Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4+ T cells and disease activity

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.

Genetic and epigenetic alteration of the programmed cell death 1 in rheumatoid arthritis

“…When we examined PDCD1 expression, over‐expression was associated with RA, not under‐expression. This finding was in contrast to our original hypothesis but was consistent with previous studies showing increased T‐cell activation in RA, activation‐induced PDCD1 expression in T lymphocytes and increased PDCD1 protein levels in RA . This prompted us to investigate whether PDCD1 polymorphism may account for altered PDCD1 expression in RA.…”

Hypomethylation of HLA-DRB1 and its clinical significance in psoriasis

“…The presence of HLA-DR was not confined to activated CD4+ and CD8+ T cells [14]. Nagafuchi et al [15] studied immunophenotyping of peripheral blood mononuclear cells on RA patients with HLA-DRB1genotype and found the frequency of memory CXCR4+CD4+ T cells was significantly related to severity of disease. A significantly higher frequency of memory CXCR4+CD4+ T cells was found in the patients with one or more susceptible HLA-DR haplotypes, moreover, on B cells, the frequency of memory CXCR4+CD4+ T cells significantly was associated with the HLA-DR expression, which suggested that the interaction between HLA-DR and T cell receptors can regulate the memory CXCR4+CD4+ T cells.…”

Reduction of CD83 Expression on B Cells and the Genetic Basis for Rheumatoid Arthritis: Comment on the Article by Thalayasingam et al

“…A, Data from the Roadmap Epigenomics Project , indicating that rs12529514 resides near a DN ase hypersensitivity site in B cells and alters an NF ‐κB binding site close by. B, Flow cytometric analysis of peripheral blood from 106 healthy donors . Plots indicate the frequencies of B cell subsets by rs12529514 genotype.…”

“…CD83 regulates the development of murine B cells . We therefore hypothesized that CD83 expression might influence the development of human B cells, and we examined the relationship between this haplotype and peripheral blood B cells in healthy subjects from our data set . Individuals with the RA risk SNP had an increased frequency of CD27−IgD− double‐negative B cells (Figure B), a subset that is increased in the peripheral blood of RA patients and thought to be pathogenic .…”

“…We therefore hypothesized that CD83 expression might influence the development of human B cells, and we examined the relationship between this haplotype and peripheral blood B cells in healthy subjects from our data set . Individuals with the RA risk SNP had an increased frequency of CD27−IgD− double‐negative B cells (Figure B), a subset that is increased in the peripheral blood of RA patients and thought to be pathogenic . Thus, the rs12529514 risk haplotype, by reducing the expression of CD83 on B cells, may induce changes in B cell differentiation and skew the B cell compartment toward a phenotype similar to that observed in RA.…”