Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis
We identified that the HLA-DRB1 disease-susceptible haplotype, shared epitope (SE), is related to peripheral blood mononuclear cells (PBMC) memory CD4+ T cell subset and CXCR4 expression on memory CD4+ T cells (Figs 1B and 2B)
Increased CXCR4 expression on memory CD4+ T cells from SE-positive RA (SE +RA) patients may explain the linkage between HLA-DRB1 genotype and destructive arthritis (Fig. 2C and Table 1)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. The frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. Both genetic and environmental factors contribute to RA pathogenesis[1]. In the RA synovium, there are ectopic lymphoid follicles as well as clonally expanded T cells and antigen-specific B cells that recognize citrullinated autoantigens[14,15] These findings strongly suggest that acquired immunity against autoantigens promotes local inflammation in the synovium, such as macrophage activation and inflammatory cytokine production, including TNF-αand IL-6. It has been reported that inflammatory cytokine-activated CD4+ T cells express high levels of CXCR421 and that T-cell-specific CXCR4-deficient mice show a dramatic decrease in the incidence of arthritis[22]
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