Levinson Ralph D, Yung Madeline, Meguro Akira, Ashouri Elham, Yu Fei, Mizuki Nobuhisa, Ohno Shigeaki, Rajalingam Raja
Ocular Inflammatory Disease Center, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America.
Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
PLoS One. 2016 Aug 4;11(8):e0160392. doi: 10.1371/journal.pone.0160392. eCollection 2016.
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt-Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher's exact probabilities. The incidence of Bx-KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral-infection that may trigger VKH pathogenesis in genetically susceptible individuals, such as HLA-DR4 carriers.
细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞是杀伤性淋巴细胞，可抵御病毒感染和肿瘤转化。与CTL类似，杀伤细胞免疫球蛋白样受体（KIR）与特定人类白细胞抗原（HLA）I类配体的相互作用可校准NK细胞的发育和反应。编码KIR和HLA配体的基因家族位于不同染色体上，其基因数量和类型存在差异。KIR和HLA基因的独立分离导致个体中KIR - HLA相互作用的变异性，这可能影响疾病易感性。我们测试了KIR - HLA组合是否与Vogt - 小柳 - 原田（VKH）病相关，VKH病是一种双侧肉芽肿性全葡萄膜炎，与HLA - DR4密切相关。我们对来自日本高度同质的本地人群的196例VKH患者和209例对照进行了病例对照研究。使用寡核苷酸杂交方法对KIR和HLA I类基因进行分型，并使用双侧Fisher精确概率法进行分析。VKH患者中Bx - KIR基因型的发生率降低（优势比[OR] 0.58，P = 0.007），主要是由于着丝粒B - KIR基序及其相关的KIRs 2DS2、2DL2、2DS3和2DL5B减少。与免疫反应不良有关的HLA - B22在VKH患者中增加（OR = 4.25，P = 0.0001）。KIR3DL1的配体HLA - Bw4在VKH患者中减少（OR = 0.59，P = 0.01）。在NK细胞发育中起作用的KIR - HLA组合2DL2 + C1/C2和3DL1 + Bw4在VKH患者中也减少（OR = 0.49，P = 0.012；OR = 0.59，P = 0.013）。除了缺失激活型KIRs 2DS2和2DS3外，还缺失这两种抑制性KIR - HLA组合的基因型在VKH患者中更为常见（OR = 1.90，P = 0.002）。这些结果表明，NK细胞（由于NK细胞发育不良以及激活型KIRs缺失）和CTL（由于HLA - B22限制）的协同低反应性未能对病毒感染发起有效的免疫反应，这可能在遗传易感个体（如HLA - DR4携带者）中触发VKH发病机制。
