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InternalMed_Harrison. MOLECULAR BASIS OF T CELL RECOGNITION OF ANTIGEN The TCR for antigen is a complex of molecules consisting of an antigen-binding heterodimer of either αβ or γδ chains noncovalently linked with five CD3 subunits (γ, δ, ε, ζ, and η) (Fig. 372e-7). The CD3 ζ chains are either disulfide-linked homodimers (CD3-ζ2) or disulfide-linked heterodimers composed of one ζ chain and one η chain. TCR-αβ or TCR-γδ molecules must be associated with CD3 molecules to be inserted into the T cell-surface membrane, TCRα being paired with TCR-β and TCR-γ being paired with TCR-δ. Molecules of the CD3 complex mediate transduction of T cell activation signals via TCRs, whereas TCR-α and -β or -γ and -δ molecules combine to form the TCR antigen-binding site.


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InternalMed_Harrison. The α, β, γ, and δ TCR for antigen molecules have amino acid sequence homology and structural similarities to immunoglobulin heavy and light chains and are members of the immunoglobulin gene superfamily of molecules. The genes encoding TCR molecules are encoded as clusters of gene segments that rearrange during the course of T cell maturation. This creates an efficient and compact mechanism for housing the diversity requirements of antigen receptor molecules. The TCR-α chain is on chromosome 14 and consists of a series of V (variable), J (joining), and C (constant) regions. The TCR-β chain is on chromosome 7 and consists of multiple V, D (diversity), J, and C TCR-β loci. The TCR-γ chain is on chromosome 7, and the TCR-δ chain is in the middle of the TCR-α locus on chromosome 14. Thus, molecules of the TCR for antigen have constant (framework) and variable regions, and the gene segments encoding the α, β, γ, and δ chains of these molecules are recombined and selected in the thymus,


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InternalMed_Harrison. molecules of the TCR for antigen have constant (framework) and variable regions, and the gene segments encoding the α, β, γ, and δ chains of these molecules are recombined and selected in the thymus, culminating in synthesis of the completed molecule. In both T and B cell precursors (see below), DNA rearrangements of antigen receptor genes involve the same enzymes, recombinase activating gene (RAG) 1 and RAG2, both DNA-dependent protein kinases.


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InternalMed_Harrison. TCR diversity is created by the different V, D, and J segments that are possible for each receptor chain by themany permutations of V, D, and J segment combinations, by “N-region diversification” due to the addition of nucleotides at the junction of rearranged gene segments, and by the pairing of individual chains to form a TCR dimer. As T cells mature in the thymus, the repertoire of antigen-reactive T cells is modified by selection processes that eliminate many autoreactive T cells,enhancetheproliferationofcellsthatfunctionappropriatelywith self-MHC molecules and antigen, and allow T cells with nonproductive TCR rearrangements to die. TCR-αβ cells do not recognize native protein or carbohydrate anti-gens.Instead,Tcells recognizeonly short(~9–13amino acids) peptide


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InternalMed_Harrison. TCR-αβ cells do not recognize native protein or carbohydrate anti-gens.Instead,Tcells recognizeonly short(~9–13amino acids) peptide PtdIns (4,5)P3 Lipid raft CD3 TCR InsP3 DAG PKC RASGRP Activation of downstream effectors such as NFkB, AP1, and NFAT to induce specific gene transcription leading to cell proliferation and differentiation Release of Ca2+ Translocation of NFAT to the nucleus ZAP-70 Integrin activation MAPK activation Cytoskeletal reorganization RAS SOS GRB2LAT PLC˛GADS HPK1 NCK ADAP ITK LCK VAV1 LFA-1 CD2CD28


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InternalMed_Harrison. FIGUrE 372e-7 Signaling through the T cell receptor. Activation signals are mediated via immunoreceptor tyrosine-based activation (ITAM) sequences in LAT and CD3 chains (blue bars) that bind to enzymes and transduce activation signals to the nucleus via the indicated intracellular activation pathways. Ligation of the T cell receptor (TCR) by MHC complexed with antigen results in sequential activation of LCK and γ-chainassociated protein kinase of 70 kDa (ZAP-70). ZAP-70 phosphorylates several downstream targets, including LAT (linker for activation of T cells) and SLP76 (SCR homology 2 [SH2] domain-containing leukocyte protein of 76 kDa). SLP76 is recruited to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein). Together, SLP76 and LAT nucleate a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal


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InternalMed_Harrison. a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal reorganization. APC, antigen-presenting cell. (Adapted from GA Koretzky et al: Nat Rev Immunol 6:67, 2006; with permission from Macmillan Publishers Ltd. Copyright 2006.) fragments derived from protein antigens taken up or produced in APCs. Foreign antigens may be taken up by endocytosis into acidified intracellular vesicles or by phagocytosis and degraded into small peptides that associate with MHC class II molecules (exogenous antigen-presentation pathway). Other foreign antigens arise endogenously in thecytosol(suchasfromreplicatingviruses)andarebrokendowninto small peptides that associate with MHC class I molecules (endogenous antigen-presenting pathway). Thus, APCs proteolytically degrade foreign proteins and display peptide fragments embedded in the MHC class I or II antigen-recognition


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InternalMed_Harrison. MHC class I molecules (endogenous antigen-presenting pathway). Thus, APCs proteolytically degrade foreign proteins and display peptide fragments embedded in the MHC class I or II antigen-recognition site on the MHC molecule surface, where foreign peptide fragments are available to bind to TCR-αβ or TCR-γδ chains of reactive T cells. CD4 molecules act as adhesives and, by direct binding to MHC class II (DR, DQ, or DP) molecules, stabilize the interaction of TCR with peptide antigen (Fig. 372e-7). Similarly, CD8 molecules also act as adhesives to stabilize the TCR-antigen interaction by direct CD8 molecule binding to MHC class I (A, B, or C) molecules.


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InternalMed_Harrison. Antigens that arise in the cytosol and are processed via the endogenous antigen-presentation pathway are cleaved into small peptides by a complex of proteases called the proteasome. From the proteasome, antigen peptide fragments are transported from the cytosol into the lumen of the endoplasmic reticulum by a heterodimeric complex termed transporters associated with antigen processing, or TAP proteins. There, MHC class I molecules in the endoplasmic reticulum membrane physically associate with processed cytosolic peptides. Following peptide association with class I molecules, peptide-class I complexes are exported to the Golgi apparatus, and then to the cell surface, for recognition by CD8+ T cells.


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InternalMed_Harrison. Antigens taken up from the extracellular space via endocytosis into intracellular acidified vesicles are degraded by vesicle proteases into peptide fragments. Intracellular vesicles containing MHC class II molecules fuse with peptide-containing vesicles, thus allowing peptide fragmentsto physically bindto MHCclass IImolecules.Peptide-MHC class II complexes are then transported to the cell surface for recognition by CD4+ T cells (Chap. 373e).


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InternalMed_Harrison. Whereas it is generally agreed that the TCR-αβ receptor recognizes peptide antigens in the context of MHC class I or class II molecules, lipids in the cell wall of intracellular bacteria such as M. tuberculosis can also be presented to a wide variety of T cells, including subsets of TCR-γδ T cells, and a subset of CD8+ TCR-αβ T cells. Importantly, bacterial lipid antigens are not presented in the context of MHC class I orIImolecules,butratherarepresentedinthecontextofMHC-related CD1 molecules. Some γδ T cells that recognize lipid antigens via CD1 molecules have very restricted TCR usage, do not need antigen priming to respond to bacterial lipids, and may actually be a form of innate rather than acquired immunity to intracellular bacteria.


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InternalMed_Harrison. Just as foreign antigens are degraded and their peptide fragments presented in the context of MHC class I or class II molecules on APCs, endogenous self-proteins also are degraded, and self-peptide fragments are presented to T cells in the context of MHC class I or class II molecules on APCs. In peripheral lymphoid organs, there are T cells that are capable of recognizing self-protein fragments but normally are anergic or tolerant, i.e., nonresponsive to self-antigenic stimulation, due to lack of self-antigen upregulating APC co-stimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) (see below).


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InternalMed_Harrison. Once engagement of mature T cell TCR by foreign peptide occurs in the context of self-MHC class I or class II molecules, binding of non-antigen-specific adhesion ligand pairs such as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR binding, and the expression of these adhesion molecules is upregulated (Fig. 372e-7). Once antigen ligation of the TCR occurs, the T cell membrane is partitioned into lipid membrane microdomains, or lipid rafts, that coalesce the key signaling molecules TCR/CD3 complex, CD28, CD2, LAT (linker for activation of T cells), intracellular activated (dephosphorylated) src family protein tyrosine kinases (PTKs), and the key CD3ζ-associated protein-70 (ZAP-70) PTK (Fig. 372e-7). Importantly, during T cell activation, the CD45 molecule, with protein tyrosine phosphatase activity, is partitioned away from the TCR complex to allow activating phosphorylation events to occur. The coalescence of signaling molecules of activated T lymphocytes in microdomains has


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InternalMed_Harrison. activity, is partitioned away from the TCR complex to allow activating phosphorylation events to occur. The coalescence of signaling molecules of activated T lymphocytes in microdomains has suggested that T cell-APC interactions can be considered immunologic synapses, analogous in function to neuronal synapses.


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InternalMed_Harrison. After TCR-MHC binding is stabilized, activation signals are transmitted through the cell to the nucleus and lead to the expression of geneproductsimportant inmediatingthewidediversityofTcellfunctions such as the secretion of IL-2. The TCR does not have intrinsic signaling activity but is linked to a variety of signaling pathways via immunoreceptor tyrosine-based activation motifs (ITAMs) expressed on the various CD3 chains that bind to proteins that mediate signal transduction. Each of the pathways results in the activation of particular transcription factors that control the expression of cytokine and cytokine receptor genes. Thus, antigen-MHC binding to the TCR induces the activation of the src family of PTKs, fyn and lck (lck is associated with CD4 or CD8 co-stimulatory molecules); phosphorylation of CD3ζ chain; activation of the related tyrosine kinases ZAP-70 and syk; and downstream activation of the calcium-dependent calcineurin pathway, the ras pathway, and the protein kinase C


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InternalMed_Harrison. of CD3ζ chain; activation of the related tyrosine kinases ZAP-70 and syk; and downstream activation of the calcium-dependent calcineurin pathway, the ras pathway, and the protein kinase C pathway. Each of these pathways leads to activation of specific families of transcription factors (including NF-AT, fos and jun, and rel/NF-κB) that form heteromultimers capable of inducing expression of IL-2, IL-2 receptor, IL-4, TNF-α, and other T cell mediators.


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InternalMed_Harrison. In addition to the signals delivered to the T cell from the TCR complex and CD4 and CD8, molecules on the T cell, such as CD28 and inducible co-stimulator (ICOS), and molecules on DCs, such as B7-1 (CD80) and B7-2 (CD86), also deliver important co-stimulatory signals that upregulate T cell cytokine production and are essential for T cell activation. If signaling through CD28 or ICOS does not occur, or if CD28 is blocked, the T cell becomes anergic rather than activated (see “Immune Tolerance and Autoimmunity” below). CTLA-4 (CD152) is similar to CD28 in its ability to bind CD80 and CD86. Unlike CD28, CTLA-4 transmits an inhibitory signal to T cells, acting as an off switch.


