 DiGeorge syndrome clinical manifestations, 177t, 180, 181t pathogenic mechanisms, 17, 177t, 180 DNA vaccines, 172 EIA See Enzyme-linked immunosorbent assay Elicitation, in adaptive immune response, 150, 152f ELISA See Enzyme-linked immunosorbent assay Endothelium, 2t Enzyme-linked immunosorbent assay (ELISA), 58 Epinephrine, 158t, 159 Epithelial cells, Epitope spreading, 195–196, 196f Erythroblastosis fetalis, 55, 131 Erythropoietin, 144 Factor I deficiency, 97–98 Fas, 73, 74f FcεRI, 153–154, 154f FcγRIIB, 131, 132f Fibrinolysis system, 2t, 10 Flow cytometry, 58–59, 59f, 60f Food allergies, 159 Fungi, in immunocompromised patients, 167t, 168t γc chain deficiency, 146, 176f, 182, 182t γ-globulins See Immunoglobulin(s) γδ T cells vs conventional T cells, NKT cells, and NK cells, 125t properties, 125 Gell and Coombs classification, 150, 151t Gene therapy, 183 Germinal center, 18, 18f, 107 Goodpasture’s disease, 194, 197t, 198 Graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation, 211–212 in pregnancy, 180 Granzyme, 73 Grave’s disease epidemiology, 199t pathogenic mechanisms, 196, 197t treatment, 200t GVHD See Graft-versus-host disease Haemophilus influenzae type B (Hib), vaccine, 34, 170t Haplotype, 82 Hapten, 28, 153 6193Indx.qxd_cc 2/6/06 01:29 PM Page 221 N Index 221 Hashimoto’s thyroiditis epidemiology, 199t pathogenic mechanisms, 197t treatment, 200t Hay fever, 157 Heart transplantation, 206t, 209 Hemagglutination, 55 Hematopoiesis, 16, 143f, 176f Hematopoietic stem cell, 17, 176f Hematopoietic stem cell transplantation, 206t, 211–212, 211t Hemolytic anemia, autoimmune See Autoimmune hemolytic anemia Hemolytic disease of the newborn, 131 Hereditary angioedema, 10, 93 Hereditary hemochromatosis, 87, 88t Hib See Haemophilus influenzae type B Histamine, inflammatory effects, 155–156, 155t Human leukocyte antigen (HLA) disease associations, 87–88, 88t gene expression patterns, 81–84, 81f, 83f, 83t genetic map, 82f heterodimers, 78f, 82f inheritance, 82–83, 83f polymorphism, 80, 81t structure, 78–79, 78f in transplantation, 204, 205f, 209–210, 209t typing, 209, 209t Humoral immunity, cytokines in, 142 Hybridoma antibodies, 37 Hyper-IgE syndrome See Job’s syndrome Hyper-IgM syndrome clinical presentation, 177t genetic defect, 111–112, 177t pathogenic mechanisms, 68, 181, 181t Hypergammaglobulinemia, 57 Hypersensitivity See Allergy(ies) and Immune response, tissue injury caused by Hypogammaglobulinemia, 132, 179 IFN See Interferon(s) Ig See Immunoglobulin(s) IgA deficiency, selective See Selective IgA deficiency IgG2 deficiency, selective See Selective IgG2 deficiency Ii chain, 87 Interleukin-1 receptor-associated kinase (IRAK), 187 Immune complex, 54, 197t, 198–199 Immune deficiencies gene therapy, 183 phagocytic cells See Phagocytic cell deficiency primary antibody See Antibody(ies), deficiencies clinical presentation, 175 diagnosis, 99, 179, 183 examples, 176f, 177t features, 178–179, 178t, 181t, 182t, 184t T cell See T cell(s), deficiency treatment, 179, 183, 187 secondary clinical presentation, 187–188 opportunistic infections in See Opportunistic infections pathophysiology, 187–188 Immune response(s) to infection characteristics, 164–165 mechanisms, 