The immune system functions by means of complex mechanisms, many of which involve the bone marrow-derived B cells and the thymus-derived T cells. Until recently, RA was believed to be a T-cell-mediated autoimmune disorder. This hypothesis was based on several factors, such as the association with HLA-DR allotypes, the dominant presence of T cells over B cells, and an assumed dependence of macrophage cytokine production on T-cell activation.

Although T cells play a crucial role in the pathogenesis of RA, newer evidence suggests that B cells exert some degree of control over T-cell activity. Recent studies involving patients with autoimmune disorders demonstrate that depletion of B cells in the peripheral bloodstream results in a decrease in disease activity despite unchanged levels of immunoglobulins. This suggests that the role of B cells in autoimmune disorders extends beyond the antibody-dependent mechanisms.

The current hypothesis implies that B cells participate in the pathogenesis of RA via three specific mechanisms.

First, and most significantly, B cells located in the synovium produce the auto-antibody rheumatoid factor (RF). The chronic inflammatory process seen in RA is perpetuated by rheumatoid factor through multiple mechanisms, including the formation of immune complexes, the production of TNF-a, T-cell involvement, and complement activation.

Second, B cells located within the syn-ovium also secrete pro-inflammatory cytokines and chemokines, which contribute to the inflammation and joint destruction seen in RA.

Last, B cells function as efficient antigen-presenting cells (APCs) and provide important costimulatory signals required for T-cell activation. Once activated, the T cells further stimulate the proliferation and differentiation of B cells through the secretion of cytokines, resulting in a vicious circle that is manifested clinically as RA. buy cialis soft tabs

The Target: CD20 Antigen

The CD20 antigen is highly expressed on B cells, excluding stem cells, pro-B lymphocytes, and plasma cells. This feature makes CD20 an attractive target for monoclonal antibody therapy, whereas its absence from stem cells, pro-B lymphocytes, and plasma cells allows for the regeneration of the B-cell population as well as the production of immunoglobulins. Decreased immunoglobulin levels are seen with prolonged anti-CD20 antibody therapy because plasma cells are derived from activated B cells. Other favorable characteristics include these facts:

  • CD20 does not modulate its own expression.
  • CD20 is not shed from cell surfaces, and it is not internalized upon antibody binding.
  • No membrane or secreted molecules interfere with its function.
  • CD20 antigen is not found in the circulation.

The Antibody: Rituximab

Rituximab is a genetically engineered chimeric monoclonal anti-CD20 antibody.

It is the only anti-CD20 antibody that the Food and Drug Administration (FDA) has approved for use in humans. Ritux-imab, by targeting CD20, produces a selective transient depletion of the B-cell population through multiple mechanisms, including antibody-dependent cellular toxicity, complement-dependent cytotoxicity, the induction of apoptosis, and alterations in the ability of B cells to respond to antigens.
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Rituximab was originally approved for use in patients with relapsed or refractory CD20-positive, B-cell non-Hodgkin’s lymphoma. On August 29, 2005, Biogen and Genentech submitted a supplemental Biologics License Application (sBLA) for the use of rituximab in patients with active RA who were responding inadequately to anti-TNF therapy. As a result of its Priority Review designation, the FDA approved the agent for the treatment of RA on February 28, 2006.