Identifying Cytokines in Rheumatoid Arthritis
Identifying Cytokines in Rheumatoid Arthritis
In 1990 Dr. Firestein and his mentor Dr. Nathan Zvaifler wrote a review article that was instrumental in changing the way scientists thought about chronic rheumatoid synovial. inflammation. In the decade prior to this article, published in Arthritis & Rheumatism, most models of RA synovitis theorized that T cells were solely responsible for orchestrating the local inflammatory response. However, Firestein and Zvaifler pointed out that many typical features of T-cell–mediated diseases were not present in the joints of patients with rheumatoid arthritis (RA). They challenged this paradigm based on their data mapping the cytokine profile of the rheumatoid arthritis synovium.
Through years of work in their lab, along with analyzing the results of other scientists, Firestein and Zvaifler concluded that:
1. Most articular T cells are small and quiescent.
2. Most cytokines produced by activated T cells (such as interleukin [IL]-2, IL-3, IL-4, γ interferon) in the rheumatoid synovium are found in relatively low concentrations compared with the amounts produced by activated T cells in well-defined T-cell–mediated diseases.
3. T cells from the rheumatoid joint or from peripheral blood of people with RA do not consistently display evidence of antigen-driven proliferation.
4. Although several T-cell–specific treatments have been tested, improvement generally is limited and temporary.
Drs. Firestein and Zvaifler went on to cite studies from their own lab as well as others demonstrating that macrophage-like cells and fibroblast-like cells in the synovium are highly activated in rheumatoid joints. They also noted that products of these cells, such as IL-1, tumor necrosis factor (TNF)-α, IL-6, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, prostaglandins and collagenase, are abundant in synovial fluids and synovial tissues. Although studies in the last few years have revealed some evidence of T-cell activation in the joint, it is quantitatively well below the highly activated state of macrophages and fibroblasts.
They stated that “The cytokine profile of the rheumatoid synovium suggests an alternative to the traditional paradigms of T-cell–driven perpetuation of synovitis.” They concluded the editorial with “The corollary is that therapeutic endeavors aimed at interrupting the flow of mononuclear cells into the joint or controlling the activation of synovial fibroblasts and/or macrophages will be more successful than current methods of treatment.” From these statements – along with the work of other fine scientists in the field – grew the class of therapy known as biologic response modifiers.
