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InternalMed_Harrison. 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 locus, with most of the variation occurring within limited segments encoding residues that interact with antigens. Detailed analysis of sequences and population distribution of these alleles strongly suggest that this diversity is actively selected by environmental pressures associated with pathogen diversity. In the DQ region, both DQA1 and DQB1 are polymorphic, with 50 DQA1 alleles and over 300 DQB1 alleles. The current nomenclature is largely analogous to that discussed above for class I, using the convention “locus * allele.”


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InternalMed_Harrison. In addition to allelic polymorphism, products of different DQA alleles can, with some limitations, pair with products of different DQB alleles through both cis and trans pairing to create combinatorial complexity and expand the number of expressed class II molecules. Because of the enormous allelic diversity in the general population, most individuals are heterozygous at all of the class I and class II loci. Thus, most individuals express six classic class I molecules (two each of HLA-A, -B, and -C) and many class II molecules—two DP, two to four DR, and multiple DQ (both cis and trans dimers).


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InternalMed_Harrison. In addition to the class I and class II genes themselves, there are numerous genes interspersed among the HLA loci that have interesting and important immunologic functions. Our current concept of the function of MHC genes now encompasses many of these additional genes, some of which are also highly polymorphic. Indeed, direct comparison of the complete DNA sequences for eight of the entire 4-Mb MHC regions from different haplotypes show >44,000 nucleotide variations, encoding an extremely high potential for biologic diversity, and at least 97 genes located in this region are known to have coding region sequence variation. Specific examples include the TAP and LMP genes, as discussed in more detail below, which encode molecules that participate in intermediate steps in the HLA class I biosynthetic pathway. Another set of HLA genes, DMA and DMB, perform an analogous function for the class II pathway. These genes encode an intracellular molecule that facilitates the proper complexing of


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InternalMed_Harrison. pathway. Another set of HLA genes, DMA and DMB, perform an analogous function for the class II pathway. These genes encode an intracellular molecule that facilitates the proper complexing of HLA class II molecules with antigen (see below). The HLA class III region is a name given to a cluster of genes between the class I and class II complexes, which includes genes for the two closely related cytokines tumor necrosis factor (TNF)-α and lymphotoxin (TNF-β); the complement components C2, C4, and Bf; heat shock protein (HSP) 70; and the enzyme 21-hydroxylase.


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InternalMed_Harrison. The class I genes HLA-A, -B, and -C are expressed in all nucleated cells, although generally to a higher degree on leukocytes than on nonleukocytes. In contrast, the class II genes show a more restricted distribution: HLA-DR and HLA-DP genes are constitutively expressed on most cells of the myeloid cell lineage, whereas all three class II gene families (HLA-DR, -DQ, and -DP) are inducible by certain stimuli provided by inflammatory cytokines such as interferon γ. Within the lymphoid lineage, expression of these class II genes is constitutive on B cells and inducible on human T cells. Most endothelial and epithelial cells in the body, including the vascular endothelium and the intestinal epithelium, are also inducible for class II gene expression, and some cells show specialized expression, such as HLA-DQA2 and HLA-DQB2 on Langerhans cells. While somatic tissues normally express only class I and not class II genes, during times of local inflammation, they are recruited by cytokine


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InternalMed_Harrison. such as HLA-DQA2 and HLA-DQB2 on Langerhans cells. While somatic tissues normally express only class I and not class II genes, during times of local inflammation, they are recruited by cytokine stimuli to express class II genes as well, thereby becoming active participants in ongoing immune responses. Class II expression is controlled largely at the transcriptional level through a conserved set of promoter elements that interact with a protein known as CIITA. Cytokine-mediated induction of CIITA is a principal method by which tissue-specific expression of HLA gene expression is controlled. Other HLA genes involved in the immune response, such as TAP and LMP, are also susceptible to upregulation by signals such as interferon γ.


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InternalMed_Harrison. In addition to extensive polymorphism at the class I and class II loci, another characteristic feature of the HLA complex is linkage disequilibrium. This is formally defined as a deviation from Hardy-Weinberg equilibrium for alleles at linked loci. This is reflected in the very low recombination rates between certain loci within the HLA complex. For example, recombination between DR and DQ loci is almost never observed in family studies, and characteristic haplotypes with particular arrays of DR and DQ alleles are found in every population. Similarly, the complement components C2, C4, and Bf are almost invariably inherited together, and the alleles at these loci are found in characteristic haplotypes. In contrast, there is a recombinational hotspot between DQ and DP, which are separated by 1–2 cM of genetic distance, despite their close physical proximity. Certain extended haplotypes encompassing the interval from DQ into the class I region are commonly found, the most notable being


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InternalMed_Harrison. by 1–2 cM of genetic distance, despite their close physical proximity. Certain extended haplotypes encompassing the interval from DQ into the class I region are commonly found, the most notable being the haplotype DR3-B8-A1, which is found, in whole or in part, in 10–30% of northern European whites. It has been hypothesized that selective pressures may maintain linkage disequilibrium in HLA, but this remains to be determined. As discussed below under HLA and immunologic disease, one consequence of the phenomenon of linkage disequilibrium has been the resulting difficulty in assigning HLA-disease associations to a single allele at a single locus.


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InternalMed_Harrison. Class I and class II molecules display a distinctive structural architecture, which contains specialized functional domains responsible for the unique genetic and immunologic properties of the HLA complex. The principal known function of both class I and class II HLA molecules is to bind antigenic peptides in order to present antigen to an appropriate T cell. The ability of a particular peptide to satisfactorily bind to an individual HLA molecule is a direct function of the molecular fit between the amino acid residues on the peptide with respect to the amino acid residues of the HLA molecule. The bound peptide forms a tertiary structure called the MHC-peptide complex, which communicates with T lymphocytes through binding to the TCR molecule. The first site of TCR-MHC-peptide interaction in the life of a T cell occurs in the thymus, where self-peptides are presented to developing thymocytes by MHC molecules expressed on thymic epithelium and hematopoietically derived


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InternalMed_Harrison. interaction in the life of a T cell occurs in the thymus, where self-peptides are presented to developing thymocytes by MHC molecules expressed on thymic epithelium and hematopoietically derived antigen-presenting cells, which are primarily responsible for positive and negative selection, respectively (Chap. 372e). Thus, the population of MHC–T cell complexes expressed in the thymus shapes the TCR repertoire. Mature T cells encounter MHC molecules in the periphery both in the maintenance of tolerance (Chap. 377e) and in the initiation of immune responses. The MHCpeptide-TCR interaction is the central event in the initiation of most antigen-specific immune responses, since it is the structural determinant of the specificity. For potentially immunogenetic peptides, the ability of a given peptide to be generated and bound by an HLA molecule is a primary feature of whether or not an immune response to that peptide can be generated, and the repertoire of peptides that a particular


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InternalMed_Harrison. given peptide to be generated and bound by an HLA molecule is a primary feature of whether or not an immune response to that peptide can be generated, and the repertoire of peptides that a particular individual’s HLA molecules can bind exerts a major influence over the specificity of that individual’s immune response.


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InternalMed_Harrison. When a TCR molecule binds to an HLA-peptide complex, it forms 373e-3 intermolecular contacts with both the antigenic peptide and with the HLA molecule itself. The outcome of this recognition event depends on the density and duration of the binding interaction, accounting for a dual specificity requirement for activation of the T cell. That is, the TCR must be specific both for the antigenic peptide and for the HLA molecule. The polymorphic nature of the presenting molecules, and the influence that this exerts on the peptide repertoire of each molecule, results in the phenomenon of MHC restriction of the T cell specificity for a given peptide. The binding of CD8 or CD4 molecules to the class I or class II molecule, respectively, also contributes to the interaction between T cell and the HLA-peptide complex, by providing for the selective activation of the appropriate T cell.


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InternalMed_Harrison. (Fig. 373e-2B) As noted above, MHC class I molecules provide a cell-surface display of peptides derived from intracellular proteins, and they also provide the signal for self-recognition by NK cells. Surface-expressed class I molecules consist of an MHC-encoded 44-kD glycoprotein heavy chain, a non-MHC-encoded 12-kD light chain β2-microglobulin, and an antigenic peptide, typically 8–11 amino acids in length and derived from intracellularly produced protein. The heavy chain displays a prominent peptide-binding groove. In HLA-A and -B molecules, the groove is ∼3 nm in length by 1.2 nm in maximumwidth (30 Å × 12 Å), whereas it is apparently somewhat wider in HLA-C. Antigenic peptides are noncovalently bound in an extended conformation within the peptide-binding groove, with both Nand C-terminal ends anchored in pockets within the groove (A and F pockets, respectively) and, in many cases, with a prominent kink, or arch, approximately one-third of the way from the N-terminus that elevates


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InternalMed_Harrison. ends anchored in pockets within the groove (A and F pockets, respectively) and, in many cases, with a prominent kink, or arch, approximately one-third of the way from the N-terminus that elevates the peptide main chain off the floor of the groove.


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InternalMed_Harrison. A remarkable property of peptide binding by MHC molecules is the ability to form highly stable complexes with a wide array of peptide sequences. This is accomplished by a combination of peptide sequence– independent and peptide sequence–dependent bonding. The former consists of hydrogen bond and van der Waals interactions between conserved residues in the peptide-binding groove and charged or polar atoms along the peptide backbone. The latter is dependent upon the six side pockets that are formed by the irregular surface produced by protrusion of amino acid side chains from within the binding groove. The side chains lining the pockets interact with some of the peptide side chains. The sequence polymorphism among different class I alleles and isotypes predominantly affects the residues that line these pockets, and the interactions of these residues with peptide residues constitute the sequence-dependent bonding that confers a particular sequence “motif” on the range of peptides that


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InternalMed_Harrison. line these pockets, and the interactions of these residues with peptide residues constitute the sequence-dependent bonding that confers a particular sequence “motif” on the range of peptides that can bind any given MHC molecule.


