Levinson R D, Du Z, Luo L, Monnet D, Tabary T, Brezin A P, Zhao L, Gjertson D W, Holland G N, Reed E F, Cohen J H M, Rajalingam R
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.
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-A29 as well as controls lacking HLA-A29. 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-A29-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-A29-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.
鸟枪弹样脉络膜视网膜病变（BCR）是一种具有特征性脉络膜淋巴细胞浸润的慢性眼部炎症性疾病，与人类白细胞抗原（HLA）-A29密切相关。尽管HLA-A29在所有人群中都很常见，但BCR仅影响一小部分HLA-A29阳性的白种人，这表明BCR还存在其他易感因素。HLA I类特异性杀伤细胞免疫球蛋白样受体（KIR）的发现引发了一系列流行病学研究，提示KIR-HLA基因组合与疾病有关。在此，我们对携带HLA-A29的BCR患者和对照以及缺乏HLA-A29的对照中的KIR-HLA配对进行了特征分析。与自身免疫相关的激活型KIR基因（KIR2DS2、2DS3和2DS4）相结合的、与弱抑制相关的KIR-HLA配对（KIR2DL2/3+HLA-C1和KIR3DL1+HLA-Bw4(T80)）会增加HLA-A29阳性个体发生BCR的风险。在HLA-A29阴性对照中观察到了与强抑制配对（KIR3DL1+HLA-Bw4(I80)和KIR2DL1+HLA-C2）以及与抗感染相关的配对（KIR3DS1+HLA-Bw4(I80)和KIR2DS1+HLA-C2）的相互关联。这些结果表明，在缺乏强抑制的情况下，KIR2DS2/S3/S4的深远影响可能会增强自然杀伤细胞和T细胞亚群针对眼内自身抗原的激活，从而促进BCR的发病机制。