165–168, 166t by microbe type, 165, 167t microbial evasion mechanisms, 169–170 tissue injury caused by characteristics, 149–151 classification, 150, 151t mechanisms, 150–151 phases, 150–151, 152f type I, 151t, 152–158, 154f, 155t type II, 151t, 159–160 type III, 151t, 160 type IV, 151t, 160–161 Immune system adaptive (acquired) See Adaptive immunity dysregulation, 133–134 See also specific conditions gene polymorphisms and, 133 homeostatic regulation, 130–133 innate See Innate immunity Immunization See also Vaccine(s) active See Active immunization passive See Passive immunization Immunoassays agar gel immunodiffusion, 56, 57f applications, 54t enzyme-linked immunosorbent assay, 58 hemagglutination, 55 immunoblotting, 58 immunofixation, 56, 57f immunofluorescence assays, 58–59, 59f, 60f immunoprecipitation, 55–56, 56f radioimmunoassays, 58 Immunoblotting, 58 Immunofixation, 56, 57f Immunofluorescence assays, 58–59, 59f, 60f Immunogenicity, 28 Immunoglobulin(s) (Ig) abnormal synthesis and cryopathies, 36 diversity, 45–49, 45t, 81t gene expression chromosomal translocations, 43 germ line configuration, 40, 41, 41f locus deletions, 41 Rag deficiency, 42 recombination, 41–45, 42f, 44f heterogeneity, 30–31, 35–36 intravenous, 29, 179 isotype characteristics, 30–31, 32t isotype switching, 34, 47–48, 48f, 72, 112, 142 monoclonal, 36–37 polymeric, 33f properties, 29, 30f structure and function, 29–34 Immunoglobulin A (IgA) properties, 32–33, 32t secretory, 33, 113–115, 113f, 114f selective deficiency, 114, 178–179, 178t Immunoglobulin D (IgD), 32t Immunoglobulin E (IgE), 32t, 152, 152f Immunoglobulin G (IgG) G2 subclass deficiency, 113 properties, 32t structure, 30, 31f Immunoglobulin M (IgM) in natural antibodies, 34–35 properties, 31, 32t, 33f Immunoprecipitation, 55–56, 56f Immunosuppressive drugs, 212–213, 212t Immunotherapy, 157–158 Immunotoxins, 37 Immunotyrosine activation motif (ITAM), 109 Infectious diseases, worldwide rates, 165 Inflammatory system, 2t Influenza A, 169 Inhibitor κB (IκB), 70f, 109t Innate immunity vs adaptive immunity, 15t characteristics, components, 2t danger signaling, 7–10 first lines of defense, 1–2 leukocyte functions, 4–7, 5f, 6f pathogen-associated molecular patterns (PAMP), response regulation, 130 Interferon(s) (IFN) activities, 9, 218 type I (IFN-α/β), 141 type II (IFN-γ) characteristics, 141–142 deficiency, 142 functions, 140t, 141 opportunistic infections and, Interleukin-1 (IL-1), 140t Interleukin-1β (IL-1β) functions, 140t, 141 redundancy with TNF-α, 138t Interleukin-2 (IL-2) characteristics, 142 functions, 140t, 142 Interleukin-4 (IL-4), 142, 152f Interleukin-5 (IL-5), 142 Interleukin-6 (IL-6), 140t Interleukin-8 (IL-8), 140t Interleukin-10 (IL-10), 132–133, 140t, 141 6193Indx.qxd_cc 2/6/06 01:29 PM Page 222 N 222 Index Interleukin-12 (IL-12), 141 Intracellular killing, 165, 166t, 167 Intravenous immunoglobulin (IVIG) for B cell deficiencies, 179 for multiple myeloma, 132 in selective IgA deficiency, 179–180 therapeutic uses, 29 Isografts, 204 Isohemagglutinins, 35, 35f, 36t Isotype switching, 34, 47–48, 48f, 72, 112, 142 IVIG See Intravenous immunoglobulin Jak/STAT signaling, 145 Jak3 gene, 182, 182t Job’s syndrome clinical