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InternalMed_Harrison. (Fig. 373e-3A) The biosynthesis of the classic MHC class I molecules reflects their role in presenting endogenous peptides. The heavy chain is cotranslationally inserted into the membrane of the endoplasmic reticulum (ER), where it becomes glycosylated and associates sequentially with the chaperone proteins calnexin and ERp57. It then forms a complex with β2-microglobulin, and this complex associates with the chaperone calreticulin and the MHC-encoded molecule tapasin, which physically links the class I complex to TAP, the MHC-encoded transporter associated with antigen processing. Meanwhile, peptides generated within the cytosol from intracellular proteins by the multisubunit, multicatalytic proteasome complex are actively transported into the ER by TAP, where they are trimmed by enzymes known as ER aminopeptidases. At this point, peptides with appropriate sequence complementarity bind specific class I molecules to form complete, folded heavy chain–β2microglobulin–peptide trimer


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InternalMed_Harrison. known as ER aminopeptidases. At this point, peptides with appropriate sequence complementarity bind specific class I molecules to form complete, folded heavy chain–β2microglobulin–peptide trimer complexes. These are transported rapidly from the ER, through the cis-and trans-Golgi where the N-linked oligosaccharide is further processed, and thence to the cell surface.


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InternalMed_Harrison. Most of the peptides transported by TAP are produced in the cytosol by proteolytic cleavage of intracellular proteins by the multisubunit, multicatalytic proteasome, and inhibitors of the proteasome dramatically reduce expression of class I–presented antigenic Chapter 373e The Major Histocompatibility Complex To cell surface Endoglycosidase H resistant Asn-linked oligosaccharide Endoglycosidase H sensitive Asn-linked oligosaccharide Degradation? alternative to calnexin Peptide trimming gp96TAP-independent peptides PDI Golgi ER lumen HSP70? HC/ribosome ERp57 HSP90?


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InternalMed_Harrison. FIgURE 373e-3 Biosynthesis of class I (A) and class II (B) molecules. A. Nascent heavy chain (HC) becomes associated with β2-microglobulin (β2m) and peptide through interactions with a series of chaperones. Peptides generated by the proteasome are transported into the endoplasmic reticulum (ER) by TAP. Peptides undergo N-terminal trimming in the ER and become associated with chaperones, including gp96 and PDI. Once peptide binds to HC-β2m, the HC-β2m-peptide trimeric complex exits the ER and is transported by the secretory pathway to the cell surface. In the Golgi, the N-linked oligosaccharide undergoes maturation, with addition of sialic acid residues. Molecules are not necessarily drawn to scale. B. Pathway of HLA class II molecule assembly and antigen processing. After transport through the Golgi and post-Golgi compartment, the class II–invariant chain complex moves to an acidic endosome, where the invariant chain is proteolytically cleaved into fragments and displaced by antigenic


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InternalMed_Harrison. the Golgi and post-Golgi compartment, the class II–invariant chain complex moves to an acidic endosome, where the invariant chain is proteolytically cleaved into fragments and displaced by antigenic peptides, facilitated by interactions with the DMA-DMB chaperone protein. This class II molecule–peptide complex is then transported to the cell surface.


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InternalMed_Harrison. peptides. A thiol-dependent oxidoreductase ERp57, which mediates disulfide bond rearrangements, also appears to play an important role in folding the class I–peptide complex into a stable multicomponent molecule. The MHC-encoded proteasome subunits LMP2 and LMP7 may influence the spectrum of peptides produced but are not essential for proteasome function.


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InternalMed_Harrison. CLASS I FUNCTION Peptide Antigen Presentation On any given cell, a class I molecule occurs in 100,000–200,000 copies and binds several hundred to several thousand distinct peptide species. The vast majority of these peptides are self-peptides to which the host immune system is tolerant by one or more of the mechanisms that maintain tolerance (e.g., clonal deletion in the thymus or clonal anergy or clonal ignorance in the periphery [Chaps. 372e and 377e]). However, class I molecules bearing foreign peptides expressed in a permissive immunologic context activate CD8 T cells, which, if naïve, will then differentiate into cytolytic T lymphocytes (CTLs). These T cells and their progeny, through their αβ TCRs, are then capable of Fas/CD95and/or perforin-mediated cytotoxicity and/or cytokine secretion (Chap. 372e) upon further encounter with the class I–peptide combination that originally activated it, or other structurally related class I–peptide complexes. As alluded to above, this


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InternalMed_Harrison. secretion (Chap. 372e) upon further encounter with the class I–peptide combination that originally activated it, or other structurally related class I–peptide complexes. As alluded to above, this phenomenon by which T cells recognize foreign antigens in the context of specific MHC alleles is termed MHC restriction, and the specific MHC molecule is termed the restriction element. The most common source of foreign peptides presented by class I molecules is viral infection, in the course of which peptides from viral proteins enter the class I pathway. The generation of a strong CTL response that destroys virally infected cells represents an important antigen-specific defense against many viral infections (Chap. 372e). In the case of some viral infections—hepatitis B, for example—CTL-induced target cell apoptosis is thought to be a more important mechanism of tissue damage than any direct cytopathic effect of the virus itself. The importance of the class I pathway in the defense against


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InternalMed_Harrison. target cell apoptosis is thought to be a more important mechanism of tissue damage than any direct cytopathic effect of the virus itself. The importance of the class I pathway in the defense against viral infection is underscored by the identification of a number of viral products that interfere with the normal class I biosynthetic pathway and thus block the immunogenetic expression of viral antigens.


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InternalMed_Harrison. Other examples of intracellularly generated peptides that can be presented by class I molecules in an immunogenic manner include peptides derived from nonviral intracellular infectious agents (e.g., Listeria, Plasmodium), tumor antigens, minor histocompatibility antigens, and certain autoantigens. There are also situations in which cell surface–expressed class I molecules are thought to acquire and present exogenously derived peptides.


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InternalMed_Harrison. HLA Class I Receptors and NK Cell Recognition (Chap. 372e) NK cells, which play an important role in innate immune responses, are activated to cytotoxicity and cytokine secretion by contact with cells that lack MHC class I expression, and NK cell activation is inhibited by cells that express MHC class I. In humans, the recognition of class I molecules by NK cells is carried out by three classes of receptor families, the killer cell–inhibitory cell receptor (KIR) family, the leukocyte Ig-like receptor (LIR) family, and the CD94/NKG2 family. The KIR family, also called CD158, is encoded on chromosome 19q13.4. KIR gene nomenclature is based on the number of domains (2D or 3D) and the presence of long (L) or short (S) cytoplasmic domains. The KIR2DL1 and S1 molecules primarily recognize alleles of HLA-C, which possess a lysine at position 80 (HLA-Cw2, -4, -5, and -6), whereas the KIR2DL2/S2 and KIR2DL3/S3 families primarily recognize alleles of HLA-C with asparagine at this position


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InternalMed_Harrison. alleles of HLA-C, which possess a lysine at position 80 (HLA-Cw2, -4, -5, and -6), whereas the KIR2DL2/S2 and KIR2DL3/S3 families primarily recognize alleles of HLA-C with asparagine at this position (HLA-Cw1, -3, -7, and -8). The KIR3DL1 and S1 molecules predominantly recognize HLA-B alleles that fall into the HLA-Bw4 class determined by residues 77–83 in the α1 domain of the heavy chain, whereas the KIR3DL2 molecule is an inhibitory receptor for HLA-A*03. One of the KIR products, KIR2DL4, is known to be an activating receptor for HLA-G. The most common KIR haplotype in whites contains one activating KIR and six inhibitory KIR genes, although there is a great deal of diversity in the population, with >100 different combinations. It appears that most individuals have at least one inhibitory KIR for a self-HLA class I molecule, providing a structural basis for NK cell target specificity, which helps prevent NK cells from attacking normal cells. The importance of KIR-HLA interactions to


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InternalMed_Harrison. KIR for a self-HLA class I molecule, providing a structural basis for NK cell target specificity, which helps prevent NK cells from attacking normal cells. The importance of KIR-HLA interactions to many immune responses is illustrated by studies associating KIR3DL1 or S1 with multiple sclerosis (Chap. 458), an autoimmune disease, but also with partial protection against HIV (Chap. 226), in both cases consistent with a role for HLA-KIR mediated NK activation. Studies also show an association of KIR2DS1 with protection from relapse following allogeneic bone marrow transplantation in acute myeloid leukemia when these inhibitory receptors in the donors do not recognize the recipient HLA-C.


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InternalMed_Harrison. The LIR gene family (CD85, also called ILT) is encoded centromeric of the KIR locus on 19q13.4, and it encodes a variety of inhibitory immunoglobulin-like receptors expressed on many lymphocyte and other hematopoietic lineages. Interaction of LIR-1 (ILT2) with NK or T cells inhibits activation and cytotoxicity, mediated by many different HLA class I molecules, including HLA-G. HLA-F also appears to interact with LIR molecules, although the functional context for this is not understood.


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InternalMed_Harrison. The third family of NK receptors for HLA is encoded in the NK complex on chromosome 12p12.3-13.1 and consists of CD94 and five NKG2 genes, A/B, C, E/H, D, and F. These molecules are C-type (calcium-binding) lectins, and most function as disulfide-bonded heterodimers between CD94 and one of the NKG2 glycoproteins. The principal ligand of CD94/NKG2A receptors is the HLA-E molecule, complexed to a peptide derived from the signal sequence of classic HLA class I molecules and HLA-G. Thus, analogous to the way in which KIR receptors recognize HLA-C, the NKG2 receptor monitors self–class I expression, albeit indirectly through peptide recognition in the context of HLA-E. NKG2C, -E, and -H appear to have similar specificities but act as activating receptors. NKG2D is expressed as a homodimer and functions as an activating receptor expressed on NK cells, γδ TCR T cells, and activated CD8 T cells. When complexed with an adaptor called DAP10, NKG2D recognizes MIC-A and MIC-B molecules and


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InternalMed_Harrison. and functions as an activating receptor expressed on NK cells, γδ TCR T cells, and activated CD8 T cells. When complexed with an adaptor called DAP10, NKG2D recognizes MIC-A and MIC-B molecules and activates the cytolytic response. NKG2D also binds a class of molecules known as ULBP, structurally related to class I molecules but not encoded in the MHC. The function of NK cells in immune responses is discussed in Chap. 372e.


