Cutting Edge: Heterozygote Advantage in Autoimmune Disease: Hierarchy of Protection/Susceptibility Conferred by HLA and Killer Ig-Like Receptor Combinations in Psoriatic Arthritis

University of Cambridge, Cambridge, England, United Kingdom
The Journal of Immunology (Impact Factor: 4.92). 11/2004; 173(7):4273-6. DOI: 10.4049/jimmunol.173.7.4273
Source: PubMed


Functionally relevant combinations of HLA and killer Ig-like receptor (KIR) genotypes influence resistance to several diseases in humans. Analysis of genetic data from such studies is challenging because it involves multiple linked and unlinked loci that exert their influence in an epistatic manner. We previously reported that subjects with certain activating receptors were susceptible to developing psoriatic arthritis (PsA), an effect that was strongest when HLA ligands for corresponding homologous inhibitory receptors were missing. In this study, we present a novel model in which susceptibility to PsA is determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. This model fits our knowledge of clonal NK cell expression of KIR and regulation of NK cell activity better than does the previous model, as reflected in a robust trend for increasing susceptibility to PsA with more activating genotypes. These data emphasize the remarkable influence of KIR/HLA combinations on this disease.

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Available from: Dafna D Gladman, Jul 30, 2014
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    • "For example, scleroderma is associated with the activating KIR2DS2 in the absence of its corresponding inhibitory KIR2DL2 [97]. Similarly, psoriatic arthritis is linked to the expression of KIR2DS1 and/or KIR2DS2 in the absence of the ligands for the corresponding homologous inhibitory receptors [93]. The presence of activating KIRs or KIR/HLA genotypes in the context of decreased NK cell inhibition (for example, absence of corresponding inhibitory KIRs or the HLA ligands for the inhibitory KIRs) therefore results in a lower activation threshold for NK cells (or potentially T cells) and predisposes to autoimmunity. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases.
    Preview · Article · Jul 2013 · Arthritis Research & Therapy
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    • "In addition, some KIRs are known to recognize HLA-C (epitopes C1 or C2), HLA-B (Bw4) or HLA-A (A3 and/or A11, as well as HLA-A allomorphs with Bw4 epitope) molecules. This makes for great variability of reactivities among individuals, depending on the presence or absence of given KIRs and their ligands, and hence differential susceptibility to several diseases (Boyton and Altmann, 2007; Goronzy and Weyand, 2003; Khakoo and Carrington, 2006; Parham, 2005; Rajagopalan and Long, 2005), including skin diseases such as psoriatic arthritis and psoriasis (Holm et al., 2005; Łuszczek et al., 2004; Nelson et al., 2004; Suzuki et al., 2004; Williams et al., 2005). However, no data are available regarding associations of KIR genes with AD, where inadequate regulation of the immunological response also plays a decisive role. "
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    ABSTRACT: Atopic dermatitis (AD) is a common skin disease of complex etiology including affected humoral and cellular immune responses. The role of NK cells in development of this disease has been recently postulated, but is still poorly documented. The current study was undertaken to determine the impact of genes for the most polymorphic NK cell receptors, known as killer cell immunoglobulin-like receptors (KIR), on the development of AD. We compared 240 patients suffering from AD with 570 healthy controls. Frequencies of the great majority of KIR genes did not differ between patients and controls, except for KIR2DS1, whose frequency was significantly (OR = 0.629, CI95% (0.45; 0.87), pcorr = 0.0454) lower in patients than in controls. These results were confirmed in a second cohort of 201 patients. When both patient groups were combined and compared to the control group, the result for KIR2DS1 achieved even higher significance (OR = 0.658, CI95% (0.5; 0.86), pcorr = 0.0158). To the best of our knowledge, this is the first report on KIR gene contribution to AD, and to allergy in general.
    Full-text · Article · Jul 2013 · Gene
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    • "Interestingly, KIR2DS1 gene appeared associated also with psoriatic arthritis (Martin et al., 2002b; Holm et al., 2005; Williams et al., 2005; Table 2). In this latter disease, both KIR2DS1 in the absence of C2, and KIR2DS2 in the absence of C1 group HLA-C alleles were observed associated with psoriatic arthritis (Martin et al., 2002b; Nelson et al., 2004) in addition to other genes (HLA-B*27 and HLA-Cw*0602), although in American population the effect of KIR2DS1 was independent from C2 presence (Williams et al., 2005). We observed also some effects of other KIR genes in psoriatic patients positive for KIR2DS1: namely, increased frequency of a deletion variant of KIR2DS4 and decreased frequency of KIR2DS3 and KIR2DS5 gene in comparison to KIR2DS1-positive controls (Ploski et al., 2006). "
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    ABSTRACT: Killer cell immunoglobulin-like receptors (KIRs) are a family of cell surface inhibitory or activating receptors expressed on natural killer cells and some subpopulations of T lymphocytes. KIR genes are clustered in the 19q13.4 region and are characterized by both allelic (high numbers of variants) and haplotypic (different numbers of genes for inhibitory and activating receptors on individual chromosomes) polymorphism. This contributes to diverse susceptibility to diseases and other clinical situations. Associations of KIR genes, as well as of genes for their ligands, with selected diseases such as psoriasis vulgaris and atopic dermatitis, rheumatoid arthritis, recurrent spontaneous abortion, and non-small cell lung cancer are discussed in the context of NK and T cell functions.
    Full-text · Article · Jan 2013 · Frontiers in Immunology
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