CCR5 (chemokine receptor-5) DNA-polymorphism influences the severity of rheumatoid arthritis

Abstract

Chemokines are critical for the inflammatory process in autoimmune diseases such as rheumatoid arthritis (RA). The chemokine receptor-5 (CCR5) mediates chemotaxis by CC-chemokines and is expressed by lymphocytes with the Th1 phenotype and monocyte/macrophages. A 32 bp deletion in the CCR5 (CCR5-⌬32 allele) abolishes receptor expression in homozygotes, while CCR5-⌬32 carriers would express less receptor than wild-type homozygotes. This polymorphism is related to the resistance to HIV-1 infection and progression towards AIDS. We hypothesized that the CCR5-⌬32 allele may modulate the severity of disease in RA. A total of 160 RA-patients (71 and 89 with severe and non-severe phenotypes, respectively) and 500 healthy individuals from the same Caucasian population (Asturias, northern Spain) were genotyped. Carriers of the CCR5-⌬32 allele were at a significantly higher frequency (P = 0.012) in non-severe compared to severe patients (17% vs 4%). Our results suggest that the CCR5-⌬32 polymorphism is a genetic marker related to the severity of RA. Genes and Immunity (2000) 1, 288-289.Keywords: chemokines; CCR5-⌬32 allele; rheumatoid arthritis; disease severity Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease of the joints characterized by the infiltration of the synovial membrane with T lymphocytes and macrophages, and pannus formation over the underlying cartilage and bone. The inflammatory process observed in RA is mediated by chemotactic factors released by the inflamed tissues. Chemokines display a potent chemotactic activity for cells of the immune system, playing an important role in both the destructive and the fibrovasculoproliferative phases of RA.1 The chemokine receptor-5 (CCR5) mediates chemotaxis by the CC-chemokines RANTES, MIP-1␣ and MIP-1␤. This receptor is expressed by lymphocytes exhibiting the Th1-phenotype and by monocytes/macrophages. 2In addition to its role in inflammation, CCR5 also acts as an HIV-1 coreceptor to mediate the first step in cell entry:fusion of the viral envelope with the membrane in the the target CD4 + cell. A 32 bp deletion at the coding region of the CCR5 gene, the CCR5-⌬32 mutation, leads to the expression of reduced amounts of the CCR5 protein in heterozygous individuals.3 CCR5-⌬32 homozygotes do not express the receptor and have nearly complete resistence to HIV-1 infection despite repeated exposure, while heterozygotes progress slowly towards AIDS compared to wild-type homozygotes. 4 The CCR5-

Negative association between the chemokine receptor CCR5-Δ32 polymorphism and rheumatoid arthritis: a meta-analysis

“…Refined analysis by rheumatoid factor status and gender were precluded by the lack of availability of such information from all studies. Of the 5 studies, three studies provided proportion of female patients, 12,14,15 which ranged from 71 to 84%, similar to frequencies of female RA patients in other published studies. Only one study provided the proportion of patients positive for rheumatoid factor.…”

“…It has been reported that individuals heterozygous for CCR5-D32 have a milder phenotype of disease. 12,15 However, others have concluded that the presence of CCR5-D32 does not influence the phenotype of RA. 13,17 Counter to the proposed role of CCR5 in RA are observations of individual RA patients who are homozygous for CCR5-D32.…”

“…[12][13][14][15][16] Two of them demonstrated statistically significant negative associations between CCR5-D32 and RA. 13,14 Three other studies did not demonstrate statistically significant associations but suggested a negative association.…”

Chemokines and their receptors in rheumatoid arthritis: Future targets?

“…As a prelude to chemokine targeting in humans, one study has shown decreased severity and incidence of RA in patients with the CCR5 ⌬32 allele, which codes for a nonfunctional CCR5 allele (123,124). Another study showed that this allele was found less frequently in patients with RA (125).…”

Polymorphisms in CCL2&CCL5 chemokines/chemokine receptors genes and their association with diseases

“…The CCR5Δ32 is a genetic marker related to the severity of RA 115 . Recent study provides further evidence for a protective effect of the CCR5Δ32 variant on rheumatoid arthritis in a New Zealand cohort 116 .…”