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InternalMed_Harrison. T CELL EXHAUSTION IN VIRAL INFECTIONS AND CANCER In chronic viral infections such as HIV-1, hepatitis C virus, and hepatitis B virus and in chronic malignancies, the persistence of antigen disrupts memory T cell function, resulting in defects in memory T cell responses. This has been defined as T cell exhaustion and is associated with T cell programmed cell death protein 1 (PD-1) (CD279) expression. Exhausted T cells have compromised proliferation and lose the ability to produce effector molecules, like IL-2, TNF-α, and IFN-γ. PD-1 downregulates T cell responses and is associated with T cell exhaustion and disease progression. For this reason, inhibition of T cell PD-1 activity to enhance effectorTcellfunction isbeing explored as atargetforimmunotherapy in both viral infections and certain malignancies.


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InternalMed_Harrison. T CELL SUPERANTIGENS Conventional antigens bind to MHC class I or II molecules in the groove of the αβ heterodimer and bind to T cells via the V regions of the TCR-α and -β chains. In contrast, superantigens bind directly to the lateral portion of the TCR-β chain and MHC class II β chain and stimulate T cells based solely on the Vβ gene segment used independent of the D, J, and Vα sequences present. Superantigens are protein molecules capable of activating up to 20% of the peripheral T cell pool, whereas conventional antigens activate <1 in 10,000 T cells. T cell superantigens include staphylococcal enterotoxins and other bacterial products. Superantigen stimulation of human peripheral T cells occurs in the clinical setting of staphylococcal toxic shock syndrome, leading to massive overproduction of T cell cytokines that leads to hypotension and shock (Chap. 172).


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InternalMed_Harrison. B CELLS Mature B cells constitute 10–15% of human peripheral blood lymphocytes, 20–30% of lymph node cells, 50% of splenic lymphocytes, and ~10% of bone marrow lymphocytes. B cells express on their surface intramembrane immunoglobulin (Ig) molecules that function as B cell receptors (BCRs) for antigen in a complex of Ig-associated α and β signaling molecules with properties similar to those described in T cells (Fig. 372e-8). Unlike T cells, which recognize only processed peptide fragments of conventional antigens embedded in the notches of MHC class I and class II antigens of APCs, B cells are capable of Introduction to the Immune System Fab region Light chain BCR SLP65 Release of Ca2+ Activation of downstream effectors Ig˜Ig°PtdIns(4,S)P3 InsP3 a b MAPK activation Cytoskeletal reorganization RAS PLC˛NCK VAV1 LYN SOS GRB2 DAG PKC˜RASGRP BTK SYK


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InternalMed_Harrison. FIGUrE 372e-8 B cell receptor (BCR) activation results in the sequential activation of protein tyrosine kinases, which results in the formation of a signaling complex and activation of downstream pathways as shown. Whereas SLP76 is recruited to the membrane through GADS and LAT, the mechanism of SLP65 recruitment is unclear. Studies have indicated two mechanisms: (a) direct binding by the SH2 domain of SLP65 to immunoglobulin (Ig) of the BCR complex or (b) membrane recruitment through a leucine zipper in the amino terminus of SLP65 and an unknown binding partner. ADAP, adhesionand degranulation-promoting adaptor protein; AP1, activator protein 1; BTK, Bruton’s tyrosine kinase; DAG, diacylglycerol; GRB2, growth factor receptor-bound protein 2; HPK1, hematopoietic progenitor kinase 1; InsP3, inositol-1,4,5-trisphosphate; ITK, interleukin-2-inducible T cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C;


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InternalMed_Harrison. 1; InsP3, inositol-1,4,5-trisphosphate; ITK, interleukin-2-inducible T cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RASGRP, RAS guanyl-releasing protein; SOS, son of sevenless homologue; SYK, spleen tyrosine kinase. (Adapted from GA Koretzky et al: Nat Rev Immunol 6:67, 2006; with permission from Macmillan Publishers Ltd. Copyright 2006.) recognizingand proliferating towhole unprocessed native antigens via antigen binding to B cell–surface Ig (sIg) receptors. B cells also express surface receptors for the Fc region of IgG molecules (CD32) as well as receptors for activated complement components (C3d or CD21, C3b or CD35). The primary function of B cells is to produce antibodies. B cells also serve as APCs and are highly efficient at antigen processing. Their antigen-presenting function is enhanced by a variety of cytokines. Mature B cells are derived


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InternalMed_Harrison. to produce antibodies. B cells also serve as APCs and are highly efficient at antigen processing. Their antigen-presenting function is enhanced by a variety of cytokines. Mature B cells are derived from bone marrow precursor cells that arise continuously throughout life (Fig. 372e-6).


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InternalMed_Harrison. B lymphocyte development can be separated into antigen-independent and antigen-dependent phases. Antigen-independent B cell development occurs in primary lymphoid organs and includes all stages of B cell maturation up to the sIg+ mature B cell. Antigen-dependent B cell maturation is driven by the interaction of antigen with the mature B cell sIg, leading to memory B cell induction, Ig class switching, and plasma cell formation. Antigen-dependent stages of B cell maturation occur in secondary lymphoid organs, including lymph node, spleen, and gut Peyer’s patches. In contrast to the T cell repertoire that is generated intrathymically before contact with foreign antigen, the repertoire of B cells expressing diverse antigen-reactive sites is modified by further alteration of Ig genes after stimulation by antigen—a process called somatic hypermutation—that occurs in lymph node germinal centers.


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InternalMed_Harrison. DuringBcelldevelopment,diversityoftheantigen-bindingvariable region of Ig is generated by an ordered set of Ig gene rearrangements that are similar to the rearrangements undergone by TCR α, β, γ, and δ genes. For the heavy chain, there is first a rearrangement of D segments to J segments, followed by a second rearrangement between a V gene segment and the newly formed D-J sequence; the C segment is aligned to the V-D-J complex to yield a functional Ig heavy chain gene (V-D-J-C). During later stages, a functional κ or γ light chain gene is generated by rearrangement of a V segment to a J segment, ultimately yielding an intact Ig molecule composed of heavy and light chains.


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InternalMed_Harrison. The process of Ig gene rearrangement is regulated and results in a single antibody specificity produced by each B cell, with each Ig molecule comprising one type of heavy chain and one type of light chain. Although each B cell contains two copies of Ig light and heavy chain genes, only one gene of each type is productively rearranged and expressed in each B cell, a process termed allelic exclusion.


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InternalMed_Harrison. Thereare~300Vκgenes and5 Jκgenes,resultinginthe pairingofVκ and Jκ genes to create >1500 different kappa light chain combinations. There are ~70 Vλgenes and 4Jλgenes for >280 different lambda light chain combinations. The number of distinct light chains that can be generated is increased by somatic mutations within the V and J genes, thus creating large numbers of possible specificities from a limited amount of germline genetic information. As noted above, in heavy chain Ig gene rearrangement, the VH domain is created by the joining of three types of germline genes called VH, DH, and JH, thus allowing for even greater diversity in the variable region of heavy chains than of light chains.


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InternalMed_Harrison. The most immature B cell precursors (early pro-B cells) lack cytoplasmic Ig (cIg) andsIg (Fig.372e-6). Thelarge pre-Bcellis marked by theacquisitionofthesurfacepre-BCRcomposedofμheavy (H)chains and a pre-B light chain, termed ψLC. ψLC is a surrogate light chain receptor encoded by the nonrearranged V pre-B and the γ5 light chain locus (the pre-BCR). Pro-and pre-B cells are driven to proliferate and mature by signals from bone marrow stroma—in particular, IL-7. Light chain rearrangement occurs in the small pre-B cell stage such that the full BCR is expressed at the immature B cell stage. Immature B cells have rearranged Ig light chain genes and express sIgM. As immature B cells develop into mature B cells, sIgD is expressed as well as sIgM. At this point, B lineage development in bone marrow is complete,andBcellsexitintotheperipheralcirculationandmigrateto secondary lymphoid organs to encounter specific antigens.


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InternalMed_Harrison. Random rearrangements of Ig genes occasionally generate self-reactive antibodies, and mechanisms must be in place to correct these mistakes. One such mechanism is BCR editing, whereby autoreactive BCRs are mutated to not react with self-antigens. If receptor editing is unsuccessful in eliminating autoreactive B cells, then autoreactive B cellsundergonegativeselectioninthebonemarrowthroughinduction of apoptosis after BCR engagement of self-antigen.


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InternalMed_Harrison. After leaving the bone marrow, B cells populate peripheral B cell sites, such as lymph node and spleen, and await contact with foreign antigens that react with each B cell’s clonotypic receptor. Antigen-driven B cell activation occurs through the BCR, and a process known as somatic hypermutation takes place whereby point mutations in rearranged H-and L-genes give rise to mutant sIg molecules, some of which bind antigen better than the original sIg molecules. Somatic hypermutation, therefore, is a process whereby memory B cells in peripheral lymph organs have the best binding, or the highest-affinity antibodies. This overall process of generating the best antibodies is called affinity maturation of antibody.


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InternalMed_Harrison. Lymphocytes that synthesize IgG, IgA, and IgE are derived from sIgM+, sIgD+ mature B cells. Ig class switching occurs in lymph node and other peripheral lymphoid tissue germinal centers. CD40 on B cells and CD40 ligand on T cells constitute a critical co-stimulatory receptor-ligand pair of immune-stimulatory molecules. Pairs of CD40+ B cells and CD40 ligand+ T cells bind and drive B cell Ig class switching via T cell-produced cytokines such as IL-4 and TGF-β. IL-1, -2, -4, -5, and -6 synergize to drive mature B cells to proliferate and differentiate into Ig-secreting cells.


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InternalMed_Harrison. IL-1, -2, -4, -5, and -6 synergize to drive mature B cells to proliferate and differentiate into Ig-secreting cells. Humoral Mediators of adaptive Immunity: Immunoglobulins Immunoglobulins are the products of differentiated B cells and mediate the humoral arm of the immune response. The primary functions of antibodies are to bind specifically to antigen and bring about the inactivation or removal of the offending toxin, microbe, parasite, or other foreign substance from thebody.ThestructuralbasisofIg moleculefunctionandIggeneorganization has provided insight into the role of antibodies in normal protective immunity, pathologic immune-mediated damage by immune complexes, and autoantibody formation against host determinants.


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InternalMed_Harrison. All immunoglobulins have the basic structure of two heavy and two light chains (Fig. 372e-8). Immunoglobulin isotype (i.e., G, M, A, D, E) is determined by the type of Ig heavy chain present. IgG and IgA isotypes can be divided further into subclasses (G1, G2, G3, G4, and A1, A2) based on specific antigenic determinants on Ig heavy chains. The characteristics of human immunoglobulins are outlined in Table 372e-12. The four chains are covalently linked by disulfide bonds. Each chain is made up of a V region and C regions (also called domains), themselves made up of units of ~110 amino acids. Light chains have one variable (VL) and one constant (CL) unit; heavy chains have one variable unit (VH) and three or four constant (CH) units, depending on isotype. As the name suggests, the constant, or C, regions of Ig molecules are made up of homologous sequences and share the same primary structure as all other Ig chains of the same isotype and subclass. Constant regions are involved in


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InternalMed_Harrison. or C, regions of Ig molecules are made up of homologous sequences and share the same primary structure as all other Ig chains of the same isotype and subclass. Constant regions are involved in biologic functions of Ig molecules. The CH2 domain of IgG and the CH4 units of IgM are involved with the binding of the C1q portion of C1 during complement activation. The CH region at the carboxy-terminal end of the IgG molecule, the Fc region, binds to surface Fc receptors (CD16, CD32, CD64) of macrophages, DCs, NK cells, B cells, neutrophils, and eosinophils. The Fc of IgA binds to FcαR (CD89), and the Fc of IgE binds to FcεR (CD23).


