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KIR in Type 1 Diabetes

Disparate Distribution of Activating and Inhibitory Natural Killer Cell Receptors in Patients Versus HLA-Matched Control Subjects

¹ Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
² Department of Medical Genetics, University Medical Center, Utrecht, the Netherlands
³ Department of Clinical Genetics, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, the Netherlands

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.

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