Adaptive immunity in the joint of rheumatoid arthritis

Abstract

Adaptive immunity plays central roles in the pathogenesis of rheumatoid arthritis (RA), as it is regarded as an autoimmune disease. Clinical investigations revealed infiltrations of B cells in the synovium, especially those with ectopic lymphoid neogenesis, associate with disease severity. While some B cells in the synovium differentiate into plasma cells producing autoantibodies such as anti-citrullinated protein antibody, others differentiate into effector B cells producing proinflammatory cytokines and expressing RANKL. Synovial B cells might also be important as antigen-presenting cells. Synovial T cells are implicated in the induction of antibody production as well as local inflammation. In the former, a recently identified CD4 T cell subset, peripheral helper T (Tph), which is characterized by the expression of PD-1 and production of CXCL13 and IL-21, is implicated, while the latter might be mediated by Th1-like CD4 T cell subsets that can produce multiple proinflammatory cytokines, including IFN-c, TNF-a, and GM-CSF, and express cytotoxic molecules, such as perforin, granzymes and granulysin. CD8 T cells in the synovium are able to produce large amount of IFN-c. However, the involvement of those lymphocytes in the pathogenesis of RA still awaits verification. Their antigen-specificity also needs to be clarified.

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“…It was reported that IL-4 produced by Th2 T cells inhibits OCs formation and function in vitro [86,99,100]; nonetheless, no functional activity has been reported in vivo. On the other hand, Th1 CD4 + T cells, which counter regulate Th2 cells, are found in the synovium fluid of patients with active RA [101], although it has been demonstrated that the secretion of IFN-γ by this T cell subset strongly inhibits osteoclastogenesis and protects against bone tissue degradation by OCs [102].…”

“…It is clear now that the identity of T cell subsets is critical in guiding their role on bone remodeling system, during homeostasis or in pathological conditions [67]. In particular, Th1, Th2, Th17, Th22, and T reg CD4 + and CD8 + cells have been shown to influence bone metabolism [67,[86][87][88][89]. In the RA scenario-the best studied human disease in osteoimmunology-the importance of Th17 CD4 + T cells is evident, beginning by their infiltration into the synovium and the association of disease susceptibility with specific variants of T-cells-related genes, such as HLA-DR (MHC class II cell surface receptor encoded by the human leukocyte Ag gene complex), Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22), and C-C Motif Chemokine Receptor 6 (CCR6) [40,63].…”

“…Interestingly, it has been found that a particular type of Th17 CD4 + T cells, derived from FoxP3 + Treg CD4 + T cells (called exFoxP3 Th17 T cells), have a much stronger pro-osteoclastogenic activity than conventional Th17 CD4 + T cells [86,93]. Under arthritic conditions induced in mice model, FoxP3 + Treg CD4 + T cells lose FoxP3 by the action of IL-6 produced by synovial fibroblasts [46,83,94].…”

“…IFN-γ induces a strong inhibition of the RANKL-induced activation of the NF-κB, via a rapid degradation of TRAF6 [102]. In arthritic synovium, Th1 CD4 + T cells are not considered to be activated but often display an exhausted phenotype and express low levels of IFN-γ [86][87][88][89].…”

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“…Adaptive immunity plays a central role in the pathogenesis of RA. Synovial T cells are involved in the induction of antibody production and local inflammation ( 198 ). In particular, CD4 + T cell subsets can differentiate to produce a variety of pro-inflammatory cytokines and chemokines, which are involved in the pathogenesis of RA.…”