Abstract
Behçet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54–0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.
Highlights
Behçet’s disease (BD) [OMIM #109650] is a rare, chronic and systemic vasculitis characterized by recurrent oral and genital ulcers, other clinical manifestations, such as skin lesions, ocular, gastrointestinal, and neurological disorders are relatively common
The Killer-cell Immunoglobulinlike Receptor (KIR) genes encoded activator or inhibitor molecules, in general, the molecules with long cytoplasmic tails (L) contains two immune tyrosine-based inhibitory motifs (ITIM) which transduce inhibitory signals to the Natural killer (NK) cell, whereas the molecules with short cytoplasmic tails (S) possess a positively charged amino acid residue in their transmembrane region which allows them to associate with a DAP12 molecule generating an activation signal [4]
The main finding of this study is the association of the KIR3DL1∗004 with susceptibility to BD
Summary
Behçet’s disease (BD) [OMIM #109650] is a rare, chronic and systemic vasculitis characterized by recurrent oral and genital ulcers, other clinical manifestations, such as skin lesions, ocular, gastrointestinal, and neurological disorders are relatively common This chronic disorder is an immunemediated disease in which imbalances between the innate and adaptive immune response triggered by infectious agents or environmental factors in genetically predisposed individuals have been suggested as the underlying mechanisms of the disease [1]. 625 genotypes (different sets of KIR genes) named by numbers assigned sequentially have been found in the human population. 625 genotypes (different sets of KIR genes) named by numbers assigned sequentially have been found in the human population1 Based on their gene content, two kinds of KIR haplotype groups, A and B (that give rise to the genotypes AA and Bx), have been described. A different expression in the cell membrane of diverse KIR3DL1 alleles, ranging from practically null (in KIR3DL1∗004, which encodes a misfolded receptor mostly retained inside the cell) to high expression, or production of soluble forms in the case of KIR2DS4 [5, 6]
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