title: KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ralph D
authors.initials: RD
authors.lastname: Levinson
authors.affiliation: 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.
authors.forename: Madeline
authors.initials: M
authors.lastname: Yung
authors.affiliation: Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Meguro
authors.affiliation: UCLA Immunogenetics Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Elham
authors.initials: E
authors.lastname: Ashouri
authors.affiliation: 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Mizuki
authors.affiliation: Department of Ophthalmology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo, Hokkaido, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
authors.affiliation: UCLA Immunogenetics Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America.|Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Raja
authors.identifier: http://orcid.org/0000-0001-8821-7877
authors.initials: R
authors.lastname: Rajalingam
mesh_terms: D044466:Asian People; D002877:Chromosomes, Human; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D007564:Japan; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology; D014607:Uveomeningoencephalitic Syndrome / Q000235:genetics / Q000276:immunology
chemical_list: D015804:HLA-DR4 Antigen; C433932:KIR2DS2 protein, human; C541358:KIR2DS3 protein, human; D054340:Receptors, KIR