manifestations, 153, 184–185, 184t pathogenic mechanisms, 153 Kidney transplantation, 206t Killed vaccines, 172t Lck tyrosine kinase, 71 Leukemia, phenotyping, 59 Leukocyte adhesion defect (LAD) clinical manifestations, 183–184, 184t pathogenic mechanisms, 100, 100t, 183–184, 184t Leukocytes chemotactic factor recognition, 4t congenital deficiencies, 17t, 183–185 in innate immunity, 4–7 normal levels, 17t Leukotriene(s) (LTs), 156 Leukotriene receptor antagonists, 158t Lipid mediators, 156 Lipopolysaccharide (LPS), 7, 8f, 134 Live attenuated vaccines, 171, 172t Liver transplantation, 206t Lung transplantation, 206t Lymph node(s), 18, 18f, 19t Lymphocytes See also T cell(s) antigen receptors, 21–24, 22f, 23f, 46, 64–67 cell surface molecules, 24–25, 217 chemotactic factors, 4t congenital deficiencies, 17t, 176f, 178–183 development, 16–119 normal levels, 17t recirculating pool, 19, 20f Lymphoid organs, 16–20, 18f Lymphoma, phenotyping, 59 Lysosomal trafficking regulator (LYST), 126 M cell, 114f, 115 M proteins, 30 MAC (membrane attack complex), 95, 95f Macrophages in allograft rejection, 208 chemotactic factors, 4t in immune response to microbes, 167t T cell activation and, 124t Major histocompatibility complex (MHC) See also Human leukocyte antigen in antigen presentation, 84–87, 84t, 85f deficiencies, 122, 180–181 diversity, 80–81, 81t functions, 77 genetic map, 82f structure, 78–79, 78f in T cell differentiation, 121–122 in transplantation, 77, 204, 205f, 209t Mannose-binding lectin (MBL), 92t, 94 Mannose-binding protein (MBP), 3, 94 Mast cell(s) FcεRI signaling, 153–154, 154f IgE-independent activation, 155 inflammatory mediators from, 155–157, 155t Mast cell stabilizers, 158t MBP (mannose-binding protein), Membrane attack complex (MAC), 95, 95f Membrane lysis, 95, 165, 166t Methotrexate, 212t, 213 MHC See Major histocompatibility complex Microbes immune evasion mechanisms, 169–170 immune response See Immune response(s) worldwide infection rates, 165 Mixed lymphocyte reaction (MLR), 210, 210f Monoclonal antibodies, 36–37, 112 Monoclonal gammopathies, 36–37, 57, 57f MPO (myeloperoxidase) deficiency, 185 Mucosal immunity, 113–115 Multiple myeloma IVIG therapy, 132 pathogenic mechanisms, 29–30, 46 serum protein electrophoresis, 30f, 31 Multiple sclerosis, 194, 197t, 200 Myasthenia gravis, 196, 197t, 199t Mycophenolate mofetil, 212t, 213 Myeloperoxidase (MPO) deficiency, 185 Natural antibodies, 34–35 Natural killer (NK) cells in allograft rejection, 208 vs conventional T cells, γδ T cells, and NKT cells, 125t in immune response to infectious agent, 166t, 167t, 168 physiology, properties, 73t, 126 as source of proinflammatory cytokines, 139–140, 139f Natural killer T (NKT) cells vs conventional T cells, γδ T cells, and NK cells, 125t physiology, properties, 73t, 126 as source of proinflammatory cytokines, 139–140, 139f TCR expression, 67 Negative selection, 105t, 106–107, 106t, 119t, 122 Neutropenia cyclic, 16, 17t severe congenital, 16 Neutrophil(s), 167t Neutrophil granules chemotactic factors, 4t inflammatory effects, 2t innate immune effects, 2t, Nitric oxide, NK cells See Natural killer (NK) cells NKT cells See Natural killer T (NKT) cells Nonsteroidal