Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations
Arthritis Research & Therapy
0 Immunogenetic Service, Hospital de Santo Espirito de Angra do Heroismo , Vinha Brava. 9700 Angra do Heroismo, Azores , Portugal
1 Rheumatology Unit, Hospital Monte Naranco , Avda Dres Fernandez Vega 107. 33012 Oviedo, Asturias , Spain
2 Histocompatibility and Transplantation Unit, Hospital Universtario Central de Asturias , Celestino Villamil s/n. 33006 Oviedo, Asturias , Spain
3 Functional Biology Department, University of Oviedo , Avda Julian Claveria s/n. 33006 Oviedo, Asturias , Spain
Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles
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carrying Bw4-I80 in trans position in the Spanish population
(30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds
ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7%
in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other
hand, 3DL1 was decreased in patients compared with B27
controls (p < 0.0001 in the Spanish population and p < 0.003
in Azoreans). The presence of this allele in combination with
Bw4-I80 had a protective effect against the development of AS
in the Spanish population (19.7% in AS, 35.2% in B27 controls;
p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1
in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes
may modulate the development of AS. The susceptibility to AS
could be determined by the overall balance of activating and
inhibitory composite KIR-HLA genotypes.
Introduction
The association of ankylosing spondylitis (AS) with human
leukocyte antigen (HLA)-B27 has been demonstrated worldwide,
and evidence for the role of HLA-B27 in AS comes from
linkage and association studies in humans and transgenic animal
models. However, twin studies indicate that HLA-B27
contributes only 16% of the total genetic risk for disease [1].
Genome-wide scans have implicated regions on
chromosomes 2q, 6p, 6q, 10q, 11q, 16q, 17q, and 19q in AS [2,3].
The killer immunoglobulin-like receptor (KIR) genes encode a
group of proteins that are expressed on natural killer (NK) cells
and in some T cells that are located on chromosome 19q13.4
in the leukocyte receptor complex (reviewed in [4]). KIR
proteins act as receptors that recognise major histocompatibility
complex (MHC) class I molecules and are directly involved in
the activation and inhibition of NK and possibly also in CD8+ T
cells [5,6].
Given the receptor-ligand relationship between certain
combinations of KIR and HLA class I molecules, it is reasonable to
AS = ankylosing spondylitis; HC = heavy chain; HLA = human leukocyte antigen; HWE = Hardy-Weinberg equilibrium; ILT = immunoglobulin-like
lymphocyte T receptors; KIR = killer cell immunoglobulin-like receptor; MHC = major histocompatibility complex; NK = natural killer; NKR = natural
killer receptor; OR = odds ratio; PCR = polymerase chain reaction; SSO = sequence-specific oligoprobe; SSP = sequence-specific primer; TCR =
T-cell receptor.
hypothesise a synergistic relationship between these
polymorphic loci. This could be the case of the KIR3DL1 inhibitory
receptor, the only KIR known to recognise HLA-B alleles. It
binds to HLA-B with serological-defined epitope Bw4
(determined by amino acid positions 7983 of the molecule) [7] with
an isoleucine at position 80 (Bw4-I80) [8]. The interaction of
KIR3DL1 and Bw4-I80 has an inhibitory effect on the cytotoxic
capacity of NK cells. All HLA-B27 subtypes carry Bw4
epitope, with the exception of B*2708 and other related
subtypes, which carry Bw6. From those with Bw4, B*2702 is the
only subtype with an isoleucine at position 80 (Bw4-I80). The
differences between the activating receptor KIR3DS1 and the
inhibitory 3DL1 are located in the intracytoplasmic tail. The
inhibitory receptor has a long tail containing immunoreceptor
tyrosine inhibitory motifs, whereas the activating receptor has
a short tail without this motif but with the capacity to interact
with activating adaptor proteins such as DAP12 [9]. The
ligand for KIR3DS1 has not been determined, although it has
been shown that the KIR3DS1 activating receptor in
combination with HLA-B alleles that encode molecules with isoleucine
at position 80 (HLA-B Bw4-I80) results in delayed
progression to (...truncated)