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

Diabetologia, Sep 2011

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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs00125-011-2299-x.pdf

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

K. L. Mehers 0 2 3 A. E. Long 0 2 3 A. R. van der Slik 0 2 3 R. J. Aitken 0 2 3 V. Nathwani 0 2 3 F. S. Wong 0 2 3 S. Bain 0 2 3 G. Gill 0 2 3 B. O. Roep 0 2 3 P. J. Bingley 0 2 3 K. M. Gillespie 0 2 3 0 F. S. Wong Centre for Endocrine and Diabetes Sciences, Cardiff University , Cardiff, UK 1 ) Diabetes and Metabolism, Learning and Research, University of Bristol, Southmead Hospital , Bristol, UK 2 G. Gill Dept of Diabetes/Endocrinology, University of Liverpool , Liverpool, UK 3 S. Bain Institute of Life Sciences, College of Medicine, Swansea University , Swansea, UK 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. - Natural killer (NK) cells mediate the early killing of virally infected cells and tumours and it is increasingly clear that they also contribute to crosstalk between the innate and adaptive immune responses. Increased NK cell activity has been reported in the periphery of individuals with type 1 diabetes [16], but a role for these innate immune cells in the pathogenesis of type 1 diabetes has not, however, been elucidated. NK cells act by either activating or inhibiting cytolysis [7] and their activity is controlled by the balance of inhibitory and activating receptors on the cell surface [8]. One set of human NK cell receptors are the killer immunoglobulin-like receptor (KIR) gene family of membrane glycoproteins on chromosome 19 [9], which consists of 16 genes. Each is either inhibitory or activating in function and is polymorphic both in terms of gene content and allelic variation. The order of the KIR genes along the chromosome has been determined for two distinct haplotypes, termed A and B [10] where the A or inhibitory haplotype is defined by the presence of only one activating gene, KIR2DS4, which is not functional in the majority of individuals, whereas the B or activating haplotype has five functional activating KIRs. Some KIRs interact with specific HLA class I molecules: HLA-C group 1 (HLA-C1) molecules (asparagine at position 80) serve as the ligand for two inhibitory KIRs KIR2DL2 and KIR2DL3 and possibly one activating receptor, KIR2DS2, while the activating KIR2DS1 and inhibitory KIR2DL1 signal through HLA-C group 2 (HLA-C2) molecules (lysine at position 80). KIR3DL1 and KIR3DS1 signal through HLA-Bw4. Functional variation is therefore possible, dependent on the combinations of KIRHLA class I molecules present [11]. KIRs have been associated with a range of autoimmune conditions, such as psoriatic arthritis [12], rheumatoid arthritis [13], ulcerative colitis [14] and primary sclerosing cholangitis [15]. Results from genetic studies of KIRs in type 1 diabetes have been conflicting. Most have focused on the activating receptor gene KIR2DS2 and the inhibitory receptor gene KIR2DL2, which are in complete linkage disequilibrium and share the HLA-C1 ligand. Some have shown associations [1618], while others have not [19, 20]. Genome-wide association studies of KIRs in type 1 diabetes are not yet available because this region of chromosome 19 does not have a high-coverage single nucleotide polymorphism map. HLA class I, however, is known to be associated with type 1 diabetes, independent of linkage disequilibrium effects with HLA class II [21]. Genetic interactions between functional KIR genes and their HLA ligands were analysed in well-characterised UK populations of 179 children diagnosed with type 1 diabetes before the age of 5 years, 215 children diagnosed with type 1 diabetes between the ages of 5 and 15 years, and 168 healthy controls. As it is well established that HLA class IImediated genetic susceptibility to type 1 diabetes has decreased over the last half century [22, 23], the data obtained in the first part of this study were then compared with KIRHLA-C1 frequency in a historical cohort of individuals diagnosed in childhood with type 1 diabetes diagnosed early in the 20th centurythe Golden Years cohortto establish whether determinants of NK cell function have changed over a period in which the incidence of type 1 diabetes has been increasing. Study populations Current type 1 diabetes cohort Individuals with type 1 diabetes (179 of the individuals diagnosed before the age of 5 years and 215 individuals diagnosed between the ages of 5 years and 15 years) were from either the Barts Oxford (BOX) study [24] (n = 338) or the British Diabetic Association (BDA) cohort [25] (n =56). The BOX study of childhood diabetes is a populationbased family study that, from 1985 to 2002, h (...truncated)


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs00125-011-2299-x.pdf

K. L. Mehers, A. E. Long, A. R. van der Slik, R. J. Aitken, V. Nathwani, F. S. Wong, S. Bain, G. Gill, B. O. Roep, P. J. Bingley, K. M. Gillespie. An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes, Diabetologia, 2011, pp. 3062-3070, Volume 54, Issue 12, DOI: 10.1007/s00125-011-2299-x