title: Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals.
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-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.
authors.affiliation: Ocular Inflammatory Disease Center, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095-1652, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Levinson
authors.forename: Z
authors.initials: Z
authors.lastname: Du
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: D
authors.initials: D
authors.lastname: Monnet
authors.forename: T
authors.initials: T
authors.lastname: Tabary
authors.forename: A P
authors.initials: AP
authors.lastname: Brezin
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: D W
authors.initials: DW
authors.lastname: Gjertson
authors.forename: G N
authors.initials: GN
authors.lastname: Holland
authors.forename: E F
authors.initials: EF
authors.lastname: Reed
authors.forename: J H M
authors.initials: JH
authors.lastname: Cohen
authors.forename: R
authors.initials: R
authors.lastname: Rajalingam
mesh_terms: D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002825:Chorioretinitis / Q000235:genetics* / Q000276:immunology; D005602:France; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology; D054341:Receptors, KIR3DL1 / Q000235:genetics; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D015234:HLA-A Antigens; C035524:HLA-A29 antigen; C433932:KIR2DS2 protein, human; C515083:KIR3DL1 protein, human; D054340:Receptors, KIR; D054341:Receptors, KIR3DL1