anti-inflammatory drugs (NSAIDs), 158t, 200t Nuclear factor κB (NFκB), 69, 70f, 110, 110f, 145t, 154 Nuclear factor of activated T cells (NFAT), 69, 70f, 110, 110f, 154, 155t OKT3, 212t, 213 Opportunistic infections in AIDS, 188t characteristics, 175 common types and mechanisms, 168–169, 168t in hematopoietic stem cell transplantation, 212 IFN-γ and, Opsonophagocytosis, 4, 5f, 165, 166t PAF (platelet activating factor), 156 PAMP (pathogen-associated molecular pattern), Pancreas transplantation, 206t Paroxysmal nocturnal hemoglobinuria (PNH), 100, 186 Passive immunization, 15, 16 Patch test, 161 Pathogen-associated molecular pattern (PAMP), Pemphigus vulgaris, 197t, 199t Penicillin, 28 Peptides, altered ligands in, 79–80 Perforin, 73, 74f Pernicious anemia, 21, 197t Peyer’s patches, 114f, 115 PGs (prostaglandins), 154f, 156 Phagocytic cell deficiency common infections with, 168t 6193Indx.qxd_cc 2/6/06 01:29 PM Page 223 N Index 223 features, 183–185, 184t treatment, 185 Phagocytosis See Opsonophagocytosis Platelet activating factor (PAF), 156 PNH (paroxysmal nocturnal hemoglobinuria), 100, 186 Polio vaccine, 115, 170t Polyclonal gammopathies, 57 Poly Ig receptor, 113 Polyvalent vaccines, 171, 172, 172t Positive selection, 105, 105t, 119t, 120t, 121 Pregnancy, immunological considerations, 55, 133, 180 Prostaglandin(s) (PGs), 154f, 156 Radioimmunoassays, 58 Rag genes characteristics, 41–42 deficiency, 42, 182, 182t expression of, 104, 105t, 119–120, 119t Reactive oxygen intermediates, Regulatory T (Treg) cells in immune homeostasis regulation, 132–133 in tolerance, 192 Rejection hyperacute, 211 immune mediators, 206–208, 207f pathogenic mechanisms, 208 prevention methods, 208–210, 209t, 210f, 212–213, 212t Respiratory burst, 5–6, 6f Respiratory burst oxidase, 5–6 Rh disease, 55, 131 Rheumatic fever, 133, 197t Rheumatoid arthritis pathogenic mechanisms, 197t, 199–200 treatment, 200t tuberculosis in, 138–139 Rheumatoid factor (RF), 195 Rhogam, 131 SCID See Severe combined immune deficiency Secretory component, 33, 33f, 113 Selective IgA deficiency, 177t, 178–179 Selective IgG2 deficiency, 178t, 179 Sensitization, in adaptive immune response, 150, 152f Sepsis, 8, 134, 134f Seroconversion, 164 Serum protein electrophoresis, 30f Serum sickness, 160, 197t, 198 Severe combined immune deficiency (SCID) clinical manifestations and treatment, 42, 118 genetic defects in, 42, 118, 146, 182, 182t SIRS (systemic inflammatory response syndrome), 141 Sjögren’s syndrome, 197t, 199t, 201 SLE See Systemic lupus erythematosus Somatic hypermutation, 46, 67, 107 Spleen, 19t Spondyloarthropathies, 87–88, 88t Subunit vaccines, 171, 172t Superantigens, 67 Superoxide, 5, 6f Switch recombinase deficiency, 112, 181t Systemic inflammatory response syndrome (SIRS), 141 Systemic lupus erythematosus (SLE) clinical manifestations and treatment, 198–199, 200t epidemiology, 199t pathogenic mechanisms, 197t, 199 T cell(s) activation, 68, 123–126, 124t adhesion molecules and coreceptors, 68, 68t conventional, vs γδ T cells, NKT cells, and NK cells, 125t cytotoxic See Cytotoxic T lymphocyte deficiency common infections with, 168t diagnosis, 183 features, 177t, 180–182, 181t treatment, 183 differentiation, 