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

Genes Immun. 2008 Apr;9(3):249-58. doi: 10.1038/gene.2008.13. Epub 2008 Mar 13.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity / genetics*
  • Autoimmunity / immunology
  • Base Sequence
  • Chorioretinitis / genetics*
  • Chorioretinitis / immunology
  • European Continental Ancestry Group / genetics
  • France
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • HLA-A Antigens / genetics*
  • HLA-A Antigens / immunology
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Molecular Sequence Data
  • Receptors, KIR / genetics*
  • Receptors, KIR / immunology
  • Receptors, KIR3DL1 / genetics
  • Sequence Analysis, DNA


  • HLA-A Antigens
  • HLA-A29 antigen
  • KIR2DS2 protein, human
  • KIR3DL1 protein, human
  • Receptors, KIR
  • Receptors, KIR3DL1