OVERVIEW OF PATHOGENESIS OF RHEUMATOID ARTHRITIS
Two important types of factors seem to have a strong impact in the development of rheumatoid arthritis.
1. Genetic Factors
The link to HLA-DR4, and particularly with subtypes Dw4 and Dw14, as well as with the structurally related Dw1 subtype of HLA-DR1. It is currently accepted that such DR subtypes may be structurally fitted to present a peptide to autoreactive or cross-reactive helper T lymphocytes, thus precipitating the onset of the disease.
2. Hormonal Factors
The role of hormonal factors is suggested by two observations:
1. RA is three times more frequent in females than in males, predominantly affect-ing women 30–60 years of age.
2. Pregnancy produces a remission during the third trimester, sometimes followed by exacerbation after childbirth.
These observations suggest that hormonal factors may have a significant effect on the de-velopment of rheumatoid arthritis. However, to this day the responsible factors have not been defined. On the other hand, a possible mechanism by which pregnancy would cause an improvement in the clinical picture has recently suggested by the observation that es-trogens potentiate B lymphocyte responses in vitro. This increased B-cell activity is likely to reflect a shift of predominant TH activity from TH1 to TH 2, which is considerable less pro-inflammatory.
Three main mechanisms responsible for the escape from tolerance that must be associated with the onset of RA have been proposed.
1. Decreased activity of downregulating T cells
2. Nonspecific B-cell stimulation by microbial products (e.g., bacterial lipopolysaccharide) or infectious agents (e.g., viruses)
3. Stimulation of self-reactive T lymphocytes as a consequence of the presentation of a cross-reactive peptide (possibly of infectious origin) by an activated antigen-presenting cell (e.g., dendritic cell or RF+ B cell)
The genetic linkages discussed earlier support the last theory. Also, the key role of T lymphocytes is supported by histological data (discussed earlier) and by the observations that HIV infection and immunosuppression for bone marrow transplantation, two conditions that depress helper T-lymphocyte function very profoundly, are associated with remissions of RA.
Once helper T cells are activated, a predominantly TH1 response develops. Activated TH1 cells release interferon-γ and GM-CSF, which activate macrophages and related cells, in-ducing the expression of MHC-II molecules, creating conditions for continuing and stronger stimulation of helper T lymphocytes. As this cross-stimulation of TH1 lympho-cytes and macrophages continues, chemotactic factors are released and additional lympho-cytes, monocytes, dendritic cells, and granulocytes are recruited into the area. As inflam-matory cells become activated, they release proteases and pro-inflammatory mediators, such as PGE2. The release of proteases will cause damage on the synovial and peri-synovial tissues, while the activation of osteoblasts and osteoclasts by mediators released by acti-vated lymphocytes and macrophages (particularly IL-1 and IL-6) is the cause of bone dam-age and abnormal repair.
While our understanding of the basic immune abnormalities and of the self-perpetuating circuits involved in RA has become more complete, there is considerable uncertainty about the factor(s) that may be responsible for the initiation of the disease. There is also very lit-tle knowledge about the factors that localize the disease to the joints on the initial stages. For example, there is experimental evidence supporting a critical role of DC, probably by promoting autoreactive T-cell activation, but there is no logical way to explain how the DC would be initially activated and localized to the synovial tissue. Observations in animal models suggest that arthritis can develop in the absence of autoreactivity to joint antigens, a model that could explain the association with infections such as those caused byProteusmirabilis and Epstein Barr virus. What this model fails to provide is an explanation for thelocalization of the ensuing autoimmune reaction to the joints. In addition, the MHC molecules linked to RA appear to be able to recognize peptides derived from joint tissue what triggers the initial activation of antigen-presenting cells in the joints to an extent that the recognition of self peptides takes place in an environment conducive to the develop-ment of an immune response rather than maintaining the normal state of anergy.
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