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InternalMed_Harrison. Variable regions (VL and VH) constitute the antibody-binding (Fab) region of the molecule. Within the VL and VH regions are hypervariable regions (extreme sequence variability) that constitute the antigen-binding site unique to each Ig molecule. The idiotype is defined as the specific region of the Fab portion of the Ig molecule to which antigen Introduction to the Immune System taBle 372e 12 phySIcal, chemIcal, and BIologIc propertIeS of human ImmunogloBulInS Source: After L Carayannopoulos, JD Capra, in WE Paul (ed): Fundamental Immunology, 3rd ed. New York, Raven, 1993; with permission. binds. Antibodies againstthe idiotypeportion of an antibody molecule are called anti-idiotype antibodies. The formation of such antibodies in vivo during a normal B cell antibody response may generate a negative (or “off") signal to B cells to terminate antibody production.


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InternalMed_Harrison. IgG constitutes ~75–85% of total serum immunoglobulin. The four IgG subclasses are numbered in order of their level in serum, IgG1 being found in greatest amounts and IgG4 the least. IgG subclasses have clinical relevance in their varying ability to bind macrophage and neutrophil Fc receptors and to activate complement (Table 372e-12). Moreover, selective deficiencies of certain IgG subclasses give rise to clinical syndromes in which the patient is inordinately susceptible to bacterial infections. IgG antibodies are frequently the predominant antibody made after rechallenge of the host with antigen (secondary antibody response).


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InternalMed_Harrison. IgM antibodies normally circulate as a 950-kDa pentamer with 160-kDa bivalent monomers joined by a molecule called the J chain,a 15-kDa nonimmunoglobulin molecule that also effects polymerization of IgA molecules. IgM is the first immunoglobulin to appear in the immune response (primary antibody response) and is the initial type ofantibodymadebyneonates.MembraneIgMinthemonomericform also functions as a major antigen receptor on the surface of mature B cells (Table 372e-12). IgM is an important component of immune complexes in autoimmune diseases. For example, IgM antibodies against IgG molecules (rheumatoid factors) are present in high titers in rheumatoid arthritis, other collagen diseases, and some infectious diseases (subacute bacterial endocarditis).


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InternalMed_Harrison. IgAconstitutesonly7–15%oftotalserumimmunoglobulinbutisthe predominant class of immunoglobulin in secretions. IgA in secretions (tears, saliva, nasal secretions, gastrointestinal tract fluid, and human milk) is in the form of secretory IgA (sIgA), a polymer consisting of two IgA monomers, a joining molecule, again called the J chain, and a glycoprotein called the secretory protein. Of the two IgA subclasses, IgA1 is primarily found in serum, whereas IgA2 is more prevalent in secretions. IgA fixes complement via the alternative complement pathway and has potent antiviral activity in humans by prevention of virus binding to respiratory and gastrointestinal epithelial cells.


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InternalMed_Harrison. IgD is found in minute quantities in serum and, together with IgM, is a major receptor for antigen on the naïve B cell surface. IgE, which is present in serum in very low concentrations, is the major class of immunoglobulin involved in arming mast cells and basophils by binding to these cells via the Fc region. Antigen cross-linking of IgE molecules on basophil and mastcellsurfacesresultsinrelease of mediators of the immediate hypersensitivity (allergic) response (Table 372e-12). The net result of activation of the humoral (B cell) and cellular (T cell) arms of the adaptive immune system by foreign antigen is the elimination of antigen directly by specific effector T cells or in concert with specific antibody. Figure 372e-2 is a simplified schematic diagram of theTandBcellresponsesindicatingsomeofthesecellularinteractions.


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InternalMed_Harrison. The expression of adaptive immune cell function is the result of a complex series of immunoregulatory events that occur in phases. Both T and B lymphocytes mediate immune functions, and each of these cell types, when given appropriate signals, passes through stages, from activation and induction through proliferation, differentiation, and ultimately effector functions. The effector function expressed may be at the end point of a response, such as secretion of antibody by a differentiated plasma cell, or it might serve a regulatory function that modulates other functions, such as is seen with CD4+ and CD8+ T lymphocytes that modulate both differentiation of B cells and activation of CD8+ cytotoxic T cells.


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InternalMed_Harrison. CD4 helper T cells can be subdivided on the basis of cytokines produced (Fig. 372e-2). Activated TH1-type helper T cells secrete IL-2, IFN-γ,IL-3,TNF-a,GM-CSF,andTNF-β,whereasactivatedTH2-type helper T cells secrete IL-3, -4, -5, -6, -10, and -13. TH1 CD4+ T cells, throughelaborationofIFN-γ,haveacentralroleinmediatingintracellular killing by a variety of pathogens. TH1 CD4+ T cells also provide T cell help for generation of cytotoxic T cells and some types of opsonizing antibody, and they generally respond to antigens that lead to delayed hypersensitivity types of immune responses for many intracellular viruses and bacteria (such as HIV or M. tuberculosis). In contrast, TH2 cells have a primary role in regulatory humoral immunity and isotype switching. TH2 cells, through production of IL-4 and IL-10, have a regulatory role in limiting proinflammatory responses mediated by TH1 cells (Fig. 372e-2). In addition, TH2 CD4+ T cells provide help to B cells for specific Ig production and


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InternalMed_Harrison. IL-4 and IL-10, have a regulatory role in limiting proinflammatory responses mediated by TH1 cells (Fig. 372e-2). In addition, TH2 CD4+ T cells provide help to B cells for specific Ig production and respond to antigens that require high antibody levels for foreign antigen elimination (extracellular encapsulated bacteria such as Streptococcus pneumoniae and certain parasite infections). A new subset of the TH family has been described, termedTH17,characterizedascellsthatsecretecytokinessuchasIL-17, -22, and -26. TH17 cells have been shown to play a role in autoimmune inflammatory disorders in addition to defense against extracellular bacteria and fungi, particularly at mucosal surfaces. In summary, the typeofTcellresponsegeneratedinanimmuneresponseisdetermined by the microbe PAMPs presented to the DCs, the TLRs on the DCs that become activated, the types of DCs that are activated, and the cytokines that are produced (Table 372e-4). Commonly, myeloid DCs produce IL-12 and activate TH1 T


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InternalMed_Harrison. to the DCs, the TLRs on the DCs that become activated, the types of DCs that are activated, and the cytokines that are produced (Table 372e-4). Commonly, myeloid DCs produce IL-12 and activate TH1 T cell responses that result in IFN-γ and cytotoxic T cell induction, and plasmacytoid DCs produce IFN-α and lead to TH2 responses that result in IL-4 production and enhanced antibody responses.


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InternalMed_Harrison. As shown in Figs. 372e-2 and 372e-3, upon activation by DCs, T cell subsets that produce IL-2, IL-3, IFN-γ, and/or IL-4, -5, -6, -10, and -13 are generated and exert positive and negative influences on effector T and B cells. For B cells, trophic effects are mediated by a variety of cytokines, particularly T cell–derived IL-3, -4, -5, and -6, that act at sequential stages of B cell maturation, resulting in B cell proliferation, differentiation, and ultimately antibody secretion. For cytotoxic T cells, trophic factors include inducer T cell secretion of IL-2, IFN-γ, and IL-12.


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InternalMed_Harrison. An important type of immunomodulatory T cell that controls immune responses is CD4+ and CD8+ T regulatory cells. These cells constitutively express the α chain of theIL-2receptor(CD25), produce large amounts of IL-10, and can suppress both T and B cell responses. T regulatory cells are induced by immature DCs and play key roles in maintaining tolerance to self-antigens in the periphery. Loss of T regulatory cells is the cause of organ-specific autoimmune disease in mice such as autoimmune thyroiditis, adrenalitis, and oophoritis (see “Immune Tolerance and Autoimmunity” below). T regulatory cells also play key roles in controlling the magnitude and duration of immune responses to microbes. Normally, after the initial immune response to a microbe has eliminated the invader, T regulatory cells are activated to suppress the antimicrobe response and prevent host injury. Some microbes have adapted to induce T regulatory cell activation at the site of infection to promote parasite infection


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InternalMed_Harrison. are activated to suppress the antimicrobe response and prevent host injury. Some microbes have adapted to induce T regulatory cell activation at the site of infection to promote parasite infection and survival. In Leishmania infection, the parasite locally induces T regulatory cell accumulation at skin infection sites that dampens anti-Leishmania T cell responses and prevents elimination of the parasite. It is thought that many chronic infections such as by M. tuberculosis are associated with abnormal T regulatory cell activation that prevents elimination of the microbe.


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InternalMed_Harrison. Although B cells recognize native antigen via B cell–surface Ig receptors, B cells require T cell help to produce high-affinity antibody of multiple isotypes that are the most effective in eliminating foreign antigen. This T cell dependence likely functions in the regulation of B cell responses and in protection against excessive autoantibody production. T cell–B cell interactions that lead to high-affinity antibody production require (1) processing of native antigen by B cells and expression of peptide fragments on the B cell surface for presentation to TH cells, (2) the ligation of B cells by both the TCR complex and the CD40 ligand, (3) induction of the process termed antibody isotype switching in antigen-specific B cell clones, and (4) induction of the process of affinity maturation of antibody in the germinal centers of B cell follicles of lymph node and spleen.


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InternalMed_Harrison. Naïve B cells express cell-surface IgD and IgM, and initial contact of naïve B cells with antigen is via binding of native antigen to B cell– surfaceIgM.Tcellcytokines,releasedfollowingTH2cellcontactwithB cellsorbya“bystander”effect,inducechangesinIggeneconformation that promote recombination of Ig genes. These events then result in the “switching” of expression of heavy chain exons in a triggered B cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody with the same V region antigen specificity as the original IgM antibody, for response to a wide variety of extracellular bacteria, protozoa, and helminths. CD40 ligand expression by activated T cells is critical for induction of B cell antibody isotype switching and for B cell responsiveness to cytokines. Patients with mutations in T cell CD40 ligand haveB cellsthat areunableto undergoisotypeswitching,resulting in lack of memory B cell generation and the immunodeficiency syndrome of X-linked hyper-IgM syndrome


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InternalMed_Harrison. with mutations in T cell CD40 ligand haveB cellsthat areunableto undergoisotypeswitching,resulting in lack of memory B cell generation and the immunodeficiency syndrome of X-linked hyper-IgM syndrome (Chap. 374).


