Association of killer cell immunoglobulin‐like receptor genotypes with microscopic polyangiitis

Miyashita, Risa; Tsuchiya, Naoyuki; Yabe, Toshikazu; Kobayashi, Shigeto; Hashimoto, Hiroshi; Ozaki, Shoichi; Tokunaga, Katsushi

doi:10.1002/art.21653

Cited by 37 publications

(24 citation statements)

References 13 publications

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“…Previous studies have shown that the risk of many human diseases was associated with differences in KIR gene content, including autoimmune diseases, inflammatory disorders, infectious diseases, immunodeficiency, cancer, and reproductive disorders. 17 KIR2DL1, for instance, was specifically associated with tuberculoid leprosy, 37 microscopic polyangiitis, 38 endometriosis, 39 immunodeficiency, 40 birdshot chorioretinopathy, 41 solid tumors, 42,43 leukemia, 44 and graft-versus-host disease. 45 Mechanistically, the risk may be related to the strength of interaction between the KIR gene and its HLA ligand.…”

Section: Discussionmentioning

confidence: 99%

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

Bari

Bell

Leung

et al. 2009

Blood

119

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Killer immunoglobulin-like receptors (KIRs) play an essential role in the regulation of natural killer cell functions. KIR genes are highly polymorphic in nature, showing both haplotypic and allelic variations among people. We demonstrated in both in vitro and in vivo models a significant heterogeneity in function among different KIR2DL1 alleles, including their ability to inhibit YT-Indy cells from degranulation, interferon ␥ production, and cytotoxicity against target cells expressing the HLA-Cw6 ligand. Subsequent experiments showed that the molecular determinant was an arginine residue at position 245 (R245) in its transmembrane domain that mechanistically affects both the efficiency of inhibitory signaling and durability of surface expression. Specifically, in comparison with R245-negative alleles, KIR2DL1 that included R245 recruited more Src-homology-2 domaincontaining protein tyrosine phosphatase 2 and ␤-arrestin 2, showed higher inhibition of lipid raft polarization at immune synapse, and had less down-regulation of cell-surface expression upon interaction with its ligand. Thus, our findings provide novel insights into the molecular determinant of KIR2DL1 and conceivably a fundamental understanding of KIR2DL1 allelic polymorphism in human disease susceptibility, transplant outcome, and donor selection. (Blood. 2009;114:5182-5190) IntroductionNatural killer (NK) cells are a part of our immune system that eliminates virally infected cells and tumor cells through cytolytic killing and cytokine secretion. 1 An NK cell's responses to its targets are regulated by the balance of signals generated through various activating and inhibiting receptors. 2,3 NK-cell receptors may be categorized on the basis of their ligand specificity for major histocompatibility complex class I and related molecules. Expression of various combinations of receptors on the surface of NK cells creates a diverse repertoire. 4,5 In humans, one of the most important groups of receptors that regulate NK-cell function is killer immunoglobulin-like receptors (KIRs). 6,7 The KIRs make up a family of diverse glycoproteins encoded by a compact cluster of genes located on human chromosome 19q13.4. 8,9 KIRs expressed at the surface of NK cells regulate their response by interacting with human leukocyte antigen (HLA) class I molecules. The KIR family has both activating and inhibitory receptors. KIR inhibitory receptors suppress NK cells' function using the immunoreceptor tyrosine-based inhibitory motif in their long cytoplasmic tails. Activating KIR receptors have short cytoplasmic tails and do not contain the inhibitory motif.Each of the KIR genes exhibits allelic variation as well as haplotypic variability in terms of the number and types of genes on the haplotypes. 9,10 The allelic variations of KIR genes range from 2 to more than 30. 10 The polymorphisms between the alleles of a given KIR gene can occur in its extracellular, transmembrane, or cytoplasmic domains. Polymorphism at each of these 3 domains has been associated with significant bi...

