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Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo.

ABSTRACT: Although HLA-A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA-A3 or A11 (OR = 3.76, p = 0.013), providing the first evidence that HLA-A3 and A11 may interact with KIR3DL2 in vivo. The nonsynonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR = 0.52, p = 0.018). This SNP results in a threonine-to-methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2-positive natural killer (NK) cells and also lower intensity of KIR3DL2 on expressing natural killer cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin-like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune-related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition.

SUBMITTER: Augusto DG

PROVIDER: S-EPMC4530613 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo.

Augusto Danillo G DG O'Connor Geraldine M GM Lobo-Alves Sara C SC Bass Sara S Martin Maureen P MP Carrington Mary M McVicar Daniel W DW Petzl-Erler Maria Luiza ML

European journal of immunology 20150506 7

Although HLA-A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA-A3 or A11 (OR = 3.76, p = 0.013) ...[more]

PMID: 25867094

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Project description:Pemphigus is a group of autoimmune bullous skin diseases that result in significant morbidity. As for other multifactorial autoimmune disorders, environmental factors may trigger the disease in genetically susceptible individuals. The goals of this review are to summarize the state of knowledge about the genetic variation that may affect the susceptibility and pathogenesis of pemphigus vulgaris and pemphigus foliaceus - both the endemic and the sporadic forms -, to compare and discuss the possible meaning of the associations reported, and to propose recommendations for new research initiatives. Understanding how genetic variants translate into pathogenic mechanisms and phenotypes remains a mystery for most of the polymorphisms that contribute to disease susceptibility. However, genetic studies provide a strong foundation for further developments in this field by generating testable hypotheses. Currently, results still have limited influence on disease prevention and prognosis, drug development, and clinical practice, although the perspectives for future applications for the benefit of patients are encouraging. Recommendations for the continued advancement of our understanding as to the impact of genetic variation on pemphigus include these partially overlapping goals: (1) Querying the functional effect of genetic variants on the regulation of gene expression through their impact on the nucleotide sequence of cis regulatory DNA elements such as promoters and enhancers, the splicing of RNA, the structure of regulatory RNAs and proteins, binding of these regulatory molecules to regulatory DNA elements, and alteration of epigenetic marks; (2) identifying key cell types and cell states that are implicated in pemphigus pathogenesis and explore their functional genomes; (3) integrating structural and functional genomics data; (4) performing disease-progression longitudinal studies to disclose the causal relationships between genetic and epigenetic variation and intermediate disease phenotypes; (5) understanding the influence of genetic and epigenetic variation in the response to treatment and the severity of the disease; (6) exploring gene-gene and genotype-environment interactions; (7) developing improved pemphigus-prone and non-prone animal models that are appropriate for research about the mechanisms that link genotypes to pemphigus. Achieving these goals will demand larger samples of patients and controls and multisite collaborations.

Dataset Information

Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo.

Publications

Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo.

Similar Datasets

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