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InternalMed_Harrison. Immune tolerance is defined as the absence of activation of pathogenic autoreactivity. Autoimmune diseases are syndromes caused by theactivation of T or B cells or both, with no evidence of other causes such as infections or malignancies (Chap. 377e). Once thought to be mutually exclusive, immune tolerance and autoimmunity are now both recognized to be present normally in health; when abnormal, they represent extremes from the normal state. For example, it is now known that low levels of autoreactivity of T and B cells with self-antigens in the periphery are critical to their survival. Similarly, low levels of autoreactivity and thymocyte recognition of self-antigens in the thymus are the mechanisms whereby (1) normal T cells are positively selected to survive and leave the thymus to respond to foreign microbes in the periphery and (2) T cells highly reactive to self-antigens are negatively selected and die to prevent overly self-reactive T cells from getting into the periphery


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InternalMed_Harrison. respond to foreign microbes in the periphery and (2) T cells highly reactive to self-antigens are negatively selected and die to prevent overly self-reactive T cells from getting into the periphery (central tolerance). However, not all self-antigens are expressed in the thymus to delete highly self-reactive T cells, and there are mechanisms for peripheral tolerance induction of T cells as well. Unlike the presentation of microbial antigens by mature DCs, the presentation of self-antigens by immature DCs neither activates nor matures the DCs to express high levels of co-stimulatory molecules such as B7-1 (CD80) or B7-2 (CD86). When peripheral T cells are stimulated by DCs expressing self-antigens in the context of HLA molecules, sufficient stimulation of T cells occurs to keep them alive, but otherwise they remain anergic, or nonresponsive, until they contact a DC with high levels of co-stimulatory molecules expressing microbial antigens. In the latter setting, normal T cells then


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InternalMed_Harrison. but otherwise they remain anergic, or nonresponsive, until they contact a DC with high levels of co-stimulatory molecules expressing microbial antigens. In the latter setting, normal T cells then become activated to respond to the microbe. If B cells have high-self-reactivity BCRs, they normally undergo either deletion in the bone marrow or receptoreditingtoexpress a less autoreactivereceptor.Althoughmany autoimmune diseases are characterized by abnormal or pathogenic autoantibody production (Table 372e-13), most autoimmune diseases are caused by a combination of excess T and B cell reactivity.


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InternalMed_Harrison. Multiple factors contribute to the genesis of clinical autoimmune disease syndromes, including genetic susceptibility (Table 372e-13), environmental immune stimulants such as drugs (e.g., procainamide andphenytoin[Dilantin]withdrug-inducedsystemiclupuserythematosus), infectious agent triggers (such as Epstein-Barr virus and auto-antibody production against red blood cells and platelets), and loss of T regulatory cells (leading to thyroiditis, adrenalitis, and oophoritis). Immunity at Mucosal Surfaces Mucosa covering the respiratory, digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and the ducts of all exocrine glands contain cells of the innate and adaptive mucosal immune system that protect these surfaces against pathogens. In the healthy adult, mucosa-associated lymphoid tissue (MALT) contains 80% of all immune cells within the body and constitutes the largest mammalian lymphoid organ system.


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InternalMed_Harrison. MALT has three main functions: (1) to protect the mucous membranes from invasive pathogens; (2) to prevent uptake of foreign antigens from food, commensal organisms, and airborne pathogens and particulate matter; and (3) to prevent pathologic immune responses from foreign antigens if they do cross the mucosal barriers of the body (Fig. 372e-9).


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InternalMed_Harrison. MALT is a compartmentalized system of immune cells that functions independently from systemic immune organs. Whereas the systemic immune organs are essentially sterile under normal conditions and respond vigorously to pathogens, MALT immune cells are continuously bathed in foreign proteins and commensal bacteria, and they must select those pathogenic antigens that must be eliminated. MALT contains anatomically defined foci of immune cells in the intestine, tonsil, appendix, and peribronchial areas that are inductive sites for mucosal immune responses. From these sites, immune T and B cells migrate to effector sites in mucosal parenchyma and exocrine glands where mucosal immune cells eliminate pathogen-infected cells. In addition to mucosal immune responses, all mucosal sites have strong mechanical and chemical barriers and cleansing functions to repel pathogens.


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InternalMed_Harrison. Key components of MALT include specialized epithelial cells called “membrane” or “M” cells that take up antigens and deliver them to DCs or other APCs. Effector cells in MALT include B cells producing antipathogen neutralizing antibodies of secretory IgA as well as IgG isotype, T cells producing similar cytokines as in systemic immune system response, and T helper and cytotoxic T cells that respond to pathogen-infected cells. Secretory IgA is produced in amounts of >50 mg/kg of body weight per 24h and functions toinhibitbacterialadhesion, inhibit macromolecule absorption in the gut, neutralize viruses, and enhance antigen elimination in tissue through binding to IgA and receptor-mediated transport of immune complexes through epithelial cells.


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InternalMed_Harrison. Recent studies have demonstrated the importance of commensal gut and other mucosal bacteria to the health of the human immune system. Normal commensal flora induces anti-inflammatory events in the gut and protects epithelial cells from pathogens through TLRs and other PRR signaling. When the gut is depleted of normal commensal flora, the immune system becomes abnormal, with loss of TH1 T cell function. Restoration of the normal gut flora can reestablish the balance in T helper cell ratios characteristic of the normal immune system. When the gut barrier is intact, either antigens do not transverse the gut epithelium or, when pathogens are present, a self-limited, protectiveMALTimmuneresponse eliminates the pathogen(Fig.372e-9). However, when the gut barrier breaks down, immune responses to commensal flora antigens can cause inflammatory bowel diseases such as Crohn’s disease and, perhaps, ulcerative colitis (Fig. 372e-9) (Chap. 351). Uncontrolled MALT immune responses to food antigens,


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InternalMed_Harrison. commensal flora antigens can cause inflammatory bowel diseases such as Crohn’s disease and, perhaps, ulcerative colitis (Fig. 372e-9) (Chap. 351). Uncontrolled MALT immune responses to food antigens, such as gluten, can cause celiac disease (Chap. 351).


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InternalMed_Harrison. The process of apoptosis (programmed cell death) plays a crucial role in regulating normal immune responses to antigen. In general, a wide variety of stimuli trigger one of several apoptotic pathways to eliminate microbe-infected cells, eliminate cells with damaged DNA, or eliminate activated immune cells that are no longer needed (Fig. 372e-10). The largest known family of “death receptors” is the TNF receptor (TNF-R) family (TNFR1,TNF-R2,Fas[CD95],deathreceptor3[DR3],deathreceptor4[DR4; TNF-related apoptosis-including ligand receptor 1, or TRAIL-R1], and death receptor 5 [DR5, TRAIL-R2]); their ligands are all in the TNF-α family. Binding of ligands to these death receptors leads to a signaling cascade that involves activation of the caspase family of molecules that leads to DNA cleavage and cell death. Two other pathways of programmed cell death involve nuclear p53 in the elimination of cells with abnormal DNA and mitochondrial cytochrome c to induce cell death in damaged cells


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InternalMed_Harrison. and cell death. Two other pathways of programmed cell death involve nuclear p53 in the elimination of cells with abnormal DNA and mitochondrial cytochrome c to induce cell death in damaged cells (Fig. 372e-10). A number of human diseases have now been described that result from, or are associated with, mutated apoptosis genes (Table 372e-14). These include mutations in the Fas and Fas ligand genes in autoimmune and lymphoproliferation syndromes, and multiple associations of mutations in genes in the apoptotic pathway with malignant syndromes.


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InternalMed_Harrison. Several responses by the host innate and adaptive immune systems to foreign microbes culminate in rapid and efficient elimination of microbes. In these scenarios, the classic weapons of the adaptive immunesystem(Tcells,Bcells)interfacewithcells(macrophages,DCs, NK cells, neutrophils, eosinophils, basophils) and soluble products Introduction to the Immune System


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InternalMed_Harrison. Autoantigen Autoimmune Diseases Autoantigen Autoimmune Diseases Cellor Organ-Specific Autoimmunity Acetylcholine receptor Myasthenia gravis Insulin receptor Type B insulin resistance, acanthosis, systemic lupus erythematosus (SLE) Actin Chronic active hepatitis, primary biliary cirrhosis Intrinsic factor type 1 Pernicious anemia Adenine nucleotide translator (ANT) Dilated cardiomyopathy, myocarditis Leukocyte function-associated antigen (LFA-1) Treatment-resistant Lyme arthritis β-Adrenoreceptor Dilated cardiomyopathy Aromatic L-amino acid decarboxylase Autoimmune polyendocrine syndrome type 1 (APS-1) Myelin-associated glycoprotein (MAG) Polyneuropathy Asialoglycoprotein receptor Autoimmune hepatitis Myelin-basic protein Multiple sclerosis, demyelinating diseases Bactericidal/permeability-increasing protein (Bpi) Cystic fibrosis vasculitides Myelin oligodendrocyte glycoprotein (MOG) Multiple sclerosis Calcium-sensing receptor Acquired hypoparathyroidism Myosin Rheumatic fever


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InternalMed_Harrison. protein (Bpi) Cystic fibrosis vasculitides Myelin oligodendrocyte glycoprotein (MOG) Multiple sclerosis Calcium-sensing receptor Acquired hypoparathyroidism Myosin Rheumatic fever Cholesterol side-chain cleavage enzyme (CYPlla) Autoimmune polyglandular syndrome-1 p-80-Collin Atopic dermatitis Collagen type IV-α3-chain Goodpasture’s syndrome Pyruvate dehydrogenase complex-E2 (PDC-E2) Primary biliary cirrhosis Cytochrome P450 2D6 (CYP2D6) Autoimmune hepatitis Desmin Crohn’s disease, coronary artery disease Sodium iodide symporter (NIS) Graves’ disease, autoimmune hypothyroidism Desmoglein 1 Pemphigus foliaceus Desmoglein 3 Pemphigus vulgaris SOX-10 Vitiligo F-actin Autoimmune hepatitis Thyroid and eye muscle shared protein Thyroid-associated ophthalmopathy GM gangliosides Guillain-Barré syndrome Glutamate decarboxylase (GAD65) Type 1 diabetes, stiff-person syndrome Thyroglobulin Autoimmune thyroiditis Glutamate receptor (GLUR) Rasmussen encephalitis Thyroid peroxidase Autoimmune


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InternalMed_Harrison. syndrome Glutamate decarboxylase (GAD65) Type 1 diabetes, stiff-person syndrome Thyroglobulin Autoimmune thyroiditis Glutamate receptor (GLUR) Rasmussen encephalitis Thyroid peroxidase Autoimmune Hashimoto’s thyroiditis H/K ATPase Autoimmune gastritis Thyrotropin receptor Graves’ disease 17-α-Hydroxylase (CYP17) Autoimmune polyglandular syndrome-1 Tissue transglutaminase Celiac disease 21-Hydroxylase (CYP21) Addison’s disease Transcription coactivator p75 Atopic dermatitis IA-2 (ICA512) Type 1 diabetes Tryptophan hydroxylase Autoimmune polyglandular syndrome-1 Insulin Type 1 diabetes, insulin hypoglycemic syndrome (Hirata’s disease) Tyrosinase Tyrosine hydroxylase Vitiligo, metastatic melanoma Autoimmune polyglandular syndrome-1 Systemic Autoimmunity ACTH ACTH deficiency Histone H2A-H2B-DNA Systemic lupus erythematosus Aminoacyl-tRNA histidyl synthetase Myositis, dermatomyositis IgE receptor Chronic idiopathic urticaria Aminoacyl-tRNA synthetase (several) Polymyositis, dermatomyositis


