Pathogenesis of Rheumatoid Arthritis
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Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. Although the disease is characterized by synovitis of the joints, tendon sheaths, and bursae, manifestations that do not involve the synovium are also frequent (Ref.1 and 2). The hallmarks of the synovial abnormalities in RA are synovial lining cell proliferation, neoangiogenesis, and inflammatory cell infiltration involving the myeloid, macrophage, and lymphoid lineages. In addition, the fluid-filled joint cavity contains numerous neutrophils, particularly during acute flares of RA. Disease progression can be divided into three separate, albeit interrelated, phases. Disease initiation takes place in peripheral lymphoid organs. Disease is probably initiated by dendritic cells that present self-antigens to autoreactive T cells, which in turn activate autoreactive B cells through cytokines and co-stimulatory molecules, resulting in the production of autoantibody and the deposition of immune complexes in the joint(Ref.3)

The pathology of RA is characterized by the infiltration of several inflammatory cells into both the pannus and the joint fluid, and by subsequent tissue destruction. Imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. These macrophages play a pivotal role in RA because they are numerous in the inflamed synovial membrane and at the cartilage-pannus junction. They activate MHC Class-II molecules, and secrete proinflammatory or regulatory cytokines and growth factors like IL-1, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, TNF-Alpha, GM-CSF, chemokines and chemoattractants (eg IL-8, MIP1 and MCP1), metalloproteinases and neopterin (Ref.4). TNF regulates IL-1Betaexpression, which is important for the induction of prostanoid and MMP production by synovial fibroblasts and chondrocytes (Ref.5). TNF increases the expression of adhesion molecules on endothelial cells, which recruit more cells to the joint. MCP1 and IL-8 are also secreted by macrophages and attract more cells into the joint. IL-1and TNF induce synovial fibroblasts to express IL-6, chemokines (IL-8), GM-CSFand MMPs, which contribute to cartilage and bone destruction. TNF contributes to osteoclast activation and differentiation. In addition, IL-1mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes. In addition, these chemokines, produced by RA synovial stromal cells also stimulate monocyte migration. Other cytokines such as IFN-Gamma induced chemokines also contribute to the documented morphologic and clinical features of RA (Ref.5). Autoreactive B cells can be driven by the T cells to produce IgG autoantibodies that may be directly involved in joint damage, and B cells are known to be critical in activating CD4+ T cells. As the B cell appears to play an important role in the RA process, it is appropriate to consider how B cell-mediated effects might be reduced or prevented in patients with this disease (Ref.6).

The etiology of RA also involves abnormal presentation of self antigen(s) by APCs and activation of autoreactive T-Cells. T lymphocytes play a central role in the disease process. APCs require signals from activated T-Cells for their differentiation and maturation; this subsequently enables APCs to activate newly arrived T-Cells in a specific or unspecific manner in the local inflammation. Several costimulatory molecules are involved during APC T-Cell interactions, including CD28/ CD80- CD86 and CD40- CD40L. Some of these molecules are critical in initiation of the immune response (CD28/ CD80/CD86), while CD40- CD40Lis required for the amplification of the inflammatory response. Large numbers of activated leukocytes infiltrate the synovial membrane, causing hyperplasia and inflammation, which in most cases lead to progressive destruction of cartilage and bone. Since RA is a systemic autoimmune disease, other parts/organs of the body may become affected at a later stage. Peak onset typically occurs in the fourth and fifth decades of life (Ref.7). There is also evidence that environmental factors, such as infectious agents, oral contraceptives and smoking, may play a role (Ref.8). Although the mechanisms that contribute to the pathogenesis of RA are unknown, a genetic predisposition has been identified in certain ethnic groups. This genetic predisposition, as well as the activation and affinity maturation of autoreactive T-Cells and B-Cells that are present in the joint, indicates a role for adaptive immunity in the pathogenesis of RA.