Killer cell immunoglobulin-like receptor gene-cluster 3DS1-2DL5-2DS1-2DS5 predisposes susceptibility to Vogt–Koyanagi–Harada syndrome in Japanese individuals

Abstract

Killer cell immunoglobulin-like receptors (KIR) control the effector function of natural killer (NK) cells and subsets of T cell, and the genes encoding KIRs are substantially variable among individuals. A majority (58.4%) of Japanese individuals were found to be homozygous for group A KIR haplotypes that encode only a single activating KIR2DS4. Contrarily, most of Japanese patients with Vogt–Koyanagi–Harada (VKH) disease (69.2%), a panuveitis carry Bx genotypes that encode 2–5 activating KIR receptors. Particularly, individuals carrying three activating KIR genes 3DS1, 2DS1, and 2DS5 are more frequent in patient group compared with the controls (42.2% vs 21.4%, p = 0.02). In addition, the inhibitory KIR gene 3DL1 was significantly decreased in patients compared with controls (76.9% vs 98.8%, p = 0.00006). These data suggest that the genotypes encoding a dominant activating KIR receptor repertoire predispose susceptibility to VKH disease.

Introduction

Vogt–Koyanagi–Harada (VKH) disease is an ocular inflammatory disease that consists of a bilateral panuveitis of sudden onset that in some cases evolves into a chronic and/or recurrent anterior uveitis [1], [2], [3]. Vogt–Koyanagi–Harada syndrome is rare; in a recent survey from Japan, less than 1.5 per 1000 new referrals to university-based eye clinics was for VKH disease [4]. Although the ocular inflammation may occur in isolation, at onset VKH disease can be associated with aseptic meningitis, as well as the subsequent development of vitiligo and hearing changes, as part of the putative cell-mediated autoimmune response affecting melanocytes [5], [6]. The immune response in VKH disease appears to be primarily a TH1 response by CD4 T cells. The chemokine profile in the cerebrospinal fluid was found to be similar to that described for multiple sclerosis, also a TH1-mediated disease [7]. A diminished regulatory T-cell response disease as well as interleukin (IL)–17–producing T cells (TH17 cells) stimulated by IL-23 play a role in VKH disease [8], [9], [10]. VKH disease is associated with HLA-DR4 in most populations studied; however, the strength of the association and the HLA-DR4 subtypes observed varied by ethnic population, suggesting additional environmental or genetic factors play a role in disease pathogenesis [11], [12], [13], [14].

Killer cell immunoglobulin-like receptor (KIR) genes have been associated with autoimmune and infectious diseases, including uveitis [15], [16], [17]. A family of polymorphic KIR genes located on chromosome 19 encodes for inhibitory (3DL1-3, 2DL1-3, 2DL5) and activating (3DS1, 2DS1-5) receptors, which are expressed on natural killer (NK) cells and subsets of T cells [18], [19], [20]. The inhibitory KIRs recognize distinct HLA class I molecules and stop the effector function of NK cells. Although the ligands for the activating KIRs are not known, the epidemiologic studies suggest that the activating KIRs may recognize the determinants expressed on the surface of virally infected, tumor-transformed or stressed cells and subvert these abnormal cells [15].

KIR gene content differs by haplotypes [21], [22]. Based on the gene content, KIR haplotypes are broadly classified into two groups [23]. Group A haplotypes have a fixed gene content comprising KIR3DL3-2DL3-2DP1-2DL1-3DP1-2DL4-3DL1-2DS4-3DL2, but are diversified through allelic polymorphism of the individual genes. In contrast, group B haplotypes have variable gene content comprising several genes and alleles that are not part of the A haplotype. In particular, KIR2DS1, 2DS2, 2DS3, 2DS5, 2DL2, 2DL5, and 3DS1 are associated only with group B haplotypes, and thus B haplotypes generally encode more activating KIR receptors than the A haplotype that encodes a single activating receptor, KIR2DS4. Four framework genes (KIR3DL3, 3DP1, 2DL4, and 3DL2) are conserved on both A and B haplotypes and therefore are ubiquitously present in all individuals. The combination of maternal and paternal haplotypes with distinct gene content produces diversity among individuals in their KIR gene content profile (KIR genotype), which may influence the individuals' immunity and susceptibility to disease. In this study, we examined whether the KIR genes influence susceptibility to VKH disease in Japanese, a highly homogeneous population with a prevalence of homozygous for group A KIR haplotypes [24], [25].