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Spotlight on Research for 2006
Scientists Identify Possible Lupus Susceptibility Gene
Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) have identified a gene in mice that they believe may hold a key to the development of - and perhaps treatment of - systemic lupus erythematosus in people.
Systemic lupus erythematosus, or lupus, is a chronic inflammatory disease that can affect many organs of the body, including the skin, joints, heart, lungs, kidneys and brain. It occurs when cells of the immune system - chiefly a type of white blood cells called B cells - mistakenly see the body's own proteins as foreign and mount an immune response against them. As a result, the system that was designed to protect the body from harmful invaders instead inflicts harm.
While our bodies may produce some of these so-called auto- or self-reactive B cells, they also have mechanisms to keep these cells in check. Autoreactive B cells are usually kept in check through three mechanisms:
- Deletion. Immature self-reactive B cells die when they recognize and bind to the body's proteins.
- Receptor editing. The specificity of the B cell changes so that it no longer recognizes body proteins as foreign and therefore does not target them for destruction.
- Anergy. The self-reactive B cells are paralyzed so that they cannot function when they recognize and bind to body proteins.
It's when there is a problem with these protective mechanisms that autoimmune diseases such as lupus and damage to tissues can occur. In the June 16 edition of Science, Chandra Mohan, M.D., Ph.D., of the University of Texas Southwestern Medical Center in Dallas and her colleagues show that the censoring of autoreactive B cells is impaired due to an alternative form of the gene Ly108. This gene is part of a gene family (SLAM) that has been linked to lupus-like disease in mice.
Although the role of the alternative form of the gene has been shown only in mice thus far, the finding may well have implications for human lupus, says Dr. Mohan, the study's senior author. "The role of Ly108 in human disease as well as how the gene functions at the molecular level are important areas of future research," he says."If we can find the key molecules that Ly108 communicates with to affect apoptosis, receptor editing and anergy, the hope is that some of these molecules could be good targets for therapeutic intervention."
The key benefit of such interventions, says Mohan, is that they could be more specific to the aberrant immune process in lupus rather than blocking the entire immune response - leaving people open to serious infections and other side effects - as many current therapies do. "The hope is that it would not affect all the B cells and non-B cells indiscriminately, but selectively target the autoreactive B cells", he says.
Additional support for the study was provided by the National Institute of Allergy and Infectious Diseases and the Lupus Research Institute.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
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Kumar KR et al. Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 2006;312(5780):1665-1669.