118–122, 119t receptors See T cell receptor(s) Th1 and Th2 CD4+ subsets, 71–72, 71t, 72f, 124 T cell receptor(s) (TCRs) altered peptide ligands, 79–80 vs B cell receptor, 65t CD3 expression and, 22f, 23, 64 costimulation by APC, 68, 68t MHC receptors and thymic selection, 121–122 rearrangements in cancer, 67 signaling events, 69–71, 69f, 70f signaling pathways, 109t structure, 64–67, 65f, 66f, 66t subsets, 119–120, 120t T helper (Th) cells, 71–72, 71t, 72f, 107, 108f, 124 deficiency, 181, 181t in immune response to microbes, 167t T-independent (TI) antigens, 112–113 TCRs See T cell receptor(s) Th cells See T helper (Th) cells Thrombocytopenia purpura, 194, 197t Thrush, 120–121 Thymic apoptosis, defective, 122 Thymocytes, 119–120, 120t, 121f TI (T-independent) antigens, 112–113 Tissue typing, 208–210, 209t TLR family See Toll-like receptor (TLR) family TNF-α See Tumor necrosis factor-α Tolerance, 192–193 Toll-like receptor (TLR) family in danger signaling, 7, 8f in innate immunity, 3–4, 3t Toxic shock syndrome, 67 Toxin neutralization, 166t, 167 Transfusion reaction, 159 Transient hypogammaglobulinemia of infancy, 178t, 179 Transplantation cyclosporine and, 70, 212t, 213 hematopoietic stem cell, 183, 211–212, 211t immunosuppressive therapy, 212–213, 212t MHC and, 77, 204–205, 205f principles, 204–205 rejection See Rejection special considerations by type, 206t between species, 96–97, 210–211 tolerance, 193 waiting lists, 210 Transporter associated with antigen processing (TAP), 85f, 86, 170, 180 Treg cells See Regulatory T (Treg) cells Tumor necrosis factor-α (TNF-α) functions, 140, 140t, 218 redundancy with IL-1β, 138t Tumor necrosis factor-β (TNF-β), 140t Vaccine(s) characteristics, 170–171 design and use, 171 novel strategies, 172 parenteral vs mucosal, 115 polio, 115 recommendations for children, 170t, 171 types, 171, 172t Vasectomy, autoimmune orchitis and, 194 Virus(es) in immunocompromised patients, 168t neutralization, 166t, 167 Western blotting, 58 Wiscott-Aldrich syndrome, 182 Witebsky’s postulates, 194 X-linked agammaglobulinemia (XLA), 106, 178t, 179 Xenografts, 204 Xenotransplantation, 96–97, 210–211 ZAP-70, 69, 180, 181t ζ chain, 22f, 64–65, 69f 6193Indx.qxd_cc 2/6/06 01:29 PM Page 224 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 225 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 226 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 227 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 228 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 229 Notes 6193Indx.qxd_cc 2/6/06 01:29 PM Page 230 Notes KWWS ERRNVPHGLFRVRUJ ... mature B cells Enhancement of BCR signaling IL-2R IL -2 Growth of activated B cells IL-4R IL-4 Switching to IgE IL-5R IL-5 Switching to IgA IL-6R IL-6 Differentiation of cycling B cells Increased... complexes cross-link the BCR with CR2, which is composed of the CD19 and CD21 peptides 6193ch09.qxd_mg 2/ 6/06 01:01 PM Page 1 12 N 1 12 USMLE Road Map: Immunology c Src kinases associated with CR2 promote... phenotype a Double-positive thymocytes with TCRs that bind to self MHC class I molecules are induced to become CD4–CD8+ ch10.qxd 2/ 6/06 03:13 PM Page 122 N 122 USMLE Road Map: Immunology b Double