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InternalMed_Harrison. (Fig. 373e-2C) A specialized functional architecture similar to that of the class I molecules can be seen in the example of a class II molecule depicted in Fig. 373e-2C, with an antigen-binding cleft arrayed above a supporting scaffold that extends the cleft toward the external cellular environment. However, in contrast to the HLA class I molecular structure, β2-microglobulin is not associated with class II molecules. Rather, the class II molecule is a heterodimer, composed of a 29-kD α chain and a 34-kD β chain. The amino-terminal domains of each chain form the antigen-binding elements that, like the class I molecule, cradle a bound peptide in a groove bounded by extended α-helical loops, one encoded by the A (α chain) gene and one by the B (β chain) gene. Like the class I groove, the class II antigen-binding groove is punctuated by pockets that contact the side chains of amino acid residues of the bound peptide, but unlike the class I groove, it is open at both ends. Therefore,


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InternalMed_Harrison. class II antigen-binding groove is punctuated by pockets that contact the side chains of amino acid residues of the bound peptide, but unlike the class I groove, it is open at both ends. Therefore, peptides bound by class II molecules vary greatly in length, since both the Nand C-terminal ends of the peptides can extend through the open ends of this groove. Approximately 11 amino acids 373e-5 within the bound peptide form intimate contacts with the class II molecule itself, with backbone hydrogen bonds and specific side chain interactions combining to provide, respectively, stability and specificity to the binding (Fig. 373e-4).


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InternalMed_Harrison. The genetic polymorphisms that distinguish different class II genes correspond to changes in the amino acid composition of the class II molecule, and these variable sites are clustered predominantly around the pocket structures within the antigen-binding groove. As with class I, this is a critically important feature of the class II molecule, which explains how genetically different individuals have functionally different HLA molecules.


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InternalMed_Harrison. (Fig. 373e-3B) The intracellular assembly of class II molecules occurs within a specialized compartmentalized pathway that differs dramatically from the class I pathway described above. As illustrated in Fig. 373e-3B, the class II molecule assembles in the ER in association with a chaperone molecule, known as the invariant chain. The invariant chain performs at least two roles. First, it binds to the class II molecule and blocks the peptide-binding groove, thus preventing antigenic peptides from binding. This role of the invariant chain appears to account for one of the important differences between class I and class II MHC pathways, since it can explain why class I molecules present endogenous peptides from proteins newly synthesized in the ER but class II molecules generally do not. Second, the invariant chain contains molecular localization signals that direct the class II molecule to traffic into post-Golgi compartments known as endosomes, which develop into specialized acidic


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InternalMed_Harrison. Second, the invariant chain contains molecular localization signals that direct the class II molecule to traffic into post-Golgi compartments known as endosomes, which develop into specialized acidic compartments where proteases cleave the invariant chain, and antigenic peptides can now occupy the class II groove. The specificity and tissue distribution of these proteases appear to be an important way in which the immune system regulates access to the peptide-binding groove and T cells become exposed to specific self-antigens. Differences in protease expression in the thymus and in the periphery may in part determine which specific peptide sequences comprise the peripheral repertoire for T cell recognition. It is at this stage in the intracellular pathway, after cleavage of the invariant chain, that the MHC-encoded DM molecule catalytically facilitates the exchange of peptides within the class II groove to help optimize the specificity and stability of the MHC-peptide complex.


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InternalMed_Harrison. Once this MHC-peptide complex is deposited in the outer cell membrane, it becomes the target for T cell recognition via a specific TCR expressed on lymphocytes. Because the endosome environment contains internalized proteins retrieved from the extracellular environment, the class II–peptide complex often contains bound antigens that were originally derived from extracellular proteins. In this way, the class II peptide–loading pathway provides a mechanism for immune surveillance of the extracellular space. This appears to be an important feature that permits the class II molecule to bind foreign peptides, distinct from the endogenous pathway of class I–mediated presentation.


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InternalMed_Harrison. The development of modern clinical transplantation in the decades since the 1950s provided a major impetus for elucidation of the HLA system, as allograft survival is highest when donor and recipient are HLA-identical. Although many molecular events participate in transplantation rejection, allogeneic differences at class I and class II loci play a major role. Class I molecules can promote T cell responses in several different ways. In the cases of allografts in which the host and donor are mismatched at one or more class I loci, host T cells can be activated by classic direct alloreactivity, in which the antigen receptors on the host T cells react with the foreign class I molecule expressed on the allograft. In this situation, the response of any given TCR may be dominated by the allogeneic MHC molecule, the peptide bound to it, or some combination of the two. Another type of host anti-graft T cell response involves the uptake and processing of donor MHC antigens by host


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InternalMed_Harrison. the allogeneic MHC molecule, the peptide bound to it, or some combination of the two. Another type of host anti-graft T cell response involves the uptake and processing of donor MHC antigens by host antigen-presenting cells and the subsequent presentation of the resulting peptides by host MHC molecules. This mechanism is termed indirect alloreactivity.


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InternalMed_Harrison. Chapter 373e The Major Histocompatibility Complex


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InternalMed_Harrison. P1 Pro P3 Pro P5 Pro P6 Glu P8 Pro P9 Tyr P7 LeuP4 Gln P2 Phe Arg-˜52Tyr-˜22Asn-˜11Asn-˜62Asn-˜69Ser-°30Tyr-˜9Trp-°61Lys-°71Tyr-°9Asn-°82His-°81BCFIgURE 373e-4 Specific intermolecular interactions determine peptide binding to MHC class II molecules. A short peptide sequence derived from alpha-gliadin (A) is accommodated within the MHC class II binding groove by specific interactions between peptide side chains (the P1–P9 residues illustrated in B) and corresponding pockets in the MHC class II structure. The latter are determined by the genetic polymor-phisms of the MHC gene, in this case encoding an HLA-DQ2 molecule (C). This shows the extensive hydrogen bond and salt bridge network, which tightly constrains the pMHC complex and presents the complex of antigen and restriction element for CD4 T cell recognition. (From C Kim et al: Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci USA 101:4175, 2004.)


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InternalMed_Harrison. In the case of class I molecules on allografts that are shared by the host and the donor, a host T cell response may still be triggered because of peptides that are presented by the class I molecules of the graft but not of the host. The most common basis for the existence of these endogenous antigen peptides, called minor histocompatibility antigens, is a genetic difference between donor and host at a non-MHC locus encoding the structural gene for the protein from which the peptide is derived. These loci are termed minor histocompatibility loci, and nonidentical individuals typically differ at many such loci. CD4 T cells react to analogous class II variation, both direct and indirect, and class II differences alone are sufficient to drive allograft rejection.


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InternalMed_Harrison. It has long been postulated that infectious agents provide the driving force for the allelic diversification seen in the HLA system. An important corollary of this hypothesis is that resistance to specific pathogens may differ between individuals, based on HLA genotype. Observations of specific HLA genes associated with resistance to malaria or dengue fever, persistence of hepatitis B, and to disease progression in HIV infection are consistent with this model. For example, failure to clear persistent hepatitis B or C viral infection may reflect the inability of particular HLA molecules to present viral antigens effectively to T cells. Similarly, both protective and susceptible HLA allelic associations have been described for human papilloma virus–associated cervical neoplasia, implicating the MHC as an influence in mediating viral clearance in this form of cancer.


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InternalMed_Harrison. Pathogen diversity is probably also the major selective pressure favoring HLA heterozygosity. The extraordinary scope of HLA allelic diversity increases the likelihood that most new pathogens will be recognized by some HLA molecules, helping to ensure immune fitness to the host. However, another consequence of diversification is that some alleles may become capable of recognition of “innocent bystander” molecules, including drugs, environmental molecules, and tissue-derived self-antigens. In a few instances, single HLA alleles display a strong selectivity for binding of a particular agent that accounts for a genetically determined response: Hypersensitivity to abacavir, an antiretroviral therapeutic, is directly linked to binding of abacavir in the antigen-binding pockets of HLA-B*57:01, where it is buried underneath antigenic peptides and distorts the landscape, changing T cell recognition specificity; an adverse drug reaction to abacavir is more than 500 times more likely to occur


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InternalMed_Harrison. where it is buried underneath antigenic peptides and distorts the landscape, changing T cell recognition specificity; an adverse drug reaction to abacavir is more than 500 times more likely to occur in persons with HLA-B*57:01 than in individuals without this HLA allele. Another example is chronic beryllium toxicity, which is linked to binding of beryllium by HLA-DP molecules with a specific glutamic acid polymorphic residue on the class II beta chain. Even in the case of more complex diseases, particular HLA alleles are strongly associated with certain inappropriate immune-mediated disease states, particularly for some common autoimmune disorders (Chap. 377e). By comparing allele frequencies in patients with any particular disease and in control populations, >100 such associations have been identified, some of which are listed in Table 373e-1. The strength of genetic association is reflected in the term relative risk, which is a statistical odds ratio representing the risk of disease


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InternalMed_Harrison. identified, some of which are listed in Table 373e-1. The strength of genetic association is reflected in the term relative risk, which is a statistical odds ratio representing the risk of disease for an individual carrying a particular genetic marker compared with the risk for individuals in that population without that marker. The nomenclature shown in Table 373e-1 reflects both the HLA serotype (e.g., DR3, DR4) and the HLA genotype (e.g., DRB1*03:01, DRB1*04:01). It very likely the class I and class II alleles themselves are the true susceptibility alleles for most of these associations. However, because of the extremely strong linkage disequilibrium between the DR and DQ loci, in some cases it has been difficult to determine the specific locus or combination of class II loci involved. In some cases, the susceptibility gene may be one of the HLA-linked genes located near the class I or class II region, but not the HLA gene itself, and in other cases, the susceptibility gene may be


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InternalMed_Harrison. In some cases, the susceptibility gene may be one of the HLA-linked genes located near the class I or class II region, but not the HLA gene itself, and in other cases, the susceptibility gene may be a non-HLA gene such as TNF-α, which is nearby. Indeed, since linkage disequilibrium of some haplotypes extends across large segments of the MHC region, it is quite possible that combinations of genes may account for the particular associations of HLA haplotypes with disease. For example, on some haplotypes associated with rheumatoid arthritis, both HLA-DRB1 alleles and a particular polymorphism associated with the TNF locus may be contributory to disease risk. Other candidates for similar epistatic effects include the IKBL gene and the MICA locus, potentially in combination with classic HLA class II risk alleles.


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InternalMed_Harrison. As might be predicted from the known function of the class I and class II gene products, almost all of the diseases associated with specific HLA alleles have an immunologic component to their pathogenesis. The recent development of soluble HLA-peptide recombinant molecules as biological probes of T cell function, often in multivalent complexes referred to as “MHC tetramers,” represents an opportunity to use HLA genetic associations to develop biomarkers for detection of early disease progression. However, it should be stressed that even the strong HLA associations with disease (those associations with relative risk of ≥10) implicate normal, rather than defective, alleles. Most individuals who carry these susceptibility genes do not express the associated disease; in this way, the particular HLA gene is permissive for disease but requires other environmental (e.g., the presence of specific antigens) or genetic factors for full penetrance. In each case studied, even in diseases with


InternalMed_Harrison

InternalMed_Harrison. HLA gene is permissive for disease but requires other environmental (e.g., the presence of specific antigens) or genetic factors for full penetrance. In each case studied, even in diseases with very strong HLA associations, the concordance of disease in mono-zygotic twins is higher than in HLA-identical dizygotic twins or other sibling pairs, indicating that non-HLA genes contribute to susceptibility and can significantly modify the risk attributable to HLA.


InternalMed_Harrison

InternalMed_Harrison. Another group of diseases is genetically linked to HLA, not because of the immunologic function of HLA alleles but rather because they are caused by autosomal dominant or recessive abnormal alleles at loci that happen to reside in or near the HLA region. Examples of these are 21-hydroxylase deficiency (Chap. 406), hemochromatosis (Chap. 428), and spinocerebellar ataxia (Chap. 452).


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InternalMed_Harrison. Although the associations of human disease with particular HLA alleles or haplotypes predominantly involve the class II region, there are also several prominent disease associations with class I alleles. These include the association of Behçet’s disease (Chap. 387) with HLA-B51, psoriasis vulgaris (Chap. 71) with HLA-Cw6, and, most notably, the spondyloarthritides (Chap. 384) with HLA-B27. Twenty-five HLA-B locus alleles, designated HLA-B*27:01–B*27:25, encode the family of 373e-7 B27 class I molecules. All of the subtypes share a common B pocket in the peptide-binding groove—a deep, negatively charged pocket that shows a strong preference for binding the arginine side chain. In addition, B27 is among the most negatively charged of HLA class I heavy chains, and the overall preference is for positively charged peptides. HLA-B*27:05 is the predominant subtype in whites and most other non-Asian populations, and this subtype is very highly associated with ankylosing spondylitis (AS)


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InternalMed_Harrison. is for positively charged peptides. HLA-B*27:05 is the predominant subtype in whites and most other non-Asian populations, and this subtype is very highly associated with ankylosing spondylitis (AS) (Chap. 384), both in its idiopathic form and in association with chronic inflammatory bowel disease or psoriasis vulgaris. It is also associated with reactive arthritis (ReA) (Chap. 384), with other idiopathic forms of peripheral arthritis (undifferentiated spondyloarthropathy), and with recurrent acute anterior uveitis. B27 is found in 50–90% of individuals with these conditions, compared with a prevalence of ∼7% in North American whites.


InternalMed_Harrison

InternalMed_Harrison. It can be concluded that the B27 molecule itself is involved in disease pathogenesis, based on strong evidence from clinical epidemiology and on the occurrence of a spondyloarthropathy-like disease in HLA-B27 transgenic rats. The association of B27 with these diseases may derive from the specificity of a particular peptide or family of peptides bound to B27 or through another mechanism that is independent of the peptide specificity of B27. In particular, HLA-B27 has been shown to form heavy chain homodimers, utilizing the cysteine residue at position 67 of the B57 α chain, in the absence of β2-microglobulin. These homodimers are expressed on the surface of lymphocytes and monocytes from patients with AS, and receptors including KIR3DL1, KIR3DL2, and ILT4 (LILRB2) are capable of binding to them, promoting the activation and survival of cells expressing these receptors. Alternatively, this dimerization “misfolding” of B27 may initiate an intracellular stress signaling response, called


InternalMed_Harrison

InternalMed_Harrison. them, promoting the activation and survival of cells expressing these receptors. Alternatively, this dimerization “misfolding” of B27 may initiate an intracellular stress signaling response, called the unfolded protein response (UPR), capable of modulating immune cell function, possibly in enthesial-resident T cells that act as sensors of damage and environmental stress.


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InternalMed_Harrison. As can be seen in Table 373e-1, the majority of associations of HLA and disease are with class II alleles. Several diseases have complex HLA genetic associations.


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InternalMed_Harrison. Celiac Disease In the case of celiac disease (Chap. 349), it is probable that the HLA-DQ genes are the primary basis for the disease association. HLA-DQ genes present on both the celiac-associated DR3 and DR7 haplotypes include the DQB1*02:01 gene, and further detailed studies have documented a specific class II αβ dimer encoded by the DQA1*05:01 and DQB1*02:01 genes, which appears to account for most of the HLA genetic contribution to celiac disease susceptibility. This specific HLA association with celiac disease may have a straightforward explanation: Peptides derived from the wheat gluten component gliaden are bound to the molecule encoded by DQA1*05:01 and DQB1*02:01 and presented to T cells. Gliaden-derived peptides that are implicated in this immune activation bind the DQ class II dimer best when the peptide contains a glutamine to glutamic acid substitution. It has been proposed that tissue transglutaminase, an enzyme present at increased levels in the intestinal cells of


InternalMed_Harrison

InternalMed_Harrison. II dimer best when the peptide contains a glutamine to glutamic acid substitution. It has been proposed that tissue transglutaminase, an enzyme present at increased levels in the intestinal cells of celiac patients, converts glutamine to glutamic acid in gliadin, creating peptides that are capable of being bound by the DQ2 molecule and presented to T cells.


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InternalMed_Harrison. Pemphigus Vulgaris In the case of pemphigus vulgaris (Chap. 73), there are two HLA genes associated with disease, DRB1*04:02 and DQB1*05:03. Peptides derived from desmoglein-3, an epidermal autoantigen, bind to the DRB1*04:02and DQB1*05:03-encoded HLA molecules, and this combination of specific peptide binding and disease-associated class II molecule is sufficient to stimulate desmogleinspecific T cells. A bullous pemphigoid clinical variant, not involving desmoglein recognition, has been found to be associated with HLADQB1*03:01. Juvenile Arthritis Pauciarticular juvenile arthritis (Chap. 380) is an autoimmune disease associated with genes at the DRB1 locus and also with genes at the DPB1 locus. Patients with both DPB1*02:01 and a Chapter 373e The Major Histocompatibility Complex Juvenile arthritis, pauciarticular


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InternalMed_Harrison. DRB1*04:01, –04, –05 +++ ++ related haplotypes that carry a different DQB1 gene are not. However, the relative risk associated with inheritance of this gene can be modified, depending on other HLA genes present either on the same or a second haplotype. For example, the presence of a DR2-positive haplotype containing a DQB1*06:02 gene is associated with decreased risk. This gene, DQB1*06:02, is considered “protective” for type 1 diabetes. Even some DRB1 genes that can occur on the same haplotype as DQB1*03:02 may modulate risk, so that individuals with the DR4 haplotype that contains DRB1*04:03 are less susceptible to type 1 diabetes than individuals with other DR4-DQB1*03:02 haplotypes. There are some characteristic structural features of the diabetes-associated DQ molecule encoded by DQB1*03:02, particularly the capability for binding peptides that have negatively charged amino acids near their C-termini. This may indicate a role for specific antigenic peptides or T cell interactions


InternalMed_Harrison

InternalMed_Harrison. particularly the capability for binding peptides that have negatively charged amino acids near their C-termini. This may indicate a role for specific antigenic peptides or T cell interactions in the immune response to islet-associated proteins.


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InternalMed_Harrison. Although the presence of a DR3 haplotype in combination with the DR4-DQB1*0302 haplotype is a very high-risk combination for diabetes susceptibility, the specific gene on the DR3 haplotype that is responsible for this synergy is not yet identified. Rheumatoid Arthritis The HLA genes associated with rheumatoid arthritis (RA) (Chap. 380) encode a distinctive sequence of amino acids from codons 67–74 of the DRβ molecule: RA-associated class II molecules carry the sequence LeuLeuGluGlnArgArgAlaAla or LeuLeuGluGlnLysArgAlaAla in this region, whereas non-RA-associated genes carry one or more differences in this region. These residues form a portion of the molecule that lies in the middle of the α-helical portion of the DRB1encoded class II molecule, termed the shared DQA1*05:01 DQB1*02:01 DRB1*04:02 DQB1*05:03 DQB1*03:01 aStrong negative association, i.e., genetic association with protection from diabetes. Abbreviation: GBM, glomerular basement membrane.


InternalMed_Harrison

InternalMed_Harrison. DQA1*05:01 DQB1*02:01 DRB1*04:02 DQB1*05:03 DQB1*03:01 aStrong negative association, i.e., genetic association with protection from diabetes. Abbreviation: GBM, glomerular basement membrane. DRB1 susceptibility allele (usually DRB1*08 or -*05) have a higher relative risk than expected from the additive effect of those genes alone. In juvenile patients with rheumatoid factor–positive polyarticular disease, heterozygotes carrying both DRB1*04:01 and -*04:04 have a relative risk >100, reflecting an apparent synergy in individuals inheriting both of these susceptibility genes. Type 1 Diabetes Mellitus Type 1 (autoimmune) diabetes mellitus (Chap. 417) is associated with MHC genes on more than one haplotype. The presence of both the DR3 and DR4 haplotypes in one individual confers a twentyfold increased risk for type 1 diabetes; the strongest single association is with DQB1*03:02, and all haplotypes that carry a DQB1*03:02 gene are associated with type 1 diabetes, whereas + epitope.


InternalMed_Harrison

InternalMed_Harrison. Multiple sclerosis DR2 DRB1*15:01 + The highest risk for susceptibility to RA comes in individuals who carry both a DR2 DRB5*01:01 ++ DRB1*04:01 and DRB1*04:04 gene. These DR4-positive RA-associated alleles with the shared epitope are most frequent among patients with more severe, erosive disease. ++++ Several mechanisms have been proposed that ++ link the shared epitope to immune reactivity in RA. This portion of the class II molecule may allow preferential binding of an arthritogenic peptide, it may favor the expansion of a type of self-reactive T lymphocyte, or it may itself form part of the pMHC ligand recognized by TCR that initiates synovial tissue recognition.


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InternalMed_Harrison. As noted above, HLA molecules play a key role in the selection and establishment of the antigen-specific T cell repertoire and a major role in the subsequent activation of those T cells during the initiation of an immune response. Precise genetic polymorphisms characteristic of individual alleles dictate the specificity of these interactions and thereby instruct and guide antigen-specific immune events. These same genetically determined pathways are therefore implicated in disease pathogenesis when specific HLA genes are responsible for autoimmune disease susceptibility.


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InternalMed_Harrison. The fate of developing T cells within the thymus is determined by the affinity of interaction between TCR and HLA molecules bearing self-peptides, and thus the particular HLA types of each individual control the precise specificity of the T cell repertoire (Chap. 372e). The primary basis for HLA-associated disease susceptibility may well lie within this thymic maturation pathway. The positive selection of potentially autoreactive T cells, based on the presence of specific HLA susceptibility genes, may establish the threshold for disease risk in a particular individual.


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InternalMed_Harrison. At the time of onset of a subsequent immune response, the primary role of the HLA molecule is to bind peptide and present it to antigen-specific T cells. The HLA complex can therefore be viewed as encoding genetic determinants of precise immunologic activation events. Antigenic peptides that bind particular HLA molecules are capable of stimulating T cell immune responses; peptides that do not bind are not presented to T cells and are not immunogenic. This genetic control of the immune response is mediated by the polymorphic sites within the HLA antigen–binding groove that interact with the bound peptides. In autoimmune and immune-mediated diseases, it is likely that specific tissue antigens that are targets for pathogenic lymphocytes are complexed with the HLA molecules encoded by specific susceptibility 373e-9 alleles. In autoimmune diseases with an infectious etiology, it is likely that immune responses to peptides derived from the initiating pathogen are bound and presented by


InternalMed_Harrison

InternalMed_Harrison. susceptibility 373e-9 alleles. In autoimmune diseases with an infectious etiology, it is likely that immune responses to peptides derived from the initiating pathogen are bound and presented by particular HLA molecules to activate T lymphocytes that play a triggering or contributory role in disease pathogenesis. The concept that early events in disease initiation are triggered by specific HLA-peptide complexes offers some prospects for therapeutic intervention, since it may be possible to design compounds that interfere with the formation or function of specific HLA-peptide– TCR interactions.


InternalMed_Harrison

InternalMed_Harrison. When considering mechanisms of HLA associations with immune response and disease, it is well to remember that just as HLA genetics are complex, so are the mechanisms likely to be heterogeneous. Immune-mediated disease is a multistep process in which one of the HLA-associated functions is to establish a repertoire of potentially reactive T cells, whereas another HLA-associated function is to provide the essential peptide-binding specificity for T cell recognition. For diseases with multiple HLA genetic associations, it is possible that both of these interactions occur and synergize to advance an accelerated pathway of disease. Chapter 373e The Major Histocompatibility Complex 2103 SeC tIOn 1 the IMMune SySteM In health anD DISeaSe ParT 15: Immune-Mediated, Inflammatory, and Rheumatologic Disorders


InternalMed_Harrison

InternalMed_Harrison. Immunity is intrinsic to life and an important tool in the fight for survival against pathogenic microorganisms. The human immune system can be divided into two major components: the innate immune system and the adaptive immune system (Chap. 372e). The innate immune system provides the rapid triggering of inflammatory responses based ontherecognition(atthecellsurfaceorwithincells)ofeithermolecules expressed by microorganisms or molecules that serve as “danger signals” released by cells under attack. These receptor/ligand interactions trigger signaling events that ultimately lead to inflammation. Virtually all cell lineages (not just immune cells) are involved in innate immune responses; however, myeloid cells (i.e., neutrophils and macrophages) play a major role because of their phagocytic capacity. The adaptive immune system operates by clonal recognition of antigens followed by a dramatic expansion of antigen-reactive cells and execution of an immune effector program. Most of the


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InternalMed_Harrison. capacity. The adaptive immune system operates by clonal recognition of antigens followed by a dramatic expansion of antigen-reactive cells and execution of an immune effector program. Most of the effector cells die off rapidly, whereas memory cells persist. Although both T and B lymphocytes recognizedistinctchemicalmoietiesandexecutedistinctadaptiveimmune responses, the latter is largely dependent on the former in generating long-lived humoral immunity. Adaptive responses utilize components of the innate immune system; for example, the antigen-presentation capabilities of dendritic cells help to determine the type of effector response. Not surprisingly, immune responses are controlled by a series of regulatory mechanisms.


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InternalMed_Harrison. Hundreds of gene products have been characterized as effectors or mediators of the immune system (Chap. 372e). Whenever the expression or function of one of these products is genetically impaired (provided the function is nonredundant), a primary immunodeficiency (PID) occurs.


InternalMed_Harrison

InternalMed_Harrison. PIDs are genetic diseases with primarily Mendelian inheritance. More than 250 conditions have now been described, and deleterious mutations in approximately 210 genes have been identified. The overall prevalence of PIDs has been estimated in various countries at 5 per 100,000 individuals; however, given the difficulty in diagnosing these rare and complex diseases, this figure is probably an underestimate. PIDscaninvolveallpossibleaspectsofimmuneresponses,frominnate throughadaptive, cell differentiation,andeffector functionandregulation. For the sake of clarity, PIDs should be classified according to (1) the arm of the immune system that is defective and (2) the mechanism of the defect (when known). Table 374-1 classifies the most prevalent PIDs according to this manner of classification; however, one should bear in mind that the classification of PIDs sometimes involves arbitrary decisions because of overlap and, in some cases, lack of data.


InternalMed_Harrison

InternalMed_Harrison. TheconsequencesofPIDsvarywidelyasafunctionofthemolecules thataredefective.Thisconcepttranslatesintomultiplelevelsofvulnerability to infection by pathogenic and opportunistic microorganisms, ranging from extremely broad (as in severe combined immunodeficiency [SCID]) to narrowly restricted to a single microorganism (as in Mendelian susceptibility to mycobacterial disease [MSMD]). The locations of the sites of infection and the causal microorganisms involved will thus help physicians arrive at proper diagnoses. PIDs can also lead to immunopathologic responses such as allergy (as in Wiskott-Aldrich syndrome), lymphoproliferation, and autoimmunity. A combination infections, and opportunistic infections are generally suggestive of impaired T cell immunity. Skin infec-


InternalMed_Harrison

InternalMed_Harrison. Deficiencies of the Innate Immune System • Phagocytic cells: immune defects (such as chronic granulomatous dis -Impaired production: severe congenital neutropenia (SCN) ease); however, they may also appear in the autosomal -Asplenia dominanthyper-IgEsyndrome. Table 374-2 summarizes adhesion: leukocyte adhesion deficiency (LAD) the laboratory tests that are most frequently used todiag killing: chronic granulomatous disease (CGD) nose a PID. More specific tests (notably genetic tests) are then used to make a definitive diagnosis. • Innate immunity receptors and signal transduction: The PIDs discussed below have been grouped together according to the affected cells and the mecha -Mendelian susceptibility to mycobacterial disease nisms involved (Table 374-1, Fig. 374-1). • Complement deficiencies: -Classical, alternative, and lectin pathways PrIMarY IMMUNODEFICIENCIES OF THE INNaTE IMMUNE SYSTEM


InternalMed_Harrison

InternalMed_Harrison. • Complement deficiencies: -Classical, alternative, and lectin pathways PrIMarY IMMUNODEFICIENCIES OF THE INNaTE IMMUNE SYSTEM Deficiencies of the Adaptive Immune System PIDs of the innate immune system are relatively rare and • T lymphocytes: account for approximately 10% of all PIDs.


InternalMed_Harrison

InternalMed_Harrison. Severe congenital neutropenia (SCN) consists of a group -Impaired survival, migration, Combined immunodeficiencies of inherited diseases that are characterized by severely impaired neutrophil counts (<500 polymorphonuclear DOCK8 deficiency leukocytes [PMN]/μL of blood). The condition is usually CD40 ligand deficiency manifested from birth. SCN may also be cyclic (with a Wiskott-Aldrich syndrome 3-week periodicity), and other neutropenia syndromes can also be intermittent. Although the most frequent inheritance pattern for SCN is autosomal dominant, • B lymphocytes: also exist. Bacterial infections at the interface between the body and the external milieu (e.g., the orifices, wounds, Common variable immunodeficiency (CVID) and the respiratory tract) are common manifestations. IgA deficiency Bacterial infections can rapidly progress through soft Regulatory Defects tissue and are followed by dissemination in the bloodstream. Severe visceral fungal infections can also ensue.


InternalMed_Harrison

InternalMed_Harrison. • Innate immunity Autoinflammatory syndromes (outside the scope of this chapter) The absence of pus is a hallmark of this condition. Diagnosis of SCN requires examination of the bone marrow. Most SCNs are associated with a block in granu- lopoiesis at the promyelocytic stage (Fig. 374-1). SCN has multiple etiologies, and to date, mutations in 11 differ- Autoimmunity and inflammatory diseases (IPEX, ent genes have been identified. Most of these mutations result in isolated SCN, whereas others are syndromic Abbreviations: APECED, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia; AR, auto (Chap. 80). The most frequent forms of SCN are caused somal recessive; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XL, by the premature cell death of granulocyte precursors, as X-linked.


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InternalMed_Harrison. X-linked. observed in deficiencies of GFI1, HAX1, and elastase 2 (ELANE), with the latter accounting for 50% of SCN sufof recurrent infections, inflammation, and autoimmunity can be ferers. Certain ELANE mutations cause cyclic neutropenia syndrome. observed in a number of PIDs, thus creating obvious therapeutic chal-A gain-of-function mutation in the WASP gene (see the section on lenges. Finally, some PIDs increase the risk of cancer, notably but not “Wiskott-Aldrich syndrome” below) causes X-linked SCN, which is exclusively lymphocytic cancers, e.g., lymphoma. also associated with monocytopenia.


InternalMed_Harrison

InternalMed_Harrison. As mentioned above, SCN exposes the patient to life-threatening, disseminated bacterial and fungal infections. Treatment requires care- ful hygiene measures, notably in infants. Later in life, special oral and The most frequent symptom prompting the diagnosis of a PID is the dental care is essential, along with the prevention of bacterial infection presence of recurrent or unusually severe infections. As mentioned by prophylactic administration of trimethoprim/sulfamethoxazole. above, recurrent allergic or autoimmune manifestations may also Subcutaneousinjectionofthecytokinegranulocytecolony-stimulating alert the physician to a possible diagnosis of PID. In such cases, a factor (G-CSF) usually improves neutrophil development and thus detailed account of the subject’s personal and family medical his-prevents infection in most SCN diseases. However, there are two tory should be obtained. It is of the utmost importance to gather as caveats: (1) a few cases of SCN with ELANE mutation are


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InternalMed_Harrison. his-prevents infection in most SCN diseases. However, there are two tory should be obtained. It is of the utmost importance to gather as caveats: (1) a few cases of SCN with ELANE mutation are refractorymuch medical information as possible on relatives and up to several to G-CSF and may require curative treatment via allogeneic hematogenerations of ancestors. In addition to the obvious focus on primary poietic stem cell transplantation (HSCT); and (2) a subset of G-CSFsymptoms, the clinical examination should evaluate the size of lym-treated patients carrying ELANE mutations are at a greater risk of phoid organs and, when appropriate, look for the characteristic signs developing acute myelogenous leukemia associated (in most cases)ofanumberofcomplexsyndromesthatmaybeassociatedwithaPID. withsomaticgain-of-functionmutationsoftheG-CSFreceptorgene.


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InternalMed_Harrison. The performance of laboratory tests should be guided to some extent by the clinical findings. Infections of the respiratory tract aSPLENIa (bronchi, sinuses) mostly suggest a defective antibody response. In Primary failure of the development of a spleen is an extremely rare general, invasive bacterial infections can result from complement diseasethatcanbeeithersyndromic(inIvemarksyndrome)orisolated deficiencies, signaling defects of innate immune responses, asplenia, with an autosomal dominant expression; in the latter case, mutations or defective antibody responses. Viral infections, recurrent Candida in the ribosomal protein SA gene were recently found. Due to the aNormal counts vary with age. For example, the lymphocyte count is between 3000 and 9000/μL of blood below the age of 3 months and between 1500 and 2500/μL in adults.


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InternalMed_Harrison. Abbreviations: ID, immunodeficiency; LAD, leukocyte adhesion deficiency; PMNs, polymorphonuclear leukocytes; SCID, severe combined immunodeficiency; WAS, Wiskott-Aldrich syndrome. absence of natural filtration of microbes in the blood, asplenia predisposes affected individuals to fulminant infections by encapsulated bacteria. Although most infections occur in the first years of life, cases may also arise in adulthood. The diagnosis is confirmed by abdominal ultrasonography and the detection of Howell-Jolly bodies in red blood cells. Effective prophylactic measures (twice-daily oral penicillin and appropriate vaccination programs) usually prevent fatal outcomes.


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InternalMed_Harrison. Recently an immunodeficiency combining monocytopenia and dendritic and lymphoid (B and natural killer [NK]) cell deficiency (DCML), also called monocytopenia with nontuberculous mycobacterial infections (mono-MAC), has been described as a consequence of a dominantmutationinthegene GATA2,atranscriptionfactorinvolved in hematopoiesis. This condition also predisposes to lymphedema, Neutrophil Phagocytosis Phagocytosis Killing ROS production Killing ROS production Adhesion Migration HSC CMP MB SCN WHIM LAD CGD CGD MSMD GM prog. Mono blast Pro mono Pro myelo. myelo. Monocyte Dendritic cells Tissue macrophages Bone Marrow Blood Tissue GATA2 deficiency


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InternalMed_Harrison. FIGUrE 374-1 Differentiation of phagocytic cells and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common myeloid progenitors (CMPs) and then granulocyte-monocyte progenitors (GM-prog.), which, in turn, differentiate into neutrophils (MB: myeloblasts; Promyelo: promyelocytes; myelo: myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets. Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes. Macrophages in tissues kill using the same mechanism. Following activation by interferon γ (not shown here), macrophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. CGD, chronic granulomatous diseases; GATA2, zinc finger


InternalMed_Harrison

InternalMed_Harrison. not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. CGD, chronic granulomatous diseases; GATA2, zinc finger transcription factor; LAD, leukocyte adhesion deficiencies; MSMD, Mendelian susceptibility to mycobacterial disease; SCN, severe congenital neutropenia; WHIM, warts, hypogammaglobulinemia, infections, and myelokathexis.


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InternalMed_Harrison. 2106 myelodysplasia, and acute myeloid leukemia. Infections (bacterial and viral) are life-threatening, thus indicating, together with the malignant risk, HSCT. Leukocyte adhesion deficiency (LAD) consists of three autosomal recessive conditions (LAD I,II, andIII) (Chap. 80). The mostfrequent condition (LAD I) is caused by mutations in the β2 integrin gene; followingleukocyteactivation,β2integrins mediate adhesion toinflamed endothelium expressing cognate ligands. LAD III results from a defect in a regulatory protein (kindlin, also known as Fermt 3) involved in activating the ligand affinity of β2 integrins. The extremely rare LAD II condition is the end result of a defect in selectin-mediated leukocyte rolling that occurs prior to β2 integrin binding. There is a primary defect in fucose transporter such that oligosaccharide selectin ligands are missing in this syndromic condition.


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InternalMed_Harrison. Given that neutrophils are not able to reach infected tissues, LAD renders the individual susceptible to bacterial and fungal infections in a way that is similar to that of patients with SCN. LAD also causes impaired wound healing and delayed loss of the umbilical cord. A diagnosis can be suspected in cases of pus-free skin/tissue infections and massive hyperleukocytosis (>30,000/μL) in the blood (mostly granulocytes). Patients with LAD III also develop bleeding because the β2 integrin in platelets is not functional. Use of immunofluorescence and functional assays to detect β2 integrin can help form a diagnosis. Severe forms of LAD may require HSCT, although gene therapy is also now being considered. Neutrophil-specific granule deficiency (a very rare condition caused by a mutation in the gene for transcription factor C/EBPα) results in a condition that is clinically similar to LAD.


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InternalMed_Harrison. Chronicgranulomatousdiseases(CGDs)arecharacterizedbyimpaired phagocytic killingofmicroorganismsby neutrophils and macrophages (Chap. 80). The incidence is approximately 1 per 200,000 live births. About 70% of cases are associated with X-linked recessive inheritance versusautosomalinheritanceintheremaining30%.CGDcausesdeeptissue bacterial and fungal abscesses in macrophage-rich organs such as the lymph nodes, liver, and lungs. Recurrent skin infections (such as folliculitis) are common and can promptan early diagnosis of CGD. The infectious agents are typically catalase-positive bacteria (such as Staphylococcus aureus and Serratia marcescens) but also include Burkholderia cepacia, pathogenic mycobacteria (in certain regions of the world), and fungi (mainly filamentous molds, such as Aspergillus).


InternalMed_Harrison

InternalMed_Harrison. CGD is caused by defective production of reactive oxygen species (ROS) in the phagolysosome membrane following phagocytosis of microorganisms. It results from the lack of a component of NADPH oxidase (gp91phox or p22phox) or of the associated adapter/activating proteins (p47phox, p67phox, or p40phox) that mediate the transport of electrons into the phagolysosome for creating ROS by interaction with O2. Under normal circumstances, these ROS either directly kill engulfed microorganisms or enable the rise in pH needed to activate the phagosomal proteases that contribute to microbial killing. Diagnosisof CGDisbased onassays ofROSproductionin neutrophils and monocytes (Table 374-2). As its name suggests, CGD is also a granulomatous disease. Macrophage-rich granulomas can often arise in the liver, spleen, and other organs. These are sterile granulomas that cause disease by obstruction (bladder, pylorus, etc.) or inflammation (colitis, restrictive lung disease).


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InternalMed_Harrison. The management of infections in patients with CGD can be a complex process. The treatment of bacterial infections is generally based on combination therapy with antibiotics that are able to penetrate into cells. The treatment of fungal infections requires aggressive, long-term use of antifungals. Inflammatory/granulomatous lesions are usually steroid-sensitive; however, glucocorticoids often contribute to the spread of infections. Hence, there is strong need for new therapeutic options in what is still a poorly understood disease.


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InternalMed_Harrison. The treatment of CGD mostly relies on preventing infections. It has been unambiguously demonstrated that prophylactic usage of trimethoprim/sulfamethoxazole is both well tolerated and highly effective inreducingtheriskofbacterialinfection.Dailyadministrationofazole derivatives (notably itraconazole) also reduces the frequency of fungal complications. Ithaslongbeen suggested thatinterferon γ administration is helpful, although medical experts continue to disagree over this controversial issue. Patients may do reasonably well with prophylaxis and careful management. However, other patients develop severe and persistent fungal infections and/or chronic inflammatory complications that ultimately require HSCT. The latter is an established curative approach for CGD; however, the risk-versus-benefit ratio must be carefullyassessedonacase-by-casebasis.Genetherapyapproachesare also being evaluated.


InternalMed_Harrison

InternalMed_Harrison. This group of diseases is characterized by a defect in the interleukin-12 (IL-12)–interferon (IFN) γ axis (including IL-12p40, IL-12 receptor [R] β1, IFN-γ R1 and R2, STAT1, IRF8 and ISG515 deficiencies), which ultimately leads to impaired IFN-γ-dependent macrophage activation. Both recessive and dominant inheritance modes have been observed. The hallmark of this PID is a specific and narrow vulnerability to tuberculous and nontuberculous mycobacteria. The most severe phenotype (as observed in complete IFN-γ receptor deficiency) is characterized by disseminated infection that can be fatal even when aggressive and appropriate antimycobacterial therapy is applied. In addition to mycobacterial infections, MSMD patients (and particularly those with an IL-12/IL-12 R deficiency) are prone to developing Salmonella infections. Although MSMDs are very rare, they should be considered in any patient with persistent mycobacterial infection. Treatment with IFN-γ may efficiently bypass an


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InternalMed_Harrison. to developing Salmonella infections. Although MSMDs are very rare, they should be considered in any patient with persistent mycobacterial infection. Treatment with IFN-γ may efficiently bypass an IL-12/IL-12R deficiency.


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InternalMed_Harrison. In a certain group of patients with early-onset, invasive Streptococcus pneumoniae infections or (less frequently) Staphylococcus aureus or other pyogenic infections, conventional screening for PIDs does not identify the cause of the defect in host defense. It has been established that these patients carry recessive mutations in genes that encode essential adaptor molecules (IRAK4 and MYD88) involved in the signaling pathways of the majority of known Toll-like receptors (TLRs) (Chap. 372e). Remarkably, susceptibility to infection appears to decrease after the first few years of life—perhaps an indication that adaptive immunity (once triggered by an initial microbial challenge) is then able to prevent recurrent infections.


