Prior to this new study from Yale, which was published in the August 7, 2008 online edition of Immunity, researchers thought that B lymphocytes only produced autoantibodies and plasma cells (which, in turn produce autoantibodies), if they’re first activated by T lymphocytes. Autoantibodies damage the body's cells and initiate the autoimmune disease process in many different autoimmune diseases, including systemic lupus erythematosus (SLE), Graves' disease, and rheumatoid arthritis.
Importance of the Study
The study, headed by lead investigator Mark Shlomchik, MD, PhD, suggests that new therapies designed to inactivate B lymphocytes or intervene with their activities may have important therapeutic implications. This study is the direct result of a 5-year investigation into the role of Toll-like receptors in antibody production.
This study also helps understand the results of a previous study on B cells. In this study, the same Yale researchers working with collaborators from Boston University, showed that Toll-like receptors in the body can react with “self” antigens, that is, the body’s own protein particles. In doing so, the Toll-like receptors activate B cells to make the classical autoantibodies seen in systemic lupus erythematosus (SLE). Previously, researchers thought that Toll-like receptors were only activated by molecules expressed on microbial pathogens.
The Study’s Interpretation
In their new study the Yale researchers found that this ability of self antigens to react with the Toll-like receptor stimulates B cells to begin autoantibody production. In doing so, the mechanism in which T cells activate B cells to produce antibodies is completely bypassed. In a vicious cycle, the activated B cells can go on to recruit T cells to participate in the autoimmune process. Consequently, an ongoing process occurs in which autoantibody production persists.
Why Certain Treatments Fail
The new Yale study also explains why treatments for autoimmune disease that target T lymphocytes often don’t work while some of the newer treatments aimed at B cells have shown great promise. One example, the anti-CD20 B cell inhibitor rituximab has shown to be beneficial in rheumatoid arthritis. Rituximab was approved as a treatment for arthritis in 2007.
In addition, tumor necrosis factor (TNF) inhibitors such as Enbrel are reported to evoke improvement in some chronic autoimmune diseases because of their ability to suppress B cells. In another study researchers at Rochester University found that anti-TNF drugs disrupt the architecture of structures in the lymph system called germinal centers. These centers release B cells when the immune system is stimulated, for instance, in response to infection. In healthy people, once an infection is beaten off, the germinal centers fade away. But in people with a chronic autoimmune disease, such as rheumatoid arthritis or lupus, germinal centers stick around too long, preparing an army of immune cells that wreak havoc throughout the body.
Resources:
The Arthritis Foundation Research Alert, A New View of TNF Inhibitors, Jan 22, 2008
B Cells Can Act Alone in Autoimmune Disease, Yale Researchers Report, Yale University Office of Public Affairs, August 7, 2008.
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