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  • Pathogenesis of rheumatoid arthritis

    The initiation of rheumatoid arthritis (RA) results from a combination of predetermined (genetic) and stochastic (random environmental) events. The human leukocyte antigen (HLA) major histocompatability (MHC) genes are the most important, but many other genes are involved and contribute to susceptibility and severity. The most likely mechanism for the environmental component is repeated activation of innate immunity. There is a propensity in RA for immune reactivity to develop to the neoepitopes created by the protein modification, such as citrullination, that results from environmental stressors like smoking; this leads to the production of anti-citrullinated protein antibodies (ACPA) that could initiate inflammation by fixing complement in the tissues. Like antibodies, levels of multiple cytokines gradually increase in the years before RA symptoms occur.

     

    ●Once the autoimmune process is established, the synovium in RA organizes into an invasive tissue that can degrade cartilage and bone. The rheumatoid synovium has many characteristics of a locally-invasive tumor.

     

    ●Activation of innate immunity is probably the earliest process in RA, followed by citrullination, loading of antigen-presenting cells (APCs) with either native or modified proteins in the joint, and then migration to central lymphoid organs. Once there, APCs present an array of antigens to T cells, which can then activate B cells and/or can migrate back to the synovium. It is unlikely that a single “rheumatoid antigen” exists. Instead, a broad spectrum of joint-specific antigens, such a type II collagen or nonspecific citrullinated antigens, is responsible.

     

    ●One of the earliest histopathologic responses in RA is the generation of new synovial blood vessels, which is accompanied by the transudation of fluid and the transmigration of both lymphocytes into the synovium and of polymorphonuclear leukocytes into the synovial fluid. As the new vessels develop, cytokines produced in the synovium in response to tumor necrosis factor (TNF) activate endothelial cells to produce adhesion molecules, which expedite activation-dependent sticking of leukocytes, thereby facilitating diapedesis and extravasation into the synovium.

    ●Autocrine and paracrine communication through the elaboration of a cascading network of proinflammatory cytokines plays a key role in initiation and perpetuation of RA and result in a “transformed phenotype” of synovial lining cells. Inflammatory cells are recruited to the bland synovium by the actions of interleukin (IL)-17A, TNF, IL-1, IL-6, IL-18, vascular endothelial growth factor, alarmins like IL-33 and high-mobility group box protein 1 (HMGB1), and chemokines. Retention in the synovium is facilitated by inhibition of apoptosis and other innate immunity mechanisms by interferon (IFN)-alpha and -beta, IL-15, and TNF. The T cells become organized and activated in the presence of IL-23, IL-27, IL-12, IL-15, IL-18, and chemokines. Simultaneously, the proliferative/destructive component of synovitis is generated by TNF, IL-17, bone morphogenic proteins, and transforming growth factor (TGF)-beta. Mast cell products may also have an important role.

    ●Cadherin-11, a synovial fibroblast membrane protein, mediates the organization and invasion of fibroblast-like synoviocytes (FLS) into synovial tissue. Activated rheumatoid synovium eventually destroys cartilage at the cartilage-pannus junction. The destruction of cartilage, bone, and tendons in RA is initiated largely by metalloproteinases. At sites of active RA, there is a dramatic imbalance of bone turnover in which local bone resorption outweighs bone formation.

     

    ●The role of B cells is supported by the therapeutic effect of B cell-targeted biologic agents. The mechanism of action for B cells is uncertain, but could involve either pathogenic antibody projection, cytokine production, or antigen presentation.

     

    ●The cellular components of rheumatoid synovial fluid differ from those in the synovium. As examples, neutrophils are rarely seen in RA synovium but are abundant in RA synovial effusions, and there is a predominance of CD4+ T cells in the tissue while CD8+ cells are typically more prevalent in the fluid. Products of neutrophils that are released into the synovial fluid can cause considerable damage and can potentiate inflammation in the adjacent synovium.

     

    ●Complement activation and its interactions with immune complexes are important in RA, especially in synovial effusions and at the cartilage interface. Additional factors, including nitric oxide (NO), neuropeptides, and arachidonic acid metabolites, may play a contributory role in the pathogenesis of RA.

    Ref: http://www.uptodate.com/

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