Thursday, June 8, 2023
In accordance with ACCME Standards for Commercial Support of Continuing Medical Education and the Health Science Center for
Continuing Medical Education Disclosure Policy for CME Activities, faculty members have been asked to disclose any relationship
they may have with commercial supporters of this CME activity or with companies providing drugs, medical equipment, etc, that
may have relevance to the content of their presentations. Such disclosure is intended to provide participants with sufficient
information to evaluate whether any given presentation has been influenced by the faculty's relationship(s) or financial interests
with said companies.
The following faculty have reported receiving something of value from the commercial supporter(s) of this activity or from
a corporate organization whose product(s) may have relevance to the content of their presentations:
Professor, Academic Section of Musculoskeletal Disease, University of Leeds; Clinical Director, Department of Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, England
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Although there is little doubt that immune complex formation can account for some of the hallmarks of the disease, it has become increasingly clear that T lymphocytes are central to the pathogenesis of RA.[11,16,17] The importance of T cells in RA is supported by the observations that a large number of these cells accumulate in the joints of patients with RA[18]; that T cells from the synovium of patients with RA are able to transfer disease to immunodeficient mice[19]; and that the depletion of pathogenic T cells prevents collagen-induced arthritis in mice.[20]
In response to activation by antigen presentation, CD4+ T cells initiate and regulate several cell-mediated immune processes that cause the synovial inflammation and joint destruction of RA (Figure 1). Activated CD4+ T cells release chemical mediators, such as interferon (IFN)-γ and interleukin (IL)-17, which stimulate the activity of other immune cells (such as B cells, monocytes, macrophages, and fibroblasts). These stimulated immune cells then release a second set of chemical mediators that induce inflammation and joint damage, including inflammatory cytokines IL-1 and IL-6, tumor necrosis factor (TNF)-alpha, as well as matrix metalloproteinases and other substances, such as prostaglandins and nitric oxide, which destroy connective tissue.[11] Two of these inflammatory cytokines, TNF-alpha and IL-1, appear to be of particular importance in the development of joint injury in RA. TNF-alpha is released primarily by monocytes and macrophages, although it is also released by B cells, T cells, and fibroblasts. TNF-alpha produces direct inflammatory effects by increasing the expression of cell-surface adhesion molecules that are used by leukocytes to migrate into inflammatory tissues,[16] and indirectly promotes inflammation by stimulating the release of a number of other proinflammatory cytokines, including IL-1, IL-6, and IL-8. IL-1 is also released by monocytes, macrophages, endothelial cells, B cells, and activated T cells. Both TNF-alpha and IL-1 stimulate the release of matrix metalloproteinases from fibroblasts and chondrocytes.[16]
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Figure 1. (click image to zoom) Antigen-bearing dendritic cells (DC) in the lymph node activate T cells (T) to proliferate and differentiate.
Activated T cells are essential for the initiation of the immunologic cascade underlying rheumatoid arthritis (RA) pathogenesis,
including subsequent activation of B cells (B), macrophages (M-phi), and fibroblast-like synoviocytes (FLS) (anti-CCP Abs
= anticyclic citrullinated peptide antibodies; TNF-alpha = tumor necrosis factor-alpha; IL-1 = interleukin-1; MMPs = matrix
metalloproteinases).
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CD4+ T cells also activate macrophages and chondrocytes in the synovium by direct cell-to-cell interactions that are mediated by cell-surface receptor molecules (Figure 2). In addition, CD4+ T cells stimulate the production of antibodies, including RF, by B cells and promote the proliferation of bone-resorbing osteoclasts, which contribute to further bone injury (Figure 2).[16] As T cells infiltrate the joint, their activity may be maintained by local joint antigens that are unrelated to the autoantigens that initiated the disease process.[11]
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Figure 2. (click image to zoom) Cytokines secreted by activated T cells and direct cell-to-cell interactions activate the key cells
involved in RA pathology (OC = osteoclast; C = chondrocyte; PMN = polymorphonuclear leukocyte [neutrophil]).
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Under normal circumstances, T cells do not produce immune responses to self-antigens, as cells that react to self-peptides complexed with MHC are eliminated during T-cell development in the thymus. This is the main mechanism, known as central tolerance, by which the immune system establishes and maintains nonresponsiveness or tolerance to self. In general, it is thought that T cells in patients with RA may escape tolerance to joint-specific antigens (eg, type II collagen, proteoglycans, aggrecan, and cartilage link protein) or systemic antigens (eg, immunoglobulin [Ig]G Fc, citrullinated proteins, heat shock proteins, and glucose-6-phosphate isomerase) by 2 different means.[11] The cells may escape tolerance to the self-antigen directly. Alternatively, the cells may escape tolerance to the self-antigen indirectly by a process known as molecular mimicry, in which T cells generated in response to an exogenous antigen (eg, a viral peptide) cross-react with a self-antigen.
