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Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

Genes & Immunity volume 9, pages 249–258 (2008)Cite this article

Abstract

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-Bw4T80) 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-Bw4I80 and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4I80 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.

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Acknowledgements

This work was supported by start-up funds from the Department of Pathology and Laboratory Medicine (to RR), Stein Oppenheimer Endowment Award (to RR and RL) and the MacDonald Family Foundation (to RL). We thank Damian Goodridge, Conexio Genomics, Western Australia for his help in building and optimizing KIR libraries for the use in Assign software.

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  1. R D Levinson and Z Du: These authors contributed equally to this work.

Authors and Affiliations

  1. Ocular Inflammatory Disease Center, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA

    R D Levinson & G N Holland

  2. Department of Pathology and Laboratory Medicine, UCLA Immunogenetics Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA

    Z Du, L Luo, D W Gjertson, E F Reed & R Rajalingam

  3. Service d′ophtalmologie, Hôpital Cochin Assistance Publique, Université Paris Descartes, Hôpitaux de Paris, France

    D Monnet & A P Brezin

  4. Laboratoire d’Immunologie EA 3798, Institut Fédératif de Recherche, 53 Université de Reims Champagne Ardenne, CHU Reims, France

    T Tabary & J H M Cohen

  5. Department of Biostatistics, School of Public Health, University of California at Los Angeles, Los Angeles, CA, USA

    L Zhao & D W Gjertson

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Correspondence to R Rajalingam.

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Levinson, R., Du, Z., Luo, L. et al. Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals. Genes Immun 9, 249–258 (2008). https://doi.org/10.1038/gene.2008.13

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