The inflamed synovial tissue of rheumatoid arthritis (RA) is characterized by an infiltration with Th1 cells that predominantly express the chemokine receptors CXCR3 and CCR5.
In children with JRA, synovial T cells express high levels of the Th1-chemokine receptor CC chemokine receptor 5 (CCR5), which has been implicated in susceptibility to rheumatoid arthritis.
These findings reveal that CCR5 silencing suppresses inflammatory response, inhibits viability, and promotes apoptosis of synovial cells in RA rats by inhibiting MAPK pathway.
In addition to the strong association between alleles of the HLA-DRB1*04 shared epitope and both subclinical and clinically evident CV disease, genes implicated in inflammation and metabolism, such as TNFA, MTHFR, and CCR5, seem to be associated with a higher risk of CV disease in patients with RA.
This meta-analysis demonstrates that the CCR5-Δ32 polymorphism may confer susceptibility to RA and JIA in Europeans, and suggests that the CCR5-Δ32 allele protects against the development of RA and JIA.
These results suggest that this CCR5 promoter polymorphism seems to play an important role in determining different clinical courses in both forms of rheumatoid arthritis.
Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.
The CCR5 delta32 allele seems to have some influence on RA variables including RF, which suggests that inhibition of chemokine receptors might be a potential target for disease modifying therapy in RA.
CCR5 blockade in animal models of RA results in amelioration of arthritis, suggesting that CCR5 blockade could also modify disease in patients with RA.
These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA.
However, after adjusting for gender, age at time of RA diagnosis, and the presence of shared epitope, rheumatoid factor and classic CV risk factors in the Cox regression analysis, this reduction of CV events in CCR5Δ32 allele carriers was slightly outside the range of significance (P = 0.097; hazard ratio 0.37 (95% CI 0.12 to 1.19)).
This study provides further evidence for a protective effect of the CCR5 d32 variant on rheumatoid arthritis, consistent with a role for CCR5 and its ligands in disease pathogenesis.
The expression of several potential SOX5-targeted genes, including matrix metalloproteinases (MMP-1, 2, 3 and 9), chemokines (CCL4, CCL2, CCR5 and CCR2), and pro-inflammatory cytokines (TNF-α and IL-6), were examined in RA-FLS using SOX5 gain- and loss-of-function study.
Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles)