Rheumatoid arthritis (RA)

Rheumatic diseases

Rheumatic diseases are different painful medical conditions, which primarily affect joints, tendons, ligaments, bones, and muscles. Rheumatic diseases can also affect internal organs, skin and blood vessels. Common symptoms are pain, swelling, and stiffness. Rheumatic diseases are characterized by loss of functions of connective or supportive tissues. There are many different types of rheumatic diseases, arthritis, and related conditions. The picture, from medicalgeek.com, demonstrates the arthritic and normal joints.

Rheumatoid arthritis (RA)
RA is an autoimmune rheumatic disease affecting millions of people, and is an important cause of disability and even mortality across the world. Arthritis means joint inflammation and is just a part of the rheumatic diseases. RA most often affects the joints of the hands and feet, which are usually inflamed in a symmetrical pattern so that both sides of the body are affected. RA is most likely triggered by a combination of factors such as genetic susceptibility, abnormal autoimmune responses and even environmental or biologic factors, such as infection.

Autoantigens
Autoantigens are normal tissue constituents, which can become the target of a humoral or cell-mediated immune response initiating autoimmune diseases. Determining autoantigens targeted by the autoimmune response in RA has been a priority and an essential step for understanding the molecular mechanisms involved in pathenogenesis of RA and also for the immunotherapy of patients. So far, several autoantogens such as cartilage antigens, heat shock proteins, viral/bacterial antigens and several other autoantigens have been shown to be asscociated with RA. It should be noted that RA is a systemic disease. Thus, the candidate autoantigens may not necessarily be restricted to the joint components.

Genetic factors
Genetic factors play key roles in RA either by increasing susceptibility to the disease or by worsening the disease process. The association of RA with the human leukocyte antigens (HLA) was discovered when the frequency of HLA haplotypes, such as HLA-Dw4, HLA-B27 and HLA-DR4, were found to be increased in RA patients. The HLA system or the human major histocompatibility complex (MHC) are composed of cell surface proteins, which are encoded by the genes located on chromosome 6. HLA play an essential role in normal  immune responses by presenting both non-self (microorganisms) and self antigens to T cell receptors (TCR) on T cells. This presentation may also lead to development of autoimmunity. Genetic mutation, for example, in type II collagen, has also been shown to be associated with some form of arthritis.

Immunology of RA
The immune responses in RA involve numerous different immune cell types, including B cells, T cells, neutrophils, professional antigen presenting cells such as DCs and macrophages. They also involve molecules such as antibodies and components of the complement system, which can cause further recruitment and activation of the macrophages and neutrophils to the site of inflammation. Cytokines that regulate a broad range of inflammatory responses are also involved in the pathogenesis of RA. Besides, chemokines, which are involved in recruitment of leukocytes to the site of inflammation have also been shown to play a role in the pathogenesis of RA by recruiting leukocytes to synovial tissues.

T cells
The strong association of RA with specific HLA molecules and the observations that in experimental animal models of RA the disease can be transferred by isolated T cells, are among the most acceptable arguments in favor of an essential role for T cells in RA. Among the T helper cell populations, Th1 and Th17 cells have been reported to play a pathogenic role in RA. Several reports support a role for IL-17 in promoting rheumatoid arthritis. However, careful investigations are required to further identify the importance of Th17 cells in RA. Regulatory T cells (Treg) can play a critical role in preventing autoimmune diseases. However, the importance of Treg cells in RA and whether or not defect in these cells can contribute to the pathogenesis RA is not completely known. It has been shown that patients with RA exhibited substantial increased frequency of Epstein Barr Virus (EBV)-specific effector memory CD8+ T cells, indicating a role for these cells in RA. Note that EBV can trigger RA.

B cells
B cells most likely play several roles in the development of RA via presentation of antigens, activation of T cells, secretion of antibodies and proinflammatory cytokines such as TNF and IL-6. Several autoantibodies, such as rheumatoid factor (RF), have been shown to be associated with RA. RF is an autoantibody produced against the Fc portion of IgG, which form immune complexes and contribute to RA. Conversely, a negative regulatory role for IL-10- and TGF beta-producing B cell population in animal model of RA has been reported.

Macrophages and Dendritic cells (DCs)
These professional antigen-presenting cells (APC) are very crucial for immune responces especially for activation of T cells via processing and presenting antigens bound to their MHC class II molecules. Macrophages are involved in leukocyte migration to the site of inflammation, matrix degradation and angiogenesis. These cells contribute significantly to the pathology of many chronic inflammatory diseases, including RA. The cytokine produced by these cells, such as TNF, IL-6 and IL-1 has been targeted by different biological therapies. DC also play a central role in immune and inflammatory responses and contribute significantly to the maintenance and progression of RA. Interestingly, a group of DC, plasmacytoid DC, have been shown to mediate immune tolerance. These cells play a regulatory role in RA via induction of IL-10- and TGF beta-producing Treg cells.

For further information, I encourage you to refer to the recently published review articles in the journal "Nature Reviews Rheumatology"  at: http://www.nature.com/nrrheum/index.html