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)