Background/Purpose: Rheumatoid arthritis (RA) is a common chronic inflammatory disorder characterized by bone erosions and progressive joint destruction. Genetic, epigenetic and environmental factors may induce self-tolerance breakdown, inducing autoimmunity. Killer Cell Immunoglobulin Receptors (KIR) are expressed on NK and T cytolytic cells, and recognize human leukocyte antigens class-I (HLA-A, -B, and -C). KIR/HLA interactions are important in self-tolerance maintenance, regulating the function of cytolytic cells. KIR gene cluster is located on chromosome 19q13.4 and behaves in a polygenic and polymorphic fashion. Near 100 KIR haplotypes have been described and are broadly classified in Haplotype-A (with a fixed group of genes, mainly inhibitory KIRs) and Haplotype-B (more diverse and with more activating KIRs). Every individual has two KIR haplotypes, each formed by a telomeric and a centromeric set of A or B KIR genes.

Methods: Case control study of allelic frequency of KIR and type I HLA genes in 151 RA patients and 150 healthy controls from south-eastern Spain. DNA was extracted from peripheral blood samples. KIR/HLA-I genotyping was performed by PCR-SSP/SSO. HLA-C genotypes were classified into C1 (Asn80) and C2 (Lys80), KIR haplotype was classified into A and B. Specific combinations of KIR were analysed to explore centromeric and telomeric A and B haplotypes.

Results: KIR2DL5 (p=0.049, OR=1.6, 1.01-2.53), KIR2DS3 (p=0.002, OR=2.12, 1.3-3.48) and KIR3DS1 (p=0.021, OR=1.73. 1.10-2.74) were significantly associated to RA. The presence of HLA-B*39 (p=0.028, OR=4.05, 1.1-14.84) associated to RA and HLA-A*33 (p=0.03, OR=0.24, 0.67-0.879) and HLA B*38 (p=0.035, OR=0.197, 0.042-0.916), were found protective. Moreover, RA patients showed a significantly higher frequency of KIR Haplotype B than controls (p< 0.001, OR=2.49, 1.43-4.3), also centromeric B01 (cB01) haplotype (p=0.003, OR=2.13, 1.27-3.78). In RA patients, haplotype-B correlated with absence of HLA-A*01 (Speraman’s Rho (r)=-0174, p=0.04) and HLA-B*57 (r=-0.194, p=0.02). Besides, KIR2DS3 correlated with the presence of HLA-C*06 (r=0.174, p=0.033). KIR3DS1 correlated with the presence of HLA-B*40 (r=0.227, p=0.006) and absence of both HLA-C*07 (r=-0.204, p=0.012) and HLA-B*57 (r=-0.190, p 0.022). Haplotype-B did not associate to type I HLA alleles, HLA-C genotypes, distinct clinical manifestations, severity or disability, autoimmunity or treatment profile. cB01 haplotype was associated to a less nodular (p .024) OR 0.29 (0.09-0.89) and less seropositive (p .008) OR 0.40 (0.20-0.80) rheumatoid disease.

Conclusion: Our data provide evidence that KIR/HLA-I genes, and particularly KIR haplotype, contribute to RA susceptibility. We present a novel genetic risk locus for RA, related to innate immune mechanisms implicated in self-recognition and cytolysis, mainly by NK cells. Studies focused in KIR expression and interaction with HLA or other potential ligands may improve knowledge in RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/killer-cell-immunoglobulin-receptor-and-class-i-hla-genetic-variability-in-south-eastern-spanish-rheumatoid-arthritis-patients/