Page 736 - Clinical Immunology_ Principles and Practice ( PDFDrive )

708 Part SIX Systemic Immune Diseases

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(*09) is also associated, but not in Caucasians. According to locus. These studies, replicated in European and US RA cohorts,
fine-mapping data, RA risk is linked not only to amino acids demonstrated associations between SE frequencies and antibodies
encoded by the RA SE sequence (71 and 74 positions of the to cyclic citrullinated peptides (anti-CCPs), as as opposed to
alpha helix of the DRβ chain) but also to amino acid positions rheumatoid factor (RF). Specifically, compared with healthy
11 and 13, located in the peptide binding groove of the HLA-DR controls, the odds ratio for the association between one or two
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heterodimer. Single amino acid variants have also been defined copies of the SE and anti-CCPs positivity was 4.4 and 11.8,
in HLA-B (position 9) and HLA-DPβ (position 9). Differences respectively. These findings point to SE associating not with RA
in odds ratios associated with these five amino acid variants per se, but with a clinical phenotype, in this case autoantibodies
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between ACPAs-positive and ACPAs-negative disease provide to modified proteins. An additional pathogenetic link between
further evidence that seropositive and seronegative disease are HLA and citrullination is supported by the observation that peptides
genetically distinct. On the other hand, the finding of DERAA carrying nonpolar residues such as citrulline (neutral), as opposed
encoding HLA-DRB1 alleles (DRB1*01:03, *04:02, *11:02, *11:03, to arginine (positive charge), in pocket four of the HLA-DRαβ
*13:01, *13:02, and *13:04), conferring lower disease risk, and binding groove (see Fig. 52.1) convert a poorly binding peptide
more importantly the finding of reduced radiographic progression to a higher-affinity epitope that induces robust T- and B-cell
in RA even in the presence of one copy of the SE, raises the responses in vivo. This notion is strongly supported by crystal
possibility that specific subsets of MHC class II genes may confer structures of HLA-DRαβ (DRB1*04:01 and *04:04) complexed
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an independent protective role. to peptide. Here amino acids 11, 13, 71, and 74 form part of the
Specific genotypes cosegregate with distinct clinical features. fourth anchoring peptide binding pocket, the same positions that
For example, in population-based studies, different HLA-DRB1 confer highest risk of disease, as noted above. Indeed, citrullinated
alleles influence the severity of disease (including radiographic human fibrinogen, but not the nonderivatized protein, induces
progression), with DRB1*04:01 being found in patients with chronic inflammatory arthritis in HLA-DR4 transgenic mice but
severe, seropositive, erosive RA (often with extraarticular features not their nontransgenic C57BL/6 littermates. The importance of
such as vasculitis and Felty syndrome in *04:01 homozygous or citrulline as a molecular feature of human T-cell–specific auto-
*04:01/*04:04 compound homozygote individuals). Valine at antigenic determinants is further suggested through identification
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position 11 of HLA-DRB1 confers the strongest association with of autoreactive CD4 T lymphocytes by flow cytometry using
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radiological damage and highest all-cause mortality. Statistical HLA-citrullinated-peptide tetramer complexes. These tools also
modeling points to HLA genetic polymorphism being associated permit determination of the relative proportions of antigen-reactive
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with young-onset RA. DRB1*01:01 and *10:01 are observed at effector and regulatory T-cell subsets.
a higher frequency in patients with less severe, seronegative, Genome-wide association studies (GWASs) of large patient
nonerosive disease. Inheriting two copies of alleles expressing cohorts, stratified by autoantibody serology, have contributed
the consensus sequence increases disease penetrance, time of significantly to our understanding of RA genetics. Meta-analyses
onset, and severity. Thus these genetic associations manifest as and fine-mapping studies, including custom-designed SNP arrays
clinically distinct disease entities. covering nearly 130 000 genetic variants selected from 186 loci-
On the basis of early observations, two principal models were poly defined in GWASs of autoimmune and immune-mediated
proposed to account for the association between RA and the inflammatory diseases (the Immunochip), have identified more
consensus DR β-chain sequence. Both were based on the assump- than 100 susceptibility loci, many of which have been validated
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tion that the SE is the critical genetic element linked directly to in RA populations of diverse ancestry. Among the strongest
disease. The first model proposed that the SE determines specific associations outside HLA is PTPN22, initially identified in
peptide binding and that “pathogenic” peptides bind only to candidate gene association studies. The PTPN22 gene variant
disease-associated HLA class II molecules (Fig. 52.1). This model confers risk with odds ratios ranging from 1.5 to 1.9 in Caucasian
predicted that a gradient of affinities of disease inducing peptide and European populations, and it is unusual among most genetic
for MHC class II molecules might account for the differences in variants in that it is a coding frame mutation (R620W). PTPN22
susceptibility and/or severity conferred by different HLA-DR encodes a hematopoietic cytoplasmic protein tyrosine phosphatase
molecules. Along the same lines, disease-associated alleles may whose substrates include Src and Syk family kinases, CD3ε, TCRζ,
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preclude the binding of peptides required for the generation of and signaling intermediates such as Vav. It comes as no surprise
naturally occurring Tregs specific for self-peptide antigens. The that the PTPN22 mutation, as a negative regulator of antigen
second model proposed that the SE influences T-cell receptor receptor and integrin signaling, has also been described in type
(TCR) recognition by binding and selecting autoreactive T cells 1 diabetes, a subset of SLE patients, oligoarticular juvenile
during thymic maturation and expanding these populations in idiopathic arthritis, vitiligo, Addison disease, and autoimmune
the peripheral compartment; again perturbations of a repertoire thyroid disease but not in multiple sclerosis or psoriasis. The
of Tregs could arise through opposing influences of the SE sequence. link with autoimmune diseases associated with pathogenic
Two recent lines of experimental evidence provide further autoantibodies is also intriguing. Whether the PTPN22-R620W
insights into HLA-disease associations. The first is the association variant is a loss- or gain-of-function mutant in man remains
between HLA-DR4 subtypes and telomere erosion in RA patients somewhat controversial. However, studies of Ptpn22-deficient
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and healthy donors, detectable before the age of 20. Telomere mice, and mice expressing the R620W mouse orthologue
loss has been associated with aging and immune senescence. Ptpn22-R19W, share features in T, B, and myeloid lineage indica-
Whether this implies a direct contribution of HLA-DR4 expression tive of loss of function for the R619W mutation, associated
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to accelerated differentiation of hematopoietic cells in the context with increased antigen receptor signaling. The relative contribu-
of a chronic inflammatory process is intriguing, but the relationship tions of the mutant to perturbationsin central and peripheral
certainly warrants further investigation. The second line of evidence tolerance mechanisms remain to be determined.
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pointing to specific functions of SE alleles has arisen through Scrutiny of other, non-MHC susceptibility loci point to genes
analysis of autoantibodies in RA patients typed at the HLA-DRB1 whose products are involved in proximal signaling pathways that