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Background: Oxymatrine (OMT) is one of the authentic Chinese herbal medicines which has rich and complex active ingredients. however,the relevant potential targets of oxymatrine on rheumatoid arthritis and the mechanism remains unreported. The aim of this study was to determine the regulation of oxymatrine on rheumatoid arthritis using a collagen‐induced arthritis (CIA) mice models and blood samples from RA patients. Results: Our results indicated that Tfr cells in RA patients express low levels of Blimp‐1 and CTLA‐4. Oxymatrine treatment of CIA mice alleviated joint swelling, reduced the arthritis score, and improved joint damage. While flow cytometry results showed that oxymatrine treatment reduced Tfh cells and B cells, and increased Tfr cells in the spleen of CIA mice. In addition, oxymatrine treatment significantly down‐regulated the expression of TLR9（Toll‐like Receptors 9), IL‐21, MyD88, STAT3, p‐STAT3, and CXCR5 in the synovial tissues of CIA mice, and up‐regulated the expression of Foxp3, Blimp‐1, and CTLA‐4. Conclusion: Oxymatrine can alleviate rheumatoid arthritis by regulating the TLR9‐MyD88‐STAT3 signaling pathway to maintain immune balance between Tfr‐Tfh cells. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic immunity and autoimmune disorders. We have previously found that oxymatrine (OMT), a natural alkaloid, can alleviate rheumatoid arthritis without knowing whether OMT can alleviate rheumatoid arthritis through gut microbiota. In this study, we found that OMT can alleviate collagen-induced arthritis in mice and reconstruct the immune balance of Th1/Th2, Treg/Th17, and Tfr/Tfh cells. Colon transcriptome gene enrichment analysis indicated that oxymatrine may alleviate collagen induced arthritis in mice through immune system process pathway. Furthermore, OMT significantly altered the gut microbiota variety, changed the composition of microbial colonies, and reshaped the gut microbiota of collagen-induced arthritis (CIA) mice, which may participate in the regulation of the balance of Th1/Th2, Treg/Th17, and Tfr/Tfh cells to alleviate collagen-induced arthritis in mice. [ABSTRACT FROM AUTHOR]

• Tfr cells repress excessive Tfh cell proliferation and might be responsible for controlling the auto-antibodies. • A relative decline of circulating Tfr/Tfh ratio may be involved in the immunopathogenesis of RA. • The transforming growth factor-β (TGF-β) secreted by Tfr cell may have important role in immune regulation Follicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. We recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-β (Transforming growth factor-β) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-β mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. RA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-β (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-β mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-β was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. The decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfh cells may be responsible for the immunopathogenesis of RA. [ABSTRACT FROM AUTHOR]