PMID- 27490240 OWN - NLM STAT- MEDLINE DCOM- 20170727 LR - 20221207 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 8 DP - 2016 TI - KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease. PG - e0160392 LID - 10.1371/journal.pone.0160392 [doi] LID - e0160392 AB - 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. FAU - Levinson, Ralph D AU - Levinson RD AD - 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. FAU - Yung, Madeline AU - Yung M AD - 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. FAU - Meguro, Akira AU - Meguro A AD - Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan. FAU - Ashouri, Elham AU - Ashouri E AD - UCLA Immunogenetics Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America. FAU - Yu, Fei AU - Yu F AD - 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. FAU - Mizuki, Nobuhisa AU - Mizuki N AD - Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan. FAU - Ohno, Shigeaki AU - Ohno S AD - Department of Ophthalmology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo, Hokkaido, Japan. FAU - Rajalingam, Raja AU - Rajalingam R AUID- ORCID: 0000-0001-8821-7877 AD - UCLA Immunogenetics Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America. AD - Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, United States of America. LA - eng PT - Journal Article DEP - 20160804 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (HLA-DR4 Antigen) RN - 0 (KIR2DS2 protein, human) RN - 0 (KIR2DS3 protein, human) RN - 0 (Receptors, KIR) SB - IM MH - Asian People MH - Chromosomes, Human MH - Female MH - *Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - *HLA-DR4 Antigen/genetics/immunology MH - Humans MH - Immunity, Cellular/*genetics MH - Japan MH - Killer Cells, Natural/*immunology MH - Male MH - *Receptors, KIR/genetics/immunology MH - *Uveomeningoencephalitic Syndrome/genetics/immunology PMC - PMC4973954 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2016/08/05 06:00 MHDA- 2017/07/28 06:00 PMCR- 2016/08/04 CRDT- 2016/08/05 06:00 PHST- 2016/05/18 00:00 [received] PHST- 2016/07/18 00:00 [accepted] PHST- 2016/08/05 06:00 [entrez] PHST- 2016/08/05 06:00 [pubmed] PHST- 2017/07/28 06:00 [medline] PHST- 2016/08/04 00:00 [pmc-release] AID - PONE-D-16-20142 [pii] AID - 10.1371/journal.pone.0160392 [doi] PST - epublish SO - PLoS One. 2016 Aug 4;11(8):e0160392. doi: 10.1371/journal.pone.0160392. eCollection 2016.