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

• Published in: Diabetologia Vol. 54; no. 12; pp. 3062 - 3070
• Main Authors: Mehers, K. L., Long, A. E., van der Slik, A. R., Aitken, R. J., Nathwani, V., Wong, F. S., Bain, S., Gill, G., Roep, B. O., Bingley, P. J., Gillespie, K. M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-12-2011; Springer; Springer Nature B.V
• Subjects: Adolescent; Age; Age of Onset; Arthritis; Biological and medical sciences; Child; Child, Preschool; Children; Chromosomes; Cohort Studies; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene Frequency - genetics; Gene Frequency - immunology; Genes; Genotypes; Haplotypes; Histocompatibility antigen HLA; HLA-C Antigens - genetics; HLA-C Antigens - immunology; Homozygote; Human Physiology; Humans; Immunoglobulin-like receptors; Immunoglobulins; Immunosurveillance; Infant; Internal Medicine; Killer cell immunoglobulin-like receptors; Killer Cells, Natural - immunology; Ligands; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Natural killer cells; Potassium channels (inwardly-rectifying); Receptors, Natural Killer Cell - genetics; Receptors, Natural Killer Cell - immunology; United Kingdom > UK; Natural killer cell; Human leucocyte antigen; Type 1 diabetes; Killer immunoglobulin-like receptor; Endocrinopathy; Human; Immunopathology; HLA-System; Leukocyte; Immunoglobulin receptor; Autoimmune disease; Antigen; Biological receptor
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2299-x

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.