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InternalMed_Harrison. Systemic lupus erythematosus Aminoacyl-tRNA histidyl synthetase Myositis, dermatomyositis IgE receptor Chronic idiopathic urticaria Aminoacyl-tRNA synthetase (several) Polymyositis, dermatomyositis Keratin Rheumatoid arthritis Cardiolipin Systemic lupus erythematosus, antiphospholipid syndrome Ku-DNA-protein kinase Systemic lupus erythematosus Carbonic anhydrase II Systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis Ku-nucleoprotein La phosphoprotein (La 55-B) Connective tissue syndrome Sjögren’s syndrome Collagen (multiple types) Rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis Myeloperoxidase Necrotizing and crescentic glomerulo-nephritis (NCGN), systemic vasculitis Centromere-associated proteins Systemic sclerosis Proteinase 3 (PR3) Granulomatosis with polyangiitis (Wegener’s), Churg-Strauss syndrome DNA-dependent nucleoside-stimulated ATPase Dermatomyositis RNA polymerase I–III (RNP) Systemic sclerosis, systemic lupus


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InternalMed_Harrison. 3 (PR3) Granulomatosis with polyangiitis (Wegener’s), Churg-Strauss syndrome DNA-dependent nucleoside-stimulated ATPase Dermatomyositis RNA polymerase I–III (RNP) Systemic sclerosis, systemic lupus erythematosus Fibrillarin Scleroderma Signal recognition protein (SRP54) Polymyositis Fibronectin Systemic lupus erythematosus, rheumatoid arthritis, morphea Topoisomerase-1 (Scl-70) Scleroderma, Raynaud’s syndrome Glucose-6-phosphate isomerase Rheumatoid arthritis Tublin Chronic liver disease, visceral leishmaniasis β2-Glycoprotein I (B2-GPI) Primary antiphospholipid syndrome Golgin (95, 97, 160, 180) Heat shock protein Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis Various immune-related disorders Vimentin Systemic autoimmune disease Hemidesmosomal protein 180 Bullous pemphigoid, herpes gestationis, cicatricial pemphigoid taBle 372e 13 recomBInant or purIfIed autoantIgenS recognIzed By autoantIBodIeS aSSocIated wIth human autoImmune dISorderS


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InternalMed_Harrison. Autoantigen Autoimmune Diseases Autoantigen Autoimmune Diseases Plasma Protein and Cytokine Autoimmunity C1 inhibitor Autoimmune C1 deficiency Glycoprotein IIb/IIIg and Ib/IX Autoimmune thrombocytopenia purpura C1q Systemic lupus erythematosus, mem-brane proliferative glomerulonephritis (MPGN) IgA Immunodeficiency associated with systemic lupus erythematosus, perni-cious anemia, thyroiditis, Sjögren’s syn-drome, and chronic active hepatitis Cytokines (IL-1α, IL-1β, IL-6, IL-10, LIF) Rheumatoid arthritis, systemic sclerosis, normal subjects Factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, thrombin vWF Prolonged coagulation time Oxidized LDL (OxLDL) Atherosclerosis Cancer and Paraneoplastic Autoimmunity Amphiphysin Neuropathy, small-cell lung cancer p62 (IGF-II mRNA-binding protein) Hepatocellular carcinoma (China) Cyclin B1 Hepatocellular carcinoma Recoverin Cancer-associated retinopathy DNA topoisomerase II Liver cancer Ri protein Paraneoplastic opsoclonus


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InternalMed_Harrison. protein) Hepatocellular carcinoma (China) Cyclin B1 Hepatocellular carcinoma Recoverin Cancer-associated retinopathy DNA topoisomerase II Liver cancer Ri protein Paraneoplastic opsoclonus myoclonus ataxia Desmoplakin Paraneoplastic pemphigus Gephyrin Paraneoplastic stiff-person syndrome βIV spectrin Lower motor neuron syndrome Hu proteins Paraneoplastic encephalomyelitis Synaptotagmin Lambert-Eaton myasthenic syndrome Neuronal nicotinic acetylcholine receptor Subacute autonomic neuropathy, cancer Voltage-gated calcium channels Lambert-Eaton myasthenic syndrome p53 Cancer, systemic lupus erythematosus Yo protein Paraneoplastic cerebellar degeneration taBle 372e 13 recomBInant or purIfIed autoantIgenS recognIzed By autoantIBodIeS aSSocIated wIth human autoImmune dISorderS (CONTINUED)


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InternalMed_Harrison. Source: From A Lernmark et al: J Clin Invest 108:1091, 2001; with permission. FIGUrE 372e-9 Increased epithelial permeability may be important in the development of chronic gut T cell–mediated inflammation. CD4 T cells activated by gut antigens in Peyer’s patches migrate to the lamina propria (LP). In healthy individuals, these cells die by apoptosis. Increased epithelial permeability may allow sufficient antigen to enter the LP to trigger T cell activation, breaking tolerance mediated by immunosuppressive cytokines and perhaps T regulatory cells. Proinflammatory cytokines then further increase epithelial permeability, setting up a vicious cycle of chronic inflammation. (From TT MacDonald et al: Science 307:1920, 2005; with permission.) Introduction to the Immune System (FAS, TNF, TRAIL) (˜ Radiation)


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InternalMed_Harrison. Introduction to the Immune System (FAS, TNF, TRAIL) (˜ Radiation) Death ligand Death Receptor Oxygen radicals DNA injury BIM, PUMA, other BH3-only proteins BCL-XL-BCL2 BCL2-BCL-XL ? BAX FADD Capsase 8 BAK c-FLIP SMAC/DIABLO SMAC/DIABLOCaspase 3 Caspase 9 activation Substrate cleavage ApoptosisApoptosis IAPS IAPS BID APAF1 Cytochrome cCytochrome ctBID


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InternalMed_Harrison. FIGUrE 372e-10 Pathways of cellular apoptosis. There are two major pathways of apoptosis: the death-receptor pathway, which is mediated by activation of death receptors, and the BCL2-regulated mitochondrial pathway, which is mediated by noxious stimuli that ultimately lead to mitochondrial injury. Ligation of death receptors recruits the adaptor protein FAS-associated death domain (FADD). FADD in turn recruits caspase 8, which ultimately activates caspase 3, the key “executioner” caspase. Cellular FLICE-inhibitory protein (c-FLIP) can either inhibit or potentiate binding of FADD and caspase 8, depending on its concentration. In the intrinsic pathway, proapoptotic BH3 proteins are activated by noxious stimuli, which interact with and inhibit antiapoptotic BCL2 or BCL-XL. Thus, BAX and BAK are free to induce mitochondrial permeabilization with release of cytochrome c, which ultimately results in the activation of caspase 9 through the apoptosome. Caspase 9 then activates caspase 3.


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InternalMed_Harrison. BAK are free to induce mitochondrial permeabilization with release of cytochrome c, which ultimately results in the activation of caspase 9 through the apoptosome. Caspase 9 then activates caspase 3. SMAC/DIABLO is also released after mitochondrial permeabilization and acts to block the action of inhibitors of apoptosis protein (IAPs), which inhibit caspase activation. There is potential cross-talk between the two pathways, which is mediated by the truncated form of BID (tBID) that is produced by caspase 8–mediated BID cleavage; tBID acts to inhibit the BCL2-BCL-XL pathway and to activate BAX and BAK. There is debate (indicated by the question mark) as to whether proapoptotic BH3 molecules (e.g., BIM and PUMA) act directly on BAX and BAK to induce mitochondrial permeability or whether they act only on BCL2-BCL-XL. APAF1, apoptotic protease-activating factor 1; BH3, BCL homologue; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand. (From RS Hotchkiss et al: N Engl


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InternalMed_Harrison. act only on BCL2-BCL-XL. APAF1, apoptotic protease-activating factor 1; BH3, BCL homologue; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand. (From RS Hotchkiss et al: N Engl J Med 361:1570, 2009; with permission.) of antigen particles by phagocytosis (by macrophages or neutrophils) or by direct cytotoxic mechanisms (involving macrophages, neutrophils, DCs, and lymphocytes). Under normal circumstances, orderly progression of host defenses through these phases results in a well-controlled immune and inflammatory response that protects the hostfromtheoffendingantigen.However,dysfunction of any of the host defense systems can damage host tissue and produce clinical disease. Furthermore, for certain pathogens or antigens, the normal immune response itself mightcontribute substantially tothetissuedamage. For example, the immune and inflammatory response in the brain to certain pathogens such as M. tuberculosis may be responsible for much of the morbidity rate of


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InternalMed_Harrison. substantially tothetissuedamage. For example, the immune and inflammatory response in the brain to certain pathogens such as M. tuberculosis may be responsible for much of the morbidity rate of this disease in that organ system (Chap. 202). In addition, the morbidity rate associated with certain pneumonias such as that caused by Pneumocystis jiroveci may be associated more with inflammatory infiltrates than with the tissue-destructive effects of the microorganism itself (Chap. 244).


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InternalMed_Harrison. Molecular Basis of Lymphocyte–Endothelial Cell Interactions


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InternalMed_Harrison. The control of lymphocyte circulatory patterns between the bloodstream and peripheral lymphoid organs operates at the level of lymphocyte–endothelial cell interactions to control the specificity of lymphocyte subset entry into organs. Similarly, lymphocyte–endothelial cell interactions regulate the entry of lymphocytes into inflamed tissue. Adhesion molecule expression on lymphocytes and endothelial cells regulates the retention and subsequent egress of lymphocytes within tissue sites of antigenic stimulation, delaying cell exit from tissue and preventingreentryintothe circulatinglymphocyte pool (Fig. 372e-11). All types of lymphocyte migration begin with lymphocyte attachment to specialized regions of vessels, termed high endothelial venules (HEVs). An important concept is that adhesion molecules do not generally bind their ligand until a conformational change (ligand activation) occurs in the adhesion molecule that allows ligand binding. Induction of a conformation-dependent


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InternalMed_Harrison. molecules do not generally bind their ligand until a conformational change (ligand activation) occurs in the adhesion molecule that allows ligand binding. Induction of a conformation-dependent determinant on an adhesion molecule can be accomplished by cytokines or via ligation of other adhesion molecules on the cell.


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InternalMed_Harrison. The first stage of lymphocyte–endothelial cell interactions, attachment and rolling, occurs when lymphocytes leave the stream of flowing blood cells in a postcapillary venule and roll along venule endothelial cells (Fig. 372e-11). Lymphocyte rolling is mediated by the l-selectin molecule (LECAM-1, LAM-1, CD62L) and slows cell transit time through venules, allowing time for activation of adherent cells.