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InternalMed_Harrison. Certain TLRs (TLR-3, -7, -8, and -9) are involved in the recognition of RNA and DNA and usually become engaged during viral infections. Very specific susceptibility to herpes simplex encephalitis has been described in patients with a deficiency in Unc93b (a molecule associated with TLR-3, -7, -8, and -9 required for correct subcellular localization), TLR-3, or associated signaling molecules TRIF, TBK1, and TRAF3, resulting in defective type I IFN production. The fact that no other TLR deficiencies have been found—despite extensive screening of patients with unexplained, recurrent infections—strongly suggests that these receptors are functionally redundant. Hypomorphic mutations in NEMO/IKK-γ (a member of the NF-κB complex, which is activated downstream of TLR receptors) lead to a complex, variable immunodeficiency and a number of associated features. Susceptibility to both invasive, pyogenic infections and mycobacteria may be observed in this particular setting.


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InternalMed_Harrison. The complement system is composed of a complex cascade of plasma proteins (Chap. 372e) that leads to the deposition of C3b fragments on the surface of particles and the formation of immune complexes that can culminate in the activation of a lytic complex at the bacterial surface. C3 cleavage can be mediated via three pathways: the classic, alternate, and lectin pathways. C3b coats particles as part of the opsonization process that facilitates phagocytosis following binding to cognate receptors. A deficiency in any component of the classic pathway (C1q, C1r, C1s, C4, and C2) can predispose an individual to bacterial infections that are tissue-invasive or that occur in the respiratory tract. Likewise, a C3 deficiency or a deficiency in factor I (a protein that regulates C3 consumption, thus leading to a C3 deficiency due to its absence) also results in the same type of vulnerability to infection. It has recently been reported that a very rare deficiency in ficolin-3 predisposes affected


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InternalMed_Harrison. leading to a C3 deficiency due to its absence) also results in the same type of vulnerability to infection. It has recently been reported that a very rare deficiency in ficolin-3 predisposes affected individuals to bacterial infections. Deficiencies in the alternative pathway (factors D and properdin) are associated with the occurrence of invasive Neisseria infections.


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InternalMed_Harrison. Lastly, deficiencies of any complement component involved in the lytic phase (C5, C6, C7, C8, and, to a lesser extent, C9) predispose affected individuals to systemic infection by Neisseria. This is explainedbythecriticalroleofcomplementinthelysisofthethickcell wall possessed by this class of bacteria. Diagnosisof acomplementdeficiencyrelies primarilyon testingthe status oftheclassicandalternatepathway via functional assays,i.e., the CH50andAP50tests,respectively.Wheneitherpathwayisprofoundly impaired, determination of the status of the relevant components in that pathway enables a precise diagnosis. Appropriate vaccinations and daily administration of oral penicillin are efficient means of preventing recurrent infections. It is noteworthy that several complement deficiencies (in the classic pathway and the lytic phase) may also predispose affected individuals to autoimmune diseases (notably systemic lupus erythematosus; Chap. 378).


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InternalMed_Harrison. T LYMPHOCYTE DEFICIENCIES (TaBLE 374-1, FIGS. 374-2 aND 374-3)


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InternalMed_Harrison. Given the central role of T lymphocytes in adaptive immune responses (Chap. 372e), PIDs involving T cells generallyhaveseverepathologicconsequences;this explains the poor overall prognosis and the need for early diagnosis and the early intervention with appropriate therapy. Several differentiation pathways of T cell effectors have been described, one or all of which may be affected by a given PID (Fig. 374-2). Follicular helper CD4+ T cells in germinal centers are required for T-dependent antibody production, including the generation of Ig class-switched, high-affinity antibodies. CD4+ TH1 cells provide cytokine-dependent (mostly IFN-γ-dependent) help to macrophages for intracellular killing of various microorganisms, including mycobacteria and Salmonella. CD4+ TH2 cells produce IL-4, IL-5, and IL-13 and thus recruit and activate eosinophils and other cells required to fight helminth infections. CD4+ TH17 cells produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and


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InternalMed_Harrison. and IL-13 and thus recruit and activate eosinophils and other cells required to fight helminth infections. CD4+ TH17 cells produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and lungs to fight bacterial and fungal infections. Cytotoxic CD8+ T cells can kill infected cells, notably in the context of viral infections. In addition, certain T cell deficiencies predispose affected individuals to Pneumocystis jiroveci lung infections early in life and to chronic gut/biliary duct/liver infections by Cryptosporidium and related genera later on in life. Lastly, naturally occurring or induced regulatory T cells are essential for controlling inflammation (notably reactivity to commensal bacteria in the gut) and autoimmunity. The role of other T cell subsets with limited T cell receptor (TCR) diversity (such as γδTCR T cells or natural killer T [NKT] cells) in PIDs is less well known; however, these subsets can be defective in certain PIDs, and this finding can sometimes


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InternalMed_Harrison. receptor (TCR) diversity (such as γδTCR T cells or natural killer T [NKT] cells) in PIDs is less well known; however, these subsets can be defective in certain PIDs, and this finding can sometimes contribute to the diagnosis (e.g., NKT cell deficiency in X-linked proliferative syndrome). T cell deficiencies account for approximately 20% of all cases of PID.


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InternalMed_Harrison. Severe Combined Immunodeficiencies Severe combined immunodefi-2107 ciencies (SCIDs) constitute a group of rare PIDs characterized by a profound block in T cell development and thus the complete absence of these cells. The developmental block is always the consequence of an intrinsic deficiency. The incidence of SCID is estimated to be 1 in 50,000 live births. Given the severity of the T cell deficiency, clinical consequences occur early in life (usually within 3 to 6 months of birth). The most frequent clinical manifestations are recurrent oral candidiasis, failure to thrive, and protracted diarrhea and/or acute interstitial pneumonitis caused by Pneumocystis jiroveci (although the latter can also be observed in the first year of life in children with B cell deficiencies). Severe viral infections or invasive bacterial infections can also occur. Patients may also experience complications related to infections caused by live vaccines (notably bacille Calmette-Guérin [BCG]) that may lead


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InternalMed_Harrison. or invasive bacterial infections can also occur. Patients may also experience complications related to infections caused by live vaccines (notably bacille Calmette-Guérin [BCG]) that may lead not only to local and regional infection but also to disseminated infection manifested by fever, splenomegaly, and skin and lytic bone lesions. A scaly skin eruption can be observed in a context of maternal T cell engraftment (see below). A diagnosis of SCID can be suspected based on the patient’s clinical history and, possibly, a family history of deaths in very young children (suggestive of either X-linked or recessive inheritance). Lymphocytopenia is strongly suggestive of SCIDinmorethan90%ofcases (Table 316-2).Theabsenceofathymic shadow on a chest x-ray can also be suggestive of SCID. An accurate diagnosis relies on precise determination of the number of circulating T, B, and NK lymphocytes and their subsets. T cell lymphopenia may be masked in some patients by the presence of maternal T


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InternalMed_Harrison. diagnosis relies on precise determination of the number of circulating T, B, and NK lymphocytes and their subsets. T cell lymphopenia may be masked in some patients by the presence of maternal T cells ˜IFN, etc...


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InternalMed_Harrison. HLH Cytotoxicity Tc ˜IFN, TNF, etc... TH1 ˜IFN, etc... MSMD TH2 IL4, etc... Tyk2 IL17, IL17F, IL17RA STAT1 gof TFh IL21, etc... Treg IL10, TGF°, etc... IL4, cytotoxicity NKT ˜IFN, etc... XLP Myeloid (SAP, XIAP)


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InternalMed_Harrison. FIGUrE 374-2 T cell differentiation, effector pathways, and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give rise to the T cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown. Known T cell effector pathways are indicated, i.e., γδ cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. SCID, severe combined immunodeficiency; ZAP-70, zeta-associated protein deficiency; MHCII, major histocompatibility complex class II deficiency; TAP, TAP1 and TAP2 deficiencies; Orai1, STIM1 deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of


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InternalMed_Harrison. TAP, TAP1 and TAP2 deficiencies; Orai1, STIM1 deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of hyper-IgE syndrome; STAT3, autosomal dominant form of hyper-IgE syndrome; IL17F, IL17RA, STAT1 (gof: gain of function), CMC (chronic mucocutaneous candidiasis), CD40L, ICOS, SAP deficiencies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XLP, X-linked proliferative syndromes.


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InternalMed_Harrison. 2108 Prevention of cell apoptosis DNA replication (purine metabolism) ADA ˜c cytokine-dependent signal ˜c, JAK-3, IL7R˛ Pre TCR/TCR signalling CD45, CD3˝, ˙, ˆ V(D)J recombination Rag-1/-2, Artemis, DNA PKcs, DNA L4, Cernunnos Myeloid compartment Cell survival Adenylate kinase 2 ThymusNK CD8 CD4 B CLP HSC account for 20–30% of SCID cases and result from mutations in genes encoding proteins that mediate the recombination of V(D)J gene elements in T and B cell antigen receptor genes (required for the generation of diversity in antigen recognition). The main deficiencies involve RAG-1, RAG-2, DNA-dependent protein kinase, and Artemis. A less severe (albeit variable) immunologic phenotype can result from other deficiencies in the same pathway, i.e., DNA ligase 4 and Cernunnos deficiencies. Given that these latter factors are involved in DNA repair, these deficiencies also cause developmental defects.


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InternalMed_Harrison. Defective (pre-)t cell receptor signaling in the thymus A selective T cell defect can be caused by a series of rare deficiencies in molecules involved in signaling via the pre-TCR or the TCR. These include deficiencies in CD3 subunits associated with the (pre-)TCR (i.e., CD3δ, ε, and ζ) and CD45.


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InternalMed_Harrison. FIGUrE 374-3 T cell differentiation and severe combined immunodeficiencies (SCIDs). The vertical bars indicate the five mechanisms currently known to lead to SCID. The names of deficient reticular Dysgenesis Reticular dysgeneproteins are indicated in the boxes adjacent to the vertical bars. A broken line means that deficien-sis is an extremely rare form of SCID that cy is partial or involves only some of the indicated immunodeficiencies. ADA, adenosine deaminase causes T and NK deficiencies with severe deficiency; CLPs, common lymphoid progenitors; DNAL4, DNA ligase 4; HSCs, hematopoietic stem neutropenia and sensorineural deafness. cells; NKs, natural killer cells; TCR, T cell receptor. It results from an adenylate kinase 2 deficiency. (derivedfrommaternal-fetalbloodtransfers)thatcannotbeeliminated. Patients with SCID require appropriate care with aggressive anti-Although counts are usually low (<500/μL of blood), higher maternal infective therapies, immunoglobulin replacement, and


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InternalMed_Harrison. Patients with SCID require appropriate care with aggressive anti-Although counts are usually low (<500/μL of blood), higher maternal infective therapies, immunoglobulin replacement, and (when neces-T cell counts may, under some circumstances, initially mask the pres-sary) parenteral nutrition support. In most cases, curative treatment ence of SCID. Thus, screening for maternal cells by using adequate relies on HSCT. Today, HSCT provides a very high curative potential genetic markers should be performed whenever necessary. Inheritance for SCID patients who are otherwise in reasonably good condition. patternanalysisandlymphocytephenotypingcandiscriminatebetween In this regard, neonatal screening, based on quantification of T cell various forms of SCID and provide guidance in the choice of accurate receptor excision circles (TRECs) on a Guthrie card sample, is being molecular diagnostic tests (see below). To date, five distinct causative developed. Gene therapy has been found to be


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InternalMed_Harrison. of accurate receptor excision circles (TRECs) on a Guthrie card sample, is being molecular diagnostic tests (see below). To date, five distinct causative developed. Gene therapy has been found to be successful for cases of mechanismsforSCID(Fig.374-3)havebeenidentified: X-linkedSCID(γcdeficiency)andSCIDcausedbyanADAdeficiency, although toxicity has become an issue in the treatment of the former disease that may now be overcome by use of newly generated vectors.


