Unexpected association of reduced activating KIR–HLA genotypes with autoimmune Vogt–Koyanagi–Harada disease

Aim Vogt–Koyanagi–Harada (VKH) is an uncommon autoimmune disease characterized by chronic, bilateral, diffuse, granulomatous uveitis with accompanying dermatologic, neurologic and auditory involvement. There is a higher rate of VKH in people of Asian, Mestizo, and Mediterranean descent. Our preliminary studies of small cohorts of Japanese and Mestizo reported higher incidence of activating KIRs, which corroborates the autoimmune nature of VKH. Herein, we extended our pilot study with Japanese to a larger cohort. Methods We characterized 196 patients with VKH and 209 healthy controls from Yokohama City University School of Medicine, Japan for KIR and HLA class I genes using Luminex rSSO. Results Differences between controls and patients in the distribution of KIR genotypes, HLA allotypes, and KIR–HLA pairs were tested by two-tailed Fisher’s exact probabilities (Table 1). In contrast to previous findings, Bx KIR genotypes occurred at a lower frequency in patients with VKH compared to controls (39.3% vs. 52.6%, p = 0.007). The Bx decrease was due to the differences at the centromeric half of the KIR gene complex, and consequently all variable B haplotype KIR genes at the centromeric half (2DS2, 2DL2, 2DS3, 2DL5) were reduced in patients. Compared to controls, certain HLA allotypes were significantly increased (B54, B56, Cw1) or decreased (A33, B7, B44, B46, B52, Cw12, and A2-B46-Cw1 combination) in VKH. Among all known HLA class I ligands, only Bw4 showed a significant decrease in patients (42.4% vs. 55.5%, p = 0.0097). The decrease in 2DL2 and in Bw4 was associated with a reduction in 2DL2+C1/C2 and 3DL1+Bw4 combinations in VKH. Conclusions Decreased inhibitory KIR–HLA gene combinations in patients with VKH suggest the possibility of impaired class I mediated licensing, thus generating hyporesponsive NK cells. Absence of activating KIRs 2DS2 and 2DS3 further support the notion of a poorly responding NK cells in VKH. NK cell hyporesponsiveness to certain infections might trigger an autoimmune response and pathogenesis of VKH.