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InternalMed_Harrison. The second stage of lymphocyte–endothelial cell interactions, firm adhesion with activation-dependent stable arrest,requiresstimulation oflymphocytesbychemoattractants or by endothelial cell–derived cytokines. Cytokines thought to participate in adherent cell activation include members of the IL-8 family, platelet-activation factor, leukotriene B4, and C5a. In addition, HEVs express che (microbial peptides, pentraxins, complement and coagulation systems) mokines, SLC (CCL21) and ELC (CCL19), which participate in this of the innate immune system (Chaps. 80 and 376). process. Following activation by chemoattractants, lymphocytes shed


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InternalMed_Harrison. Therearefivegeneralphasesofhostdefenses:(1)migrationofleuko-l-selectin from the cell surface and upregulate cell CD11b/18 (MACcytestositesofantigenlocalization;(2)antigen-nonspecificrecognition 1) or CD11a/18 (LFA-1) molecules, resulting in firm attachment of of pathogens by macrophages and other cells and systems of the innate lymphocytes to HEVs. immune system; (3) specific recognition of foreign antigens mediated Lymphocyte homing to peripheral lymph nodes involves adhesion byTandBlymphocytes;(4)amplificationoftheinflammatoryresponse of l-selectin to glycoprotein HEV ligands collectively referred to as with recruitment of specific and nonspecific effector cells by comple-peripheral node addressin (PNAd), whereas homing of lymphocytes ment components, cytokines, kinins, arachidonic acid metabolites, and to intestine Peyer’s patches primarily involves adhesion of the a4β7 mast cell–basophil products; and (5) macrophage, neutrophil, and lym-integrin to mucosal addressin cell adhesion


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InternalMed_Harrison. metabolites, and to intestine Peyer’s patches primarily involves adhesion of the a4β7 mast cell–basophil products; and (5) macrophage, neutrophil, and lym-integrin to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) phocyte participation in destruction of antigen with ultimate removal on the Peyer’s patch HEVs. However, for migration to mucosal aMany autoimmune diseases are associated with a myriad of major histocompatibility complex gene allele (HLA) types. They are presented here as examples. Abbreviation: MALT, mucosa-associated lymphoid tissue. Source: Adapted from L Mullauer: Mutat Res 488:211, 2001 and A Davidson, B Diamond: N Engl J Med 345:340, 2001.


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InternalMed_Harrison. Introduction to the Immune System Peyer’s patch lymphoid aggregates, naïve lymphocytes primarily use l-selectin, whereas memory lymphocytes use a4β7 integrin. a4β1 integrin (CD49d/CD29, VLA-4)–VCAM-1 interactions are important in the initial interaction of memory lymphocytes with HEVs of multiple organs in sites of inflammation (Table 372e-15).


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InternalMed_Harrison. The third stage of leukocyte emigration in HEVs is sticking and arrest. Sticking of the lymphocyte to endothelial cells and arrest at the site of sticking are mediated predominantly by ligation of a1β2 integrin LFA-1 to the integrin ligand ICAM-1 on HEVs. Whereas the first three stages of lymphocyte attachment to HEVs take only a few seconds, the fourth stage of lymphocyte emigration, transendothelial migration,takes ~10min.Althoughthemolecularmechanismsthatcontrol lymphocyte transendothelial migration are not fully characterized, the HEV CD44 molecule and molecules of the HEV glycocalyx (extracellular matrix) are thought to play important regulatory roles in this process (Fig. 372e-11). Finally, expression of matrix metalloproteases 1. Tethering and rolling 2. Chemokine signal 3. Arrest 4. Polarization and diapedesis 5. Junctional rearrangement 6. Proteolysis 8. DC migration to draining LN 7. Interstitial migration Cytokine-stimulated parenchymal cell Damaged or inflamed tissue


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InternalMed_Harrison. 4. Polarization and diapedesis 5. Junctional rearrangement 6. Proteolysis 8. DC migration to draining LN 7. Interstitial migration Cytokine-stimulated parenchymal cell Damaged or inflamed tissue Basement membrane Lymph vessel DC Blood vesssel lumen


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ECM with GAG chemoattractants

InternalMed_Harrison. ECM with GAG chemoattractants


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InternalMed_Harrison. FIGUrE 372e-11 Key migration steps of immune cells at sites of inflammation. Inflammation due to tissue damage or infection induces the release of cytokines (not shown) and inflammatory chemoattractants (red arrowheads) from distressed stromal cells and “professional” sentinels, such as mast cells and macrophages (not shown). The inflammatory signals induce upregulation of endothelial selectins and immunoglobulin “superfamily” members, particularly ICAM-1 and/or VCAM-1. Chemoattractants, particularly chemokines, are produced by or translocated across venular endothelial cells (red arrow) and are displayed in the lumen to rolling leukocytes. Those leukocytes that express the appropriate set of trafficking molecules undergo a multistep adhesion cascade (steps 1–3) and then polarize and move by diapedesis across the venular wall (steps 4 and 5). Diapedesis involves transient disassembly of endothelial junctions and penetration through the underlying basement membrane (step 6). Once in


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InternalMed_Harrison. by diapedesis across the venular wall (steps 4 and 5). Diapedesis involves transient disassembly of endothelial junctions and penetration through the underlying basement membrane (step 6). Once in the extravascular (interstitial) space, the migrating cell uses different integrins to gain “footholds” on collagen fibers and other ECM molecules, such as laminin and fibronectin, and on inflammation-induced ICAM-1 on the surface of parenchymal cells (step 7). The migrating cell receives guidance cues from distinct sets of chemoattractants, particularly chemokines, which may be immobilized on glycosaminoglycans (GAG) that “decorate” many ECM molecules and stromal cells. Inflammatory signals also induce tissue dendritic cells (DCs) to undergo maturation. Once DCs process material from damaged tissues and invading pathogens, they upregulate CCR7, which allows them to enter draining lymph vessels that express the CCR7 ligand CCL21 (and CCL19). In lymph nodes (LNs), these antigen-loaded mature


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InternalMed_Harrison. and invading pathogens, they upregulate CCR7, which allows them to enter draining lymph vessels that express the CCR7 ligand CCL21 (and CCL19). In lymph nodes (LNs), these antigen-loaded mature DCs activate naïve T cells and expand pools of effector lymphocytes, which enter the blood and migrate back to the site of inflammation. T cells in tissue also use this CCR7-dependent route to migrate from peripheral sites to draining lymph nodes through afferent lymphatics. (Adapted from AD Luster et al: Nat Immunol 6:1182, 2005; with permission from Macmillan Publishers Ltd. Copyright 2005.) capable of digesting the subendothelial basement membrane, rich in nonfibrillar collagen, appears to be required for the penetration of lymphoid cells into the extravascular sites.


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InternalMed_Harrison. AbnormalinductionofHEVformationanduseofthemoleculesdiscussed above have been implicated in the induction and maintenance of inflammation in a number of chronic inflammatory diseases. In animalmodelsoftype1diabetesmellitus,MAdCAM-1andGlyCAM-1 have been shown to be highly expressed on HEVs in inflamed pancreatic islets, and treatment of these animals with inhibitors of l-selectin and a4 integrin function blocked the development of type 1 diabetes mellitus (Chap. 417). A similar role for abnormal induction of the adhesion molecules of lymphocyte emigration has been suggested in rheumatoid arthritis (Chap. 380), Hashimoto’s thyroiditis (Chap. 405), Graves’ disease (Chap. 405), multiple sclerosis (Chap. 458), Crohn’s disease (Chap. 351), and ulcerative colitis (Chap. 351).


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InternalMed_Harrison. Immune-Complex Formation Clearance of antigen by immune-complex formation between antigen, complement, and antibody is a highly effective mechanism of host defense. However, depending on the level of immune complexes formed and their physicochemical properties, immune complexes may or may not result in host and foreign cell damage. After antigen exposure, certain types of soluble antigen-antibody complexes freely circulate and, if not cleared by the reticuloendothelial system, can be deposited in blood vessel walls and in other tissues such as renal glomeruli and cause vasculitis or glomerulonephritis syndromes (Chaps. 338 and 385). Deficiencies of early complement components are associated with inefficient clearance of immune complexes and immune complex mediated tissue damage in autoimmune syndromes, whereas deficiencies of the later complement components are associated with susceptibility to recurrent Neisseria infections (Table 372e-16).


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InternalMed_Harrison. Disease Key Effector Cell L-Selectin, Ligand GPCR Integrina aVarious β1 integrins have been linked in different ways in basal lamina and interstitial migration of distinct cell types and inflammatory settings. LFA-1 VLA-4, LFA-1 VLA-4, LFA-1 VLA-4, LFA-1 bIn some settings, Mac-1 has been linked to transmigration. cCD44 can act in concert with VLA-4 in particular models of leukocyte arrest. dTH2 cells require VAP-1 to traffic to inflamed liver. Source: From AD Luster et al: Nat Immunol 6:1182, 2005; with permission from Macmillan Publishers Ltd. Copyright 2005. Introduction to the Immune System Clq, Clr, Cls, C4 C2 C1 inhibitor Immune-complex syndromes,a pyogenic infections Immune-complex syndromes,a few with pyogenic infections Rare immune-complex disease, few with pyogenic infections


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InternalMed_Harrison. Clq, Clr, Cls, C4 C2 C1 inhibitor Immune-complex syndromes,a pyogenic infections Immune-complex syndromes,a few with pyogenic infections Rare immune-complex disease, few with pyogenic infections Immune-complex syndromes,a pyogenic infections Pyogenic infections Neisseria infections Pyogenic infections Hemolytic-uremic syndrome aImmune-complex syndromes include systemic lupus erythematosus (SLE) and SLE-like syndromes, glomerulonephritis, and vasculitis syndromes. Source: After JA Schifferli, DK Peters: Lancet 322:957, 1983. Copyright 1983, with permission from Elsevier.


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InternalMed_Harrison. Immediate-Type Hypersensitivity Helper T cells that drive antiallergen IgE responses are usually TH2-type inducer T cells that secrete IL-4, IL-5, IL-6, and IL-10. Mast cells and basophils have high-affinity receptors for the Fc portion of IgE (FcRI), and cell-bound antiallergen IgE effectively “arms” basophils and mast cells. Mediator release is triggered by antigen (allergen) interaction with Fc receptor-bound IgE, and the mediators released are responsible for the pathophysiologic changes of allergic diseases (Table 372e-11). Mediators released from mast cells and basophils can be divided into three broad functional types: (1) those that increase vascular permeability and contract smooth muscle (histamine, platelet-activating factor, SRS-A, BK-A), (2) those that are chemotactic for or activate other inflammatory cells (ECF-A, NCF, leukotriene B4), and (3) those that modulate the release of other mediators (BK-A, platelet-activating factor) (Chap. 376).


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InternalMed_Harrison. Cytotoxic reactions of antibody In this type of immunologic injury, complement-fixing (C1-binding) antibodies against normal or foreign cells or tissues (IgM, IgG1, IgG2, IgG3) bind complement via the classic pathway and initiate a sequence of events similar to that initiated by immune-complex deposition, resulting in cell lysis or tissue injury. Examples of antibody-mediated cytotoxic reactions include red cell lysis in transfusion reactions, Goodpasture’s syndrome with anti– glomerular basement membrane antibody formation, and pemphigus vulgaris withantiepidermalantibodiesinducingblisteringskindisease.


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InternalMed_Harrison. Classic Delayed-Type Hypersensitivity reactions Inflammatory reactions initiated by mononuclear leukocytes and not by antibody alone have been termed delayed-type hypersensitivity reactions. The term delayed has been used to contrast a secondary cellular response that appears 48–72 h after antigen exposure with an immediate hypersensitivity response generally seen within 12 h of antigen challenge and initiated by basophil mediator release or preformed antibody. For example, in an individual previously infected with M. tuberculosis organisms, intradermal placement of tuberculin purified protein derivative as a skin test challenge results in an indurated area of skin at 48–72 h, indicating previous exposure to tuberculosis.