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Section: Discussionmentioning

confidence: 99%

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

Bari

Bell

Leung

et al. 2009

Blood

119

View full text Add to dashboard Cite

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“…Interestingly, the absence of KIR2DS3 could have implications for current disease manifestations as KIR2DS3 appears protective against certain types of immunemediated disease. 33,34 However, it is unknown if the presence of the activatory B telomeric genes increases susceptibility to autoimmune diseases prevalent in indigenous peoples throughout the Americas. [35][36][37][38] Nonetheless, North American Aboriginal ancestry is also associated with a reduced progression to chronic HCV infection.…”

Section: Current Kir Genetic Profiles May Reflect Historical Immune Smentioning

confidence: 99%

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

et al. 2011

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Genetic differences in immune regulators influence disease resistance and susceptibility patterns. There are major health discrepancies in immune-mediated diseases between Caucasians and Canadian Aboriginal people, as well as with other indigenous people of the Americas. Environmental factors offer a limited explanation as Aboriginal people also demonstrate a rare resistance to chronic hepatitis C virus infection. Killer immunoglobulin-like receptors (KIRs) are known modulators of viral responses and autoimmune diseases. The possibility that variation in KIR cluster profiles contribute to the health outcomes of Aboriginal people was evaluated with Canadian Caucasian (n¼93, population controls) and Aboriginal (n¼86) individuals. Relative to Caucasians, the Aboriginal KIR cluster displayed a greater immune activating phenotype associated with genes of the B haplotype situated within the telomeric region. In conjunction, there was a decrease in the genes of the B haplotype from the centromeric region. Caucasian and Aboriginal cohorts further demonstrated distinct genotype and haplotype relationships enforcing the disconnect between the B haplotype centromeric and telomeric regions within the Aboriginal population. Moreover, Caucasian KIR cluster patterns reflected studies of Caucasians globally, as well as Asians. In contrast, the unique pattern of the Canadian Aboriginal cohort mirrored the phenotype of other indigenous peoples of the Americas, but not that of Caucasians or Asians. Taken together, these data suggest that historically indigenous peoples of the Americas were subject to immune selection processes that could be influencing the current disease resistance and susceptibility patterns of their descendents.

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“…The roles of HLAs from the MHC region have been investigated in immune-mediated vascular diseases (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). However, HLAs that contribute to the pathogenesis of KD have been less well characterized.…”

mentioning

confidence: 99%

HLA–E gene polymorphism associated with susceptibility to kawasaki disease and formation of coronary artery aneurysms

Lin¹,

Wan²,

Wu³

et al. 2009

Arthritis & Rheumatism

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Objective. Kawasaki disease (KD) is a pediatric systemic vasculitis of unknown cause for which a genetic influence is supposed. The purpose of this study was to identify possible genetic variants in the major histocompatibility complex (MHC) region that are associated with KD and the development of coronary artery aneurysms (CAAs) in a Taiwanese population.Methods. The 168 genetic variants covering the MHC locus were analyzed in an association study of a Taiwanese cohort of 93 KD patients and 680 unrelated healthy children matched for sex and age with the study patients.Results. Eleven single-nucleotide polymorphisms (SNPs) were associated with the occurrence of KD. The SNP located at the 3 -untranslated region of HLA-E (rs2844724) was highly associated (P < 1 ؋ 10 ؊7 ). In addition, the frequency of the C allele was higher in KD patients without CAAs than in controls (P < 0.001) due to a significantly increased frequency of the CC and CT genotypes. Plasma levels of soluble HLA-E were significantly higher in KD patients than in controls regardless of the presence of CAAs. Furthermore, there was a trend toward higher plasma levels of soluble HLA-E in KD patients with the CT and TT genotypes of the HLA-E gene polymorphism.Conclusion. Our results suggest that the HLA-E gene polymorphism may play a role in the pathogenesis of KD.

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Association of killer cell immunoglobulin‐like receptor genotypes with microscopic polyangiitis

Cited by 37 publications

References 13 publications

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

HLA–E gene polymorphism associated with susceptibility to kawasaki disease and formation of coronary artery aneurysms

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