An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Abstract

Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

Killer cell immunoglobulin‐like receptor (KIR) gene diversity in a population naturally exposed to malaria in Porto Velho, Northern Brazil

“…Moreover, some alleles of KIR2DL2 are able to cross‐react, with differing avidities, with a small number of C2 and may used it as a functional ligand that can be responsible for the inhibition of NK cells activation . A previous studies demonstrated that the KIR2DL2, KIR2DS2 and KIR2DL3 genes, which share the HLA‐C1 ligand, are involved in increased susceptibility to several diseases , including malaria . In contrast, similar associations were not observed in our population.…”

Immunogenetics of type 1 diabetes: A comprehensive review

“…For example, KIR2DL2 binds HLA-C alleles in the C1 group. Some studies have reported increased T1D risk for KIR2DL2 [103,105,108]. However, in individuals lacking a C1 allele (i.e., both alleles have HLA-C alleles in the C2 group rather than the C1 group), any risk from KIR2DL2 is necessarily absent.…”

Diversity and association of HLA/KIR receptors with type 2 diabetes in South India

“…The association of KIR genes with many diseases such as leukaemia (De Smith et al, ), T1DM (van der Slik et al, ), idiopathic bronchiectasis (Boyton et al, ), psoriasis vulgaris (Suzuki et al, ), uveitis (Levinson, ), systemic sclerosis (Salim et al, ), systemic lupus erythematosus (Hou, Zhang, & Xu, ), ankylosing spondylitis (Jiao et al, ), rheumatoid arthritis (Majorczyk et al, ) and autoimmune hepatitis (Littera et al, ) was reported. KIR genes have been reported to be associated with T1DM and LADA in several populations (van der Slik et al, ; Tan, Lin, & Huang, ; Mehers et al, ; Zhi et al, ). However, very few reports were available on KIR–HLA association with T2DM (Caselli et al, ; Guo et al, ).…”