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InternalMed_Harrison. The cellular events that result in classic delayed-type hypersensitivity responses are centered on T cells (predominantly, although not exclusively, IFN-γ, IL-2, and TNF-α-secreting TH1-type helper T cells) and macrophages. Recently NK cells have been suggested to play a major role in the form of delayed hypersensitivity that occurs following skin contact with immunogens. First, local immune and inflammatory responses at the site of foreign antigen upregulate endothelial cell adhesion molecule expression, promoting the accumulation of lymphocytes at the tissue site. In the general schemes outlined in Figs. 372e-2 and 372e-3, antigen is processed by DCs and presented to small numbers of CD4+ T cells expressing a TCR specific for the antigen. IL-12 produced by APCs induces T cells to produce IFN-γ (TH1 response). Macrophages frequently undergo epithelioid cell transformation and fuse to form multinucleated giant cells in response to IFN-γ. This type of mononuclear cell infiltrate is


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InternalMed_Harrison. IFN-γ (TH1 response). Macrophages frequently undergo epithelioid cell transformation and fuse to form multinucleated giant cells in response to IFN-γ. This type of mononuclear cell infiltrate is termed granulomatous inflammation. Examples of diseases in which delayed-type hypersensitivity plays a major role are fungal infections (histoplasmosis; Chap. 236), mycobacterial infections (tuberculosis, leprosy; Chaps. 202 and 203), chlamydial infections (lymphogranuloma venereum; Chap. 213), helminth infections (schistosomiasis; Chap. 259), reactions to toxins (berylliosis; Chap. 311), and hypersensitivity reactions to organic dusts (hypersensitivity pneumonitis; Chap. 310). In addition, delayed-type hypersensitivity responses play important roles in tissue damage in autoimmune diseases such as rheumatoid arthritis, temporal arteritis, and granulomatosis with polyangiitis (Wegener’s) (Chaps. 380 and 385).


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InternalMed_Harrison. Clinical assessment of immunity requires investigation of the four major components of the immune system that participate in host defense and in the pathogenesis of autoimmune diseases: (1) humoral immunity (B cells); (2) cell-mediated immunity (T cells, monocytes); (3) phagocytic cells of the reticuloendothelial system (macrophages), as well as polymorphonuclear leukocytes; and (4) complement. Clinical problems that require an evaluation of immunity include chronic infections, recurrent infections, unusual infecting agents, and certain autoimmune syndromes. The type of clinical syndrome under evaluation can provide information regarding possible immune defects (Chap. 374). Defects in cellular immunity generally result in viral, mycobacterial, and fungal infections. An extreme example of deficiency in cellular immunity is AIDS (Chap. 226). Antibody deficiencies result in recurrent bacterial infections, frequently with organisms such as S. pneumoniae and Haemophilus influenzae


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InternalMed_Harrison. of deficiency in cellular immunity is AIDS (Chap. 226). Antibody deficiencies result in recurrent bacterial infections, frequently with organisms such as S. pneumoniae and Haemophilus influenzae (Chap. 374). Disorders of phagocyte function are frequently manifested by recurrent skin infections, often due to Staphylococcus aureus (Chap. 80). Finally, deficiencies of early and late complement components are associated with autoimmune phenomena and recurrent Neisseria infections (Table 372e-16). For further discussion of useful initial screening tests of immune function, see Chap. 374.


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InternalMed_Harrison. Many therapies for autoimmune and inflammatory diseases involve the use of nonspecific immune-modulating or immunosuppressive agents such as glucocorticoids or cytotoxic drugs. The goal of development of new treatments for immune-mediated diseases is to design ways to specifically interrupt pathologic immune responses, leaving nonpathologic immune responses intact. Novel ways to interrupt pathologic immune responses that are under investigation include the use of anti-inflammatory cytokines or specific cytokine inhibitors as anti-inflammatory agents, the use of monoclonal antibodies against T or B lymphocytes as therapeutic agents, the use of intravenous Ig for certain infections and immune complex–mediated diseases, the use of specific cytokines to reconstitute components of the immune system, and bone marrow transplantation to replace the pathogenic immune system with a more normal immune system (Chaps. 80, 374, and 226). In particular, the use of a monoclonal antibody to B cells


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InternalMed_Harrison. system, and bone marrow transplantation to replace the pathogenic immune system with a more normal immune system (Chaps. 80, 374, and 226). In particular, the use of a monoclonal antibody to B cells (rituximab, anti-CD20 MAb) is approved in the United States for the treatment of non-Hodgkin’s lymphoma (Chap. 134) and, in combination with methotrexate, for treatment of adult patients with severe rheumatoid arthritis resistant to TNF-α inhibitors (Chap. 380). The U.S. Food and Drug Administration (FDA) approved the use of CTLA-4 antibodies in 2010 to block T cell anergy for use in cancer immunotherapy, and it was the first agent to demonstrate survival benefit in patients with advanced melanoma. Early-stage clinical trials have now shown that PD-1 blockade to reverse T cell exhaustion can induce tumor regression.


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InternalMed_Harrison. Cell-based therapies have been studied for many years, including ex vivo activation of NK cells for reinfusion into patients with malignancies and DC therapy of ex vivo priming of DCs for enhanced presentationofcancerantigens,withreinfusionofprimedDCsintothepatient. One such strategy for DC therapy has been approved by the FDA for treatment of advanced prostate cancer.


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InternalMed_Harrison. Cytokines and Cytokine Inhibitors Several TNF inhibitors are used as biological therapies in the treatment of rheumatoid arthritis; these include monoclonal antibodies, TNF-R Fc fusion proteins, and Fab fragments. Use of anti-TNF-α antibody therapies such as adalimumab, infliximab, and golimumab has resulted in clinical improvement in patients with these diseases and has opened the way for targeting TNF-α to treat other severe forms of autoimmune and/or inflammatory disease. Blockage of TNF-α has been effective in rheumatoid arthritis, psoriasis, Crohn’s disease, and ankylosing spondylitis. Other cytokine inhibitors are recombinant soluble TNF-α receptor (R) fused to human Ig and anakinra (soluble IL-1 receptor antagonist, or IL-1ra). The treatment of autoinflammatory syndromes (Table 372e-6) with recombinant IL-1 receptor antagonist can prevent symptoms in these syndromes, because the overproduction of IL-1β is a hallmark of these diseases.


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InternalMed_Harrison. TNF-αR-Fc fusion protein (etanercept) and IL-1ra act to inhibit the activity of pathogenic cytokines in rheumatoid arthritis, i.e., TNF-α and IL-1, respectively. Similarly, anti-IL-6, IFN-β, and IL-11 act to inhibit pathogenic proinflammatory cytokines. Anti-IL-6 (tocilizumab) inhibits IL-6 activity, whereas IFN-β and IL-11 decrease IL-1 and TNF-α production. Of particular note has been the successful use of IFN-γ in the treatment of the phagocytic cell defect in chronic granulomatous disease (Chap. 80).


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InternalMed_Harrison. Monoclonal antibodies to T and B Cells The OKT3 MAb against human T cells has been used for several years as a T cell-specific immunosuppressive agent that can substitute for horse antithymocyte globulin (ATG) in the treatment of solid organ transplant rejection. OKT3 produces fewer allergic reactions than ATG but does induce human anti-mouse Ig antibody—thus limiting its use. Anti-CD4 MAb therapy has been used in trials to treat patients with rheumatoid arthritis. While inducing profound immunosuppression, anti-CD4 MAb treatment also induces susceptibility to severe infections. Treatment of patients with a MAb against the T cell molecule CD40 ligand (CD154) is under investigation to induce tolerance to organ transplants, with promising results reported in animal studies. Monoclonal antibodies to the CD25 (IL-2a) receptor (basiliximab) are being used for treatment of graft-versus-host disease in bone marrow transplantation, and anti-CD20 MAb (rituximab) is used to treat hematologic


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InternalMed_Harrison. to the CD25 (IL-2a) receptor (basiliximab) are being used for treatment of graft-versus-host disease in bone marrow transplantation, and anti-CD20 MAb (rituximab) is used to treat hematologic neoplasms, autoimmune diseases, kidney transplant rejection, and rheumatoid arthritis. The anti-IgE monoclonal antibody (omalizumab) is used for blocking antigen-specific IgE that causes hay fever and allergic rhinitis (Chap. 376); however, side effects of anti-IgE include increased risk of anaphylaxis. Studies have shown that TH17 cells, in addition to TH1, are mediators of inflammation in Crohn’s disease, and anti–IL-12/ IL-23p40 antibody therapy has been studied as a treatment.


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InternalMed_Harrison. It is important to realize the potential risks of these immunosuppressive monoclonal antibodies. Natalizumab is a humanized IgG antibody against an a4 integrin that inhibits leukocyte migration into tissues and has been approved for treatment of multiple sclerosis in the United States. Both it and anti-CD20 (rituximab) have been associated with the onset of progressive multifocal leukoencephalopathy (PML)—a serious and usually fatal CNS infection caused by JC polyomavirus. Efalizumab, a humanized IgG monoclonal antibody previously approved for treatment of plaque psoriasis, has now been taken off the market due to reactivation of JC virus leading to fatal PML. Thus, use of any currently approved immunosuppressant immunotherapies should be undertaken with caution and with careful monitoring of patients according to FDA guidelines.


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InternalMed_Harrison. Tolerance Induction Specific immunotherapy has moved into a new erawiththe introduction of solubleCTLA-4 protein intoclinical trials. Use of this molecule to block T cell activation via TCR/CD28 ligation during organ or bone marrow transplantation has showed promising results in animals and in early human clinical trials. Specifically, treatment of bone marrow with CTLA-4 protein reduces rejection of the graft in HLA-mismatched bone marrow transplantation. In addition, promising results with soluble CTLA-4 have been reported in the downmodulation of autoimmune T cell responses in the treatment of psoriasis; and it is being studied for treatment of systemic lupus erythematosus (Chap. 378).


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InternalMed_Harrison. Intravenous Immunoglobulin (IVIg) IVIg has been used successfully to block reticuloendothelial cell function and immune complex clearance in various immune cytopenias such as immune thrombocytopenia (Chap. 140). In addition, IVIg is useful for prevention of tissue damage in certain inflammatory syndromes such as Kawasaki disease (Chap. 385) and as Ig replacement therapy for certain types of immunoglobulin deficiencies (Chap. 374). In addition, controlled clinical trials support the useof IVIginselectedpatientswith graft-versus-host disease, multiple sclerosis, myasthenia gravis, Guillain-Barré syndrome, and chronic demyelinating polyneuropathy.


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InternalMed_Harrison. Stem Cell Transplantation Hematopoietic stem cell transplantation (SCT) is now being comprehensively studied to treat several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and scleroderma. The goal of immune reconstitution in autoimmune disease syndromes is to replace a dysfunctional immune system with a normally reactive immune cell repertoire. Preliminary results in patients with scleroderma and lupus have showed encouraging results. Controlledclinicaltrialsinthesethreediseasesarenowbeinglaunched in the United States and Europe to compare the toxicity and efficacy of conventional immunosuppression therapy with that of myeloablative autologous SCT. Recently, SCT was used in the setting of HIV-1 infection. HIV-1 infection of CD4+ T cells requires the presence of surface CD4 receptor and the chemokine receptor 5 (CCR5) co-receptor. Studies have demonstrated that patients who are homozygous for a 32-bp deletion in the CCR5 allele do not express CD4+ T


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InternalMed_Harrison. of surface CD4 receptor and the chemokine receptor 5 (CCR5) co-receptor. Studies have demonstrated that patients who are homozygous for a 32-bp deletion in the CCR5 allele do not express CD4+ T cell CCR5 and thus are resistant to HIV-1 infection with HIV-1 strains that use this co-receptor. Stem cells from a homozygous CCR5 delta32 donor were transplanted to an HIV-infected patient following standard conditioning for such transplants, and the patient has maintained longterm control of the virus without antiretrovirals. Thus, a number of recentinsightsintoimmune system function havespawned anewfield of interventional immunotherapy and have enhanced the prospect for development of more specific and nontoxic therapies for immune and inflammatory diseases.


