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. This is a chronic, debilitating autoimmune disease of unknown etiology affecting diarthrodial joints. Although the disease is characterized by synovitis of the joints, tendon sheaths, and bursae, manifestations that do not involve the synovium are also frequent [1,2]. These articular and systemic manifestations are mediated by hyperplasia of the synovial lining cells and extensive infiltration of macrophages, lymphocytes, fibroblasts, and leukocytes in joints, where a variety of cytokines, prostaglandins, and proteolytic enzymes are responsible for the process of the inflammation. 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 [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. Chemokines, as well as other inflammatory mediators, play key roles in the pathogenesis of RA, and the coordinated production of chemokines and proinflammatory cytokines is important in the orchestration of the inflammatory responses observed in patients with RA. Imbalance between pro- and anti-inflammatory cytokine activities favors the induction of autoimmunity, chronic inflammation, and thereby joint damage. Monocytes that are attracted to the RA joint differentiate into macrophages and become activated. 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 (Major Histocompatibility Complex 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 (Tumor Necrosis Factor), GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor), chemokines and chemoattractants (eg IL-8, MIP1 [Macrophage Inflammatory Protein-1] and MCP1 [Monocyte Chemoattractant Protein]), metalloproteinases, and neopterin [4]. TNF regulates IL-1Beta expression, which is important for the induction of prostanoid and MMP (Matrix Metalloproteinases) production by synovial fibroblasts and chondrocytes. Cellular interactions mediated by TNF and IL-1, cytokines that are mainly produced by activated macrophages are prominent factors leading to cartilage damage in RA [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-1 and TNF induce synovial fibroblasts to express IL-6, chemokines (IL-8), GM-CSF, and MMPs, which contribute to cartilage and bone destruction. TNF contributes to osteoclast activation and differentiation. In addition, IL-1 mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes. However, these cells of the innate immune system possess broad proinflammatory, destructive, and remodeling capacities, and considerably contribute to inflammation and joint destruction both in the acute and chronic phases of RA. In addition, these chemokines, produced by RA synovial stromal cells also stimulate monocyte migration. Other cytokines such as IFN-Gamma (Interferon-Gamma) induced chemokines also contribute to the documented morphologic and clinical features of RA [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. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in RA patients under a continuous stimulation. Being much more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present antigens to T lymphocytes in the synovial environment [6].

The etiology of RA also involves abnormal presentation of self antigen(s) by APCs (antigen-presenting cells) and activation of autoreactive T-cells. T lymphocytes play a central role in the disease process. The rheumatoid synovial membrane is rich in MHC Class-II, APCs, and CD4+ T-cells. However, it is not clear whether T-cell activation occurs before entry to the tissue, during transendothelial migration, or in the synovium. 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. Activated T-cells promote the disease progression by inducing the secretion of pro-inflammatory cytokines (in particular, TNF-Alpha) from macrophages and synovial cells in a contact-dependent manner. Several costimulatory molecules are involved during APC–T-cell interactions, including CD28/CD80-86 and CD40-CD40L. Some of these molecules are critical in initiation of the immune response (CD28/CD80/86), while CD40-CD40L is required for the amplification of the inflammatory response. Early indications of RA are swelling and pain of the proximal interphalangeal and metacarpophalangeal joints. Later, the larger joints become affected, especially those of the knee, elbow, and ankle. 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. An example of this is the formation of rheumatoid noduli. Peak onset typically occurs in the fourth and fifth decades of life [7]. Like many autoimmune diseases, RA occurs more frequently in women than in men (3:1 ratio), suggesting a role for sex hormones. Thyroid or other neuroendocrine hormones can also influence RA, at least partly through actions on macrophages. There is also evidence that environmental factors, such as infectious agents, oral contraceptives, and smoking, may play a role [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.


Pathway

Pathogenesis of Rheumatoid Arthritis

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References
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  2. Klarenbeek NB, Güler-Yüksel M, van der Heijde DM, et al. (2010) Clinical synovitis in a particular joint is associated with progression of erosions and joint space narrowing in that same joint, but not in patients initially treated with infliximab. Ann Rheum Dis 69(12):2107-13. Epub 2010 Jul 7.
  3. Rommel C, Camps M, Ji H (2007) PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?  Nat Rev Immunol 7(3):191-201. Epub 2007 Feb 9. Review.
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  8. Pedersen M, Jacobsen S, Klarlund M, et al. (2006) Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res Ther 8(4):R133.