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InternalMed_Harrison. Deficiency The most frequent SCID phenotype (accounting for Lastly, a third option for the treatment of ADA deficiency consists of 40–50% of all cases) is the absence of both T and NK cells. This out- enzyme substitution with a pegylated enzyme.


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InternalMed_Harrison. come results from a deficiency in either the common γ chain (γc) receptor that is shared by several cytokine receptors (the IL-2, -4, -7, Thymic Defects A profound T cell defect can also result from faulty -9, -15, and -21 receptors) or Jak-associated kinase (JAK) 3 that binds development of the thymus, as is most often observed in rare cases to the cytoplasmic portion of the γc chain receptor and induces signal of DiGeorge syndrome—a relatively common condition leading to a transduction following cytokine binding. The former form of SCID constellation of developmental defects. In approximately 1% of such (γc deficiency) has an X-linked inheritance mode, while the second is cases, the thymus is completely absent, leading to virtually no mature autosomal recessive. A lack of the IL-7Rα chain (which, together with T cells. However, expansion of oligoclonal T cells can occur and is γc, forms the IL-7 receptor) induces a selective T cell deficiency. associated with skin lesions. Diagnosis


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InternalMed_Harrison. (which, together with T cells. However, expansion of oligoclonal T cells can occur and is γc, forms the IL-7 receptor) induces a selective T cell deficiency. associated with skin lesions. Diagnosis (using immunofluorescence in situ hybridization) is based on the identification of a hemizygouspurine metabolism Deficiency Ten to 20% of SCID patients exhibit deletion in the long arm of chromosome 22. To recover the capability a deficiency in adenosine deaminase (ADA), an enzyme of purine for T cell differentiation, these cases require a thymic graft. CHARGE metabolism that deaminates adenosine (ado) and deoxyadenosine (colobomaoftheeye,heartanomaly,choanal atresia,retardation, geni(dAdo). An ADA deficiency results in the accumulation of ado and tal and ear anomalies) syndrome (CHD7 deficiency) is a less frequent dAdo metabolites that induce premature cell death of lymphocyte pro-cause of impaired thymus development. Lastly, the very rare “nude”


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InternalMed_Harrison. and ear anomalies) syndrome (CHD7 deficiency) is a less frequent dAdo metabolites that induce premature cell death of lymphocyte pro-cause of impaired thymus development. Lastly, the very rare “nude” genitors.TheconditionresultsintheabsenceofBandNKlymphocytes defectischaracterizedbytheabsenceofbothhairandthethymus. as well as T cells. The clinical expression of complete ADA deficiency


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InternalMed_Harrison. Omenn Syndrome Omenn syndrome consists of a subset of T cell defi typically occurs very early in life. Since ADA is a ubiquitous enzyme, ciencies that present with a unique phenotype, including early-onset its deficiency can also cause bone dysplasia with abnormal costochonerythrodermia, alopecia, hepatosplenomegaly, and failure to thrive. dral junctions and metaphyses (found in 50% of cases) and neurologic These patients usually display T cell lymphocytosis, eosinophilia, and defects. The very rare purine nucleoside phosphorylase (PNP) defilow B cell counts. It has been found that the T cells of these patients ciency causes a profound although incomplete T cell deficiency that is exhibit a low TCR heterogeneity. This peculiar syndrome is the con-often associated with severe neurologic impairments.


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InternalMed_Harrison. sequence of hypomorphic mutations in genes usually associated with Defective rearrangements of t anD b cell receptors A series of SCID SCID, i.e., RAG-1, RAG-2, or (less frequently) Artemis or IL-7Rα. conditions are characterized by a selective deficiency in T and B The impaired homeostasis of differentiating T cells thus causes this lymphocytes with autosomal recessive inheritance. These conditions immune system–associated disease. These patients are very fragile, requiringsimultaneousanti-infectivetherapy,nutritionalsupport,and immunosuppression. HSCT provides a curative approach.


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InternalMed_Harrison. Functional T Cell Defects (Fig. 374-2) AsubsetofTcellPIDswithautosomal inheritance is characterized by partially preserved T cell differentiation but defective activation resulting in abnormal effector function. There are many causes of these defects, but all lead to susceptibility to viral and opportunistic infections, chronic diarrhea, and failure to thrive, with onset during childhood. Careful phenotyping and in vitro functional assays are required to identify these diseases, the best characterized of which are the following. Zeta-associateD protein 70 (Zap70) Deficiency Zeta-associated protein 70 (ZAP70) is recruited to the TCR following antigen recognition. A ZAP70 deficiency leads typically to an almost complete absence of CD8+ T cells; CD4+ T cells arepresent but cannot be activated in vitro by TCR stimulation.


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InternalMed_Harrison. calcium signaling Defects A small number of patients have been reported who exhibit a profound defect in in vitro T and B cell activation as a result of defective antigen receptor-mediated Ca2+ influx. This defect is caused by a mutation in the calcium channel gene (ORAI-) or its activator (STIM-1). It is noteworthy that these patients are also prone to autoimmune manifestations (blood cytopenias) and exhibit a nonprogressive muscle disease. human leukocyte antigen (hla) class ii Deficiency Defective expression of HLAclassIImoleculesisthehallmarkofagroupoffourrecessivegenetic defects all of which affect molecules (RFX5, RFXAP, RFXANK, and CIITA) involved in the transactivation of the genes coding for HLA class


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InternalMed_Harrison. II. As a result, low but variable CD4+ T cell counts are observed in addition to defective antigen-specific T and B cell responses. These patients are particularly susceptible to herpesvirus, adenovirus, and enterovirus infections and chronic gut/liver Cryptosporidium infections. hla class i Deficiency Defective expression of molecules involved in antigen presentation by HLA class I molecules (i.e., TAP-1, TAP-2, and Tapasin) leads to reduced CD8+ T cell counts, loss of HLA class I antigen expression, and a particular phenotype consisting of chronic obstructive pulmonary disease and severe vasculitis.


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InternalMed_Harrison. other Defects A variety of other T cell PIDs have been described, some of which are associated with a precise molecular defect (e.g., IL-2-inducible T cell kinase [ITK] deficiency, IL-21 receptor deficiency, CARD11 deficiency). These conditions are also characterized by profound vulnerability to infections, such as severe Epstein-Barr virus (EBV)–induced B cell proliferation and autoimmune disorders in ITK deficiency. Milder phenotypes are associated with CD8 and CD3γ deficiencies. HSCTisindicatedformostofthesediseases,althoughtheprognosisis worse than in SCID because many patients are chronically infected at the time of diagnosis. Fairly aggressive immunosuppression and myeloablation may be necessary to achieve engraftment of allogeneic stem cells.


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InternalMed_Harrison. T Cell Primary Immunodeficiencies with DNa repair Defects This is a group of PIDs characterized by a combination of T and B cell defects of variable intensity, together with a number of nonimmunologic features resulting from DNA fragility. The autosomal recessive disorder ataxia-telangiectasia (AT) is the most frequently encountered condition in this group. It has an incidence of 1:40,000 live births and causes B cell defects (low IgA, IgG2 deficiency, and low antibody production), which often require immunoglobulin replacement. AT is associated with a progressive T cell immunodeficiency. As the name suggests, the hallmark features of AT are telangiectasia and cerebellar ataxia. The latter manifestations may not be detectable before the age of 3–4 years, so that AT should be considered in young children with IgA deficiency and recurrent and problematic infections. Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7


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InternalMed_Harrison. young children with IgA deficiency and recurrent and problematic infections. Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. AT is caused by a mutation in the gene encoding the ATM protein—a kinase that plays an important role in the detection and repair of DNA lesions (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that 2109 carries a very high risk of lymphoma, leukemia, and (during adulthood) carcinomas. A variant of AT (“AT-like disease”) is caused by mutation in the MRE11 gene.


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InternalMed_Harrison. Nijmegen breakage syndrome (NBS)isalesscommonconditionthat also results from chromosome instability (with the same cytogenetic abnormalities as in AT). NBS is characterized by a severe T and B cell combined immune deficiency with autosomal recessive inheritance. Individuals with NBS exhibit microcephaly and a bird-like face, but have neither ataxia nor telangiectasia. The risk of malignancies is very high. NBS results from a deficiency in nibrin (NBSI, a protein associatedwithMRE11 and Rad50thatisinvolved incheckingDNAlesions) caused by hypomorphic mutations.


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InternalMed_Harrison. Severe forms of dyskeratosis congenita (also known as Hoyeraal-Hreidarsson syndrome) combine a progressive immunodeficiency thatcan alsoincludean absence ofB and NK lymphocytes,progressive bone marrow failure, microcephaly, in utero growth retardation, and gastrointestinal disease. The disease can be X-linked or, more rarely, autosomal recessive. It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1).


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InternalMed_Harrison. Finally, immunodeficiency with centromeric and facial anomalies (ICF) is a complex syndrome of autosomal recessive inheritance that variably combines a mild T cell immune deficiency with a more severe B cell immune deficiency, coarse face, digestive disease, and mild mental retardation. A diagnostic feature is the detection by cytogenetic analysis of multiradial aspects in multiple chromosomes (most frequently 1, 9, and 16) corresponding to an abnormal DNA structure secondary to defective DNA methylation. It is the consequence of a deficiency in the DNA methyltransferase DNMT3B, or ZBTB24.