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InternalMed_Harrison. Introduction to the Immune System the Major histocompatibility Complex Gerald T. Nepom THE HLA COMPLEX AND ITS PRODUCTS The human major histocompatibility complex (MHC), commonly 373e called the human leukocyte antigen (HLA) complex, is a 4-megabase (Mb) region on chromosome 6 (6p21.3) that is densely packed with expressed genes. The best known of these genes are the HLA class I and class II genes, whose products are critical for immunologic specificity and transplantation histocompatibility, and they play a major role in susceptibility to a number of autoimmune diseases. Many other genes in the HLA region are also essential to the innate and antigen-specific functioning of the immune system. The HLA region shows extensive conservation with the MHC of other mammals in terms of genomic organization, gene sequence, and protein structure and function. The HLA class I genes are located in a 2-Mb stretch of DNA at the telomeric end of the HLA region (Fig. 373e-1). The classic (MHC class


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InternalMed_Harrison. gene sequence, and protein structure and function. The HLA class I genes are located in a 2-Mb stretch of DNA at the telomeric end of the HLA region (Fig. 373e-1). The classic (MHC class Ia) HLA-A, -B, and -C loci, the products of which are integral par-ticipants in the immune response to intracellular infections, tumors, and allografts, are expressed in all nucleated cells and are highly poly-morphic in the population. Polymorphism refers to a high degree of allelic variation within a genetic locus that leads to extensive variation between different individuals expressing different alleles. More than 2000 alleles at HLA-A, nearly 3000 alleles at HLA-B, and more than 1700 at HLA-C have been identified in different human populations, making this the most highly polymorphic segment known within the human genome. Each of the alleles at these loci encodes a heavy chain (also called an α chain) that associates noncovalently with the nonpoly-morphic light chain β2-microglobulin, encoded on


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InternalMed_Harrison. the human genome. Each of the alleles at these loci encodes a heavy chain (also called an α chain) that associates noncovalently with the nonpoly-morphic light chain β2-microglobulin, encoded on chromosome 15. The nomenclature of HLA genes and their products is based on a revised World Health Organization (WHO) nomenclature, in which alleles are given a single designation that indicates locus, allotype, and sequence-based subtype. For example, HLA-A*02:01 indicates subtype 1 of a group of alleles that encode HLA-A2 molecules. Subtypes that differ from each other at the nucleotide but not the amino acid sequence level are designated by an extra numeral (e.g., HLA-B*07:02:01 and HLA-B*07:02:02 are two variants of HLA-B*07:02, both encoding the same HLA-B7 molecule). The nomenclature of class II genes, discussed below, is made more complicated by the fact that both chains of a class II molecule are encoded by closely linked HLA-encoded loci, each of which may be polymorphic, and by the


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InternalMed_Harrison. II genes, discussed below, is made more complicated by the fact that both chains of a class II molecule are encoded by closely linked HLA-encoded loci, each of which may be polymorphic, and by the presence of differing numbers of isotypic DRB loci in different and provides inhibitory signals to both NK cells and T cells, presumably in the service of maintaining maternofetal tol-erance. Pathologic expression in cancer and infections may also deliver a simi-lar inhibitory immunologic function; 16 HLA-G alleles have been identified. The protein product of HLA-F is found mainly intracellularly, and the function of this locus, which encodes four alleles but has multiple transcriptional varia-tions, remains largely unknown. Additional class I–like genes have been identified, some HLA-linked and some encoded on other chromosomes, that show only distant homology to the class Ia and Ib molecules but share the three-dimensional class I structure.


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InternalMed_Harrison. genes have been identified, some HLA-linked and some encoded on other chromosomes, that show only distant homology to the class Ia and Ib molecules but share the three-dimensional class I structure. 0RPS18RXRBDPB2DNADMALMP2TAP1DPB1COLIIA2MICABCTUBBEAGFMOGHFEMICCPOU5F1TCF19DPA2DPA1LMP7DQB1DRB1DRB2DRAC4BLTAMICBC4ACYP21BTAP250010001500200020003000350040002500DMBDOBDQA2RAGELPAATBfC2CK11˜DQB2DQA1DRB3FIgURE 373e-1 Physical map of the HLA region, showing the class I and class II loci, other immu-nologically important loci, and a sampling of other genes mapped to this region. Gene orientation is indicated by arrowheads. Scale is in kilobase (kb). The approximate genetic distance from DP to A is 3.2 cM. This includes 0.8 cM between A and B (including 0.2 cM between C and B), 0.4–0.8 cM between B and DR-DQ, and 1.6–2.0 cM between DR-DQ and DP.


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InternalMed_Harrison. individuals. It has become clear that accurate HLA genotyping requires DNA sequence analysis, and the identification of alleles at the DNA sequence level has contributed greatly to the understanding of the role of HLA molecules as peptide-binding ligands, to the analysis of associations of HLA alleles with certain diseases, to the study of the population genetics of HLA, and to a clearer understanding of the contribution of HLA differences to allograft rejection and graft-versushost disease. Current databases of HLA class I and class II sequences can be accessed by the Internet (e.g., from the IMGT/HLA Database, http://www.ebi.ac.uk/imgt/hla), and frequent updates of HLA gene lists are published in several journals.


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InternalMed_Harrison. The biologic significance of this MHC genetic diversity, resulting in extreme variation in the human population, is evident from the perspective of the structure of MHC molecules. As shown in Fig. 373e-2, the MHC class I and class II genes encode MHC molecules that bind small peptides, and together this complex (pMHC; peptide-MHC) forms the ligand for recognition by T lymphocytes, through the antigen-specific T cell receptor (TCR). There is a direct link between the genetic variation and this structural interaction: The allelic changes in genetic sequence result in diversification of the peptide-binding capabilities of each MHC molecule and in differences for specific TCR binding. Thus, different pMHC complexes bind different antigens and are targets for recognition by different T cells.


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InternalMed_Harrison. The class I MHC and class II MHC structures, shown in Fig. 373e-2 B, C, are structurally closely related; however, there are a few key differences. While both bind peptides and present them to T cells, the binding pockets have different shapes, which influence the types of immune responses that result (discussed below). In addition, there are structural contact sites for T cell molecules known as CD8 and CD4, expressed on the class I or class II membrane-proximal domains, respectively. This ensures that when peptide antigens are presented by class I molecules, the responding T cells are predominantly of the CD8 class, and similarly, that T cells responding to class II pMHC complexes are predominantly CD4.


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InternalMed_Harrison. The nonclassic, or class Ib, MHC molecules, HLA-E, -F, and -G, are much less polymorphic than MHC Ia and appear to have distinct functions. The HLA-E molecule has a peptide repertoire displaying signal peptides cleaved from classic MHC class I molecules and is the major self-recognition target for the natural killer (NK) cell–inhibitory receptors NKG2A or NKG2C paired with CD94 (see below and Chap. 372e). This appears to be a function of immune surveillance, because loss of MHC class I signal peptides serves as a surrogate marker for injured or infected cells, leading to release of the inhibitory signal and subsequent activation of NK cells. HLA-E can also bind and present peptides to CD8 T cells, albeit with a limited scope, as only three HLA-E alleles are known. HLA-G is expressed mainly in stem cells and in extravillous trophoblasts, the fetal cell population directly in contact with maternal tissues. It binds a wide array of peptides, is expressed inLTB six different alternatively


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InternalMed_Harrison. in stem cells and in extravillous trophoblasts, the fetal cell population directly in contact with maternal tissues. It binds a wide array of peptides, is expressed inLTB six different alternatively spliced forms,


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InternalMed_Harrison. Chapter 373e The Major Histocompatibility Complex FIgURE 373e-2 A. The trimolecular complex of TCR (top), MHC molecule (bottom), and a bound peptide form the structural determinants of specific antigen recognition. Other panels (B and C) show the domain structure of MHC class I (B) and class II (C) molecules. The α1 and α2 domains of class I and the α1 and β1 domains of class II form a β-sheet platform that forms the floor of the peptide-binding groove, and α helices that form the sides of the groove. The α3 (B) and β2 domains (C) project from the cell surface and form the contact sites for CD8 and CD4, respectively. (Adapted from EL Reinherz et al: Science 286:1913, 1999; and C Janeway et al: Immunobiology Bookshelf, 2nd ed. Garland Publishing, New York, 1997; with permission.)


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InternalMed_Harrison. Those on chromosome 6p21 include MIC-A and MIC-B, which are encoded centromeric to HLA-B, and HLA-HFE, located 3 to 4 cM (centi-Morgan) telomeric of HLA-F. MIC-A and MIC-B do not bind peptide but are expressed on gut and other epithelium in a stress-inducible manner and serve as activation signals for certain γδ T cells, NK cells, CD8 T cells, and activated macrophages, acting through the activating NKG2D receptors. Ninety-one MIC-A and 40 MIC-B alleles are known, and additional diversification comes from variable alanine repeat sequences in the transmembrane domain. Due to this structural diversity, MIC-A can be recognized as a foreign tissue target during organ transplantation, contributing to graft failure. HLA-HFE encodes the gene defective in hereditary hemochromatosis (Chap. 428). Among the non-HLA, class I–like genes, CD1 refers to a family of molecules that present glycolipids or other nonpeptide ligands to certain T cells, including T cells with NK activity; FcRn binds IgG


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InternalMed_Harrison. Among the non-HLA, class I–like genes, CD1 refers to a family of molecules that present glycolipids or other nonpeptide ligands to certain T cells, including T cells with NK activity; FcRn binds IgG within lysosomes and protects it from catabolism (Chap. 372e); and Zn-α2-glycoprotein 1 binds a nonpeptide ligand and promotes catabolism of triglycerides in adipose tissue. Like the HLA-A, -B, -C, -E, -F, and -G heavy chains, each of which forms a heterodimer with β2-microglobulin (Fig. 373e-2), the class I–like molecules, HLA-HFE, FcRn, and CD1 also bind to β2-microglobulin, but MIC-A, MIC-B, and Zn-α2-glycoprotein 1 do not.


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InternalMed_Harrison. The HLA class II region is also illustrated in Fig. 373e-1. Multiple class II genes are arrayed within the centromeric 1 Mb of the HLA region, forming distinct haplotypes. A haplotype refers to an array of alleles at polymorphic loci along a chromosomal segment. Multiple class II genes are present on a single haplotype, clustered into three major subregions: HLA-DR, -DQ, and -DP. Each of these subregions contains at least one functional alpha (A) locus and one functional beta (B) locus. Together these encode proteins that form the α and β polypeptide chains of a mature class II HLA molecule. Thus, the DRA and DRB genes encode an HLA-DR molecule; DQA and DQB genes encode HLA-DQ molecules; and DPA and DPB genes encode HLA-DP molecules. There are several DRB genes (DRB1, DRB2, DRB3, etc.), so that two expressed DR molecules are encoded on most haplotypes by combining the α-chain product of the DRA gene with separate β chains. More than 1000 alleles have been identified at the HLA-DRB1