Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that may affect many tissues and organs, but mainly targets the synovial membrane, cartilage and bone. RA affects about 1% of the world's population, is three times more frequent in women than in men, and is associated with significant disability and increased mortality. The articular manifestations of RA are mediated by extensive infiltration of inflammatory cells into the synovium and proliferation of synovial fibroblasts of the joint lining, leading to the formation of pannus tissue which invades and destroys the articular cartilage and bone.The crucial triggers for the onset of RA are still not completely understood, but genetic and environmental factors both appear to play roles. Several genetic loci (HLA-DR4 and related allotypes of MHC class II, PTPN22, PAD14, CTLA4, FcγR, and various cytokines) have been shown to have an association with the susceptibility and severity of RA. Environmental factors (pathogen, smoking) may also have an impact on the induction and progression of the disease.
The key features of RA are autoimmunity, chronic inflammation and destruction of the cartilage and bones.
The etiology of RA seems to involve abnormal presentation of self-antigens by antigen presenting cells (APC) and activation of autoreactive CD4+ T cells. Auto-antigens are generated from damaged joint tissues and necrotic cells in response to articular injury, either prior to disease initiation or during its course. Self-antigen bound to MHC class II on the surface of APC are recognized by T cells via T-cell receptor (TCR). This process requires several costimulatory molecules, including CD28-CD80/CD86, and cytokine-driven stimuli. The synovial milieu contains numerous cytokines produced principally by dendritic cells, monocytes, synovial fibroblasts and macrophages, such as IL-1, IL-6, IL-7, IL-12, IL-15, IL-18, IL-23, TGFβ and TNF (PMIDs: 18454151,17676045,18771589,16200070,17525752). These cytokines promote the expansion and differentiation of the T helper 1 (Th1) and Th17 cell populations. Activated T cells promote the disease progression by secreting cytokines such as TNF, IL-17 and IFN-γ (PMIDs: 18166487, 18400188, 18771589, 17525752), which lead to the proliferation, activation and cytokine release from synovial fibroblasts, monocytes, and neutrophils. T cells also induce the production of pro-inflammatory cytokines from macrophages, fibroblasts and endothelial cells in a cell-contact-mediated mechanism. They also release RANKL (PMIDs: 17572649,18799853,17525752) and to a lesser extent M-CSF (PMID: 17525752), which are the primary mediators of osteoclastogenesis.
Furthermore, autoreactive T cells play a role in the production of autoantibodies by providing help to B cells. Autoantibodies specific for IgGFc, known as rheumatoid factors, or specific for citrullinated peptides (ACPA) are present in the majority of patients prior to clinical detection of RA. Studies suggest that the disease involves abnormal B cell - T cell interaction, with presentation of self-antigen by B cells to T cells, eliciting T cell help and production of rheumatoid factors and ACPA by plasma cells (PMIDs: 6334356,17132692). Once rheumatoid factors recognize the Fc portion of IgG, they form an immune complex, which enhances macrophage activation through Fc receptors and induces activation of the complement cascade, thus exacerbating inflammation (PMID: 17121483). In addition to autoantibody production, activated B cells secrete cytokines such as IL-1, IL-6, IL-10, IL-15 and TNF, which activates macrophages, synovial fibroblasts, endothelial cells, osteoclasts and chondrocytes and therefore contribute to RA pathogenesis (PMID: 17525752).
Presence of activated autoreactive T cells and B cells in the joint indicates a role for adaptive immunity in the pathogenesis of RA.