KIR in Type 1 Diabetes

Abstract

Killer cell immunoglobulin-like receptors (KIRs) modulate natural killer cell and T-cell function by interacting with HLA class 1 ligands on target cells. Both KIR and HLA are highly polymorphic. We studied the influence of KIR and HLA class 1 genes on the susceptibility to develop type 1 diabetes. The results showed increased numbers of activating KIR genes in patients compared with control subjects (P ‫؍‬ 0.049). The combination of the activating KIR2DS2 gene, together with its putative HLA ligand, was present more frequently in patients than in diabetes high-risk HLA-matched control subjects (P ‫؍‬ 0.030). Moreover, our results imply that an increase in activating KIR2DS2-HLA ligand pairs combined with a lack of inhibitory KIR-HLA ligand pairs is associated with an additional risk to develop type 1 diabetes in individuals with diabetes high-risk HLA alleles (P ‫؍‬ 0.035). We propose that the genetic imbalance between KIR and their HLA class 1 ligands may enhance the activation of T-cells with a low affinity for pancreatic self-antigens, thereby contributing to the pathogenesis of type 1 diabetes.

Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility

“…[29][30][31][32][33][34][35] Our initial statistical analysis indicated a possible involvement of the activating KIR2DS2 and the inhibitory KIR2DL2 in the development of UC. Both genes displayed a high level of linkage disequilibrium with each other (previously reported in Hsu et al 39 ), occurring independently in only three of the samples genotyped in this study.…”

“…[29][30][31][32][33]35,38 Analysis revealed KIR2DL3 in the presence of HLA-C1 as the dominant association, significantly reduced in UC patients (P ¼ 0.019, odds ratio (OR) ¼ 0.577, 95% confidence interval (CI) ¼ 0.364-0.915), and the loss of significance with KIR2DL2 and -2DS2 (Figure 1). KIR2DL2 and -2DS2 in the presence of their shared ligand HLA-C1 also failed to reach significance (-2DL2/HLA-C1: OR ¼ 1.311, 95% CI ¼ 0.881-1.950; -2DS2/HLA-C1: OR ¼ 1.286, 95% CI ¼ 0.866-1.911).…”

“…Analysis of KIR/HLA ligand combination is increasingly of interest in the genetic study of inflammatory disorders, resulting in the discovery of KIR associations with psoriasis vulgaris, 29,30 psoriatic arthritis, 31 scleroderma, 32 rheumatoid arthritis 33 and type I diabetes. 34,35 In addition, celiac disease has been linked to 19q13.4, 36 where the KIR cluster is located, although genotype analysis of a limited number of KIR genes (KIR2DL1, -2DL2, -2DL3 and -2DL5) failed to detect an association. 37 The aim of this study was to investigate the role of the functional and positional candidate genes encoding NKG2D, the KIRs and the HLA ligands of KIR in determining susceptibility to UC.…”

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

“…25,34 However, activating Ly49 do not signal normally in certain mouse strains such as 129X1. 35 To further explore the possibility that the activating Ly49 in NOD NK cells contribute to the onset of diabetes, their functional activity in Chinese hamster ovary (CHO) cell cytotoxicity and MCMV infection assays was assessed.…”

“…These individuals generally have an increased number of activating KIR in their genome compared to healthy controls or are more likely to possess KIR haplotypes containing specific activating KIR. 8,25 Mapping studies in the NOD mouse model have shown that a diabetes susceptibility locus (idd 6) is present on chromosome 6 near the Ly49 gene cluster. 26 In agreement with this finding, NOD mice congenic for C57BL/6 (B6) NK1.1, a marker near the Ly49 cluster, manifested reduced disease incidence and improved NK and NKT cell performance as compared to wild-type NOD mice.…”