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MGH researchers first to identify genetic malfunction in type 1 diabetes

A research study from the Massachusetts General Hospital (MGH) has identified a gene malfunction that appears to be central to the development of type 1 diabetes. The study in a classic animal model of type 1 diabetes found that a gene required to help teach the immune system to recognize so-called "self" proteins is somehow inactivated, even though its sequence is not mutated. The scientists also found that the inactivation of this gene called Lmp2 has a profound impact on another key protein called nuclear factor kappa-B (NF-kB), a major controller of several immune system activities. Finding ways to correct or circumvent the malfunction identified in this study may lead to ways of preventing or stopping the autoimmune reaction at the heart of type 1 diabetes.

"This is a true genetic abnormality we can associate with type 1 diabetes," says Denise Faustman, MD, PhD, of the MGH Diabetes Unit, who led the study appearing in the December issue of Molecular and Cellular Biology. "While Lmp2 is located in a portion of the genome that had been linked to the disease, it hadn't been considered a candidate because its sequence is normal. But studying the gene's function has showed us a previously unsuspected problem: In the immune system cells we looked at, the Lmp2 protein virtually disappears by the time these mice reach a certain age, therefore most likely initiating their diabetes."

Type 1 diabetes (also called juvenile or insulin-dependent diabetes) is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells of the pancreas. Normally, immune system components called T cells learn not to attack the body's own tissues through the action of MHC Class I molecules, which sit on the surface of B cells and macrophages. There the molecules display tiny bits of "self" proteins to the T cells, the immune system's killers, essentially teaching them to ignore the body's own tissues. Another kind of MHC molecule, cal
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Contact: Susan McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
23-Nov-1999


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