Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A29-positive individuals

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR–HLA gene combinations in disease. Here, we characterized KIR–HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29 . KIR–HLA pairs implicated for weak inhibition ( KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4 T80 ) in combination with activating KIR genes associated with autoimmunity ( KIR2DS2 , 2DS3 and 2DS4 ) augment the risk of developing BCR in HLA-A*29 -positive individuals. The reciprocal association of strong inhibitory pairs ( KIR3DL1+HLA-Bw4 I80 and KIR2DL1+HLA-C2 ) in combination with those implicated in protection from infection ( KIR3DS1+HLA-Bw4 I80 and KIR2DS1+HLA-C2 ) was observed in HLA-A*29 -negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.