Association of Functional Polymorphisms of KIR3DL1/DS1 With Behçet's Disease

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.

Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population—Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures

“…The AA genotype was most frequent (ID: 1, 24.15%), followed by six BX genotypes (ID: 4, 2, 5, 7, 3 and 6) which, together, account for more than 50% of individuals; and by the two most common BB profiles (ID: 71 and 72; 3.14 and 2.66%, respectively). The overall distribution of KIR-gene frequencies and profiles observed in our sample is not dissimilar from those reported in other Caucasoid populations, and it is also consistent with those found in other large samples of Spanish individuals (40,(51)(52)(53).…”

The association of Behçet's syndrome with HLA-B51 as understood in 2021

“…Of these, Phe at 67, Leu at 116, Thr at 116, and Glu at 152 of the HLA-B molecules are considered critical as these residues located in the MHC-I antigen-binding groove affect the binding of antigenic peptides. Moreover, Phe at 67 and Thr at 116 are involved in the interactions of HLA-B molecules with killer immunoglobulin-like receptors (KIR)3DL1 and KIR3DS1, which regulate the activation of natural killer (NK) cells and CD8+ T cells [ 30 ]. Likewise, residues 67 and 116 are considered critical in disease-susceptible HLA-A molecules [ 9 ▪▪ ].…”

Associations of Genes for Killer Cell Immunoglobulin-like Receptors and Their Human Leukocyte Antigen-A/B/C Ligands with Abdominal Aortic Aneurysm

“…However, in the HLA-A-Bw4/KIR3DL1 interaction, other amino acid residues within and outside the Bw4 motif sequence also play a role; as Saunders et al 2021 write, “differential recognition across HLA-Bw4 allotypes is therefore likely a product of polymorphic residues in both the a1 and a2 domains, differences in peptide repertoire and conformation, as well as KIR3DL1 allotype” [ 39 ]. The inhibitory KIR3DL1 is one of the most polymorphic alleles of all the KIR loci and is divided into three allotype groups: KIR3DL1Null (*004, *019), which show no expression at the cell surface, KIR3DL1Low (*005, *007) showing low expression, and KIR3DL1High (*001, *002, *008, *009, *015, *020) exhibiting high expression at the cell surface [ 28 , 29 , 44 , 45 ]. However, our test did not differentiate exactly between these groups, particularly between KIR3DL1Null and KIR3DL1Low, dividing KIR3DL1 into two groups only.…”