Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis

Harvey, David; Pointon, J J; Sleator, C.; Meenagh, Ashley; Farrar, C; Sun, Ji; Senitzer, David; Middleton, Derek; Brown, Matthew A.; Wordsworth, B P

doi:10.1136/ard.2008.095927

Cited by 40 publications

(39 citation statements)

References 15 publications

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“…[31][32][33][34] KIR3DL1 and KIR3DS1 allele distribution was analyzed in both cohorts and showed no significant deviation from Hardy-Weinberg equilibrium (P.0.05). We found that the KIR3DL1 allele was underrepresented (P,0.01, OR50.52) and the KIR3DS1 allele was overrepresented (P,0.01, OR51.93) in the AS group compared to healthy controls (Table 1).…”

Section: Resultsmentioning

confidence: 96%

“…15,18,23,24 A number of studies has been conducted to identify possible associations between autoimmune conditions and KIR genes. [25][26][27][28][29][30][31][32][33][34][35] In particular, a number of works demonstrate 5 These authors contributed equally to this work. 16 Among the numerous KIR genes, the KIR3DL1/3DS1 locus is of particular interest with respect to AS because KIR3DL1 is the only KIR that recognizes HLA-B molecules of the Bw4 serotype, including HLA-B27.…”

Section: Introductionmentioning

confidence: 99%

“…33 In contrast, no increase in KIR3DS1 carriers among AS patients was noted in a study cohort from the United Kingdom. 34 The contradictory data may be explained by the different inclusion criteria used in each study.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of functional KIR3DL1 to ankylosing spondylitis

et al. 2010

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Increasing evidence points to a role for killer immunoglobulin-like receptors (KIRs) in the development of autoimmune diseases. In particular, a positive association of KIR3DS1 (activating receptor) and a negative association of KIR3DL1 (inhibitory receptor) alleles with ankylosing spondylitis (AS) have been reported by several groups. However, none of the studies analyzed these associations in the context of functionality of polymorphic KIR3DL1. To better understand how the KIR3DL1/3DS1 genes determine susceptibility to AS, we analyzed the frequencies of alleles and genotypes encoding functional (KIR3DL1*F) and non-functional (KIR3DL1*004) receptors. We genotyped 83 AS patients and 107 human leukocyte antigen (HLA)-B27-positive healthy controls from the Russian Caucasian population using a two-stage sequence-specific primer PCR, which distinguishes KIR3DS1, KIR3DL1*F and KIR3DL1*004 alleles. For the patients carrying two functional KIR3DL1 alleles, those alleles were additionally genotyped to identify KIR3DL1*005 and KIR3DL1*007 alleles, which are functional but are expressed at low levels. KIR3DL1 was negatively associated with AS at the expense of KIR3DL1*F but not of KIR3DL1*004. This finding indicates that the inhibitory KIR3DL1 receptor protects against the development of AS and is not simply a passive counterpart of the segregating KIR3DS1 allele encoding the activating receptor. However, analysis of genotype frequencies indicates that the presence of KIR3DS1 is a more important factor for AS susceptibility than the absence of KIR3DL1*F. The activation of either natural killer (NK) or T cells via the KIR3DS1 receptor can be one of the critical events in AS development, while the presence of the functional KIR3DL1 receptor has a protective effect. Nevertheless, even individuals with a genotype that carried two inhibitory KIR3DL1 alleles expressed at high levels could develop AS.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Contribution of functional KIR3DL1 to ankylosing spondylitis

et al. 2010

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“…Two studies reported association of the KIR3DS1 allele with ankylosing spondylitis in HLA-B*27-positive individuals from Spain, the Azores, China, and Thailand, 24, 25 however this association was not found in HLA-B*27-positive individuals from Ireland or the United Kingdom. 26, 27 A recent study suggests a role for a different KIR, KIR3DL2, in HLA-B*27-positive ankylosing spondylitis, 28 raising the question whether a different KIR may also contribute to Behçet’s disease.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease

et al. 2016

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The Behçet’s disease (BD)-associated HLA allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells — KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity. We tested whether KIR-regulated mechanisms contribute to BD by testing for association of KIR3DL1/KIR3DS1 genotypes with disease in 1799 BD patients and 1710 healthy controls from Turkey, as well as in different subsets of individuals with HLA-type-defined ligands for the KIR3D receptors. HLA types were imputed from SNP genotypes determined with the Immunochip. The presence of inhibitory KIR3DL1 or activating KIR3DS1 alleles did not differ significantly between cases and controls (KIR3DL1: 92.9% vs 93.4%, Pdominant = 0.55; KIR3DS1: 42.7% vs 41.0%, Pdominant = 0.29). The KIR3DL1/KIR3DS1 alleles were also present at similar frequencies among cases and controls bearing HLA-B with a Bw4 motif; HLA-B with a Bw4 motif with isoleucine at position 80; and HLA-B*51. Our results suggest that pathogenic mechanisms associated with HLA-B*51 do not primarily involve differential interactions with KIR3DL1 and KIR3DS1 receptors. However, due to the complexity of this locus (i.e., sequence variation, copy number variation), we cannot exclude a role for other types of KIR variation in the pathogenesis of BD.

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“…Gabriel's study did not describe any impact on PFS for KIR2DL1; however, authors showed that KIR2DL1 frequency was 94%, slightly higher than ours (86.8%), but lower than that described for British Caucasians (97.0 to 97.2%). 47,48 Differences in KIR2DL1 frequency between both series, in view of the rapid progressive disease observed for KIR2DL1…”

Section: Kir3ds1mentioning

confidence: 98%

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

Martínez‐Sánchez¹,

Periago

Legáz³

et al. 2015

OncoImmunology

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L3¡ (20% vs. 83%, p < 0.00001) as well as KIR3DL1 ¡ (23% vs. 82%, p < 0.00001) genotypes had a dramatic negative impact on the 3-y progression-free survival (PFS), particularly in patients with lowtumor burden. Remarkably, myeloma-PCs, compared to K562 and other hematological cancers, showed substantial over-expression of HLA-I ("increasing-self" instead of missing-self), including HLA-C, and mild expression of ligands for NKc activating receptors (aRec) CD112, CD155, ULBP-1 and MICA/B, which apparently renders myeloma-PCs susceptible to lysis mainly by licensed NKc. KIR2DL1patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myelomaPCs (4% vs. 15%; p < 0.05, compared to controls). These results support a model where immunosurveillance of no-missing-self cancers, e.g., myeloma, mainly depends on NKc licensing.

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Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis

Abstract: Neither the KIR gene content of particular KIR haplotypes nor KIR3DL2 polymorphisms contribute to AS.

Cited by 40 publications

References 15 publications

Contribution of functional KIR3DL1 to ankylosing spondylitis

Contribution of functional KIR3DL1 to ankylosing spondylitis

Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

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