Using genetically altered mice, Yale researchers have generated a clearer picture of the origins of B cells and their involvement in autoimmune diseases such as lupus, rheumatoid arthritis and diabetes.
Published in the September 20 issue of Science, the study, led by Mark Shlomchik, M.D., associate professor of laboratory medicine at Yale School of Medicine, looked at B cells' reactions to its own toxins, known as antigens. B lymphocyte cells normally produce antibodies to viruses and bacteria, which protect against infection. However, when these antibodies are directed toward the body's own components they are called "autoantibodies," which can cause inflammation and autoimmune disease.
"B cells that react with 'self' antigens (autoreactive B cells) are very important in the origins of these autoimmune diseases," said Shlomchik. "These B cells make autoantibodies, and also stimulate white blood cells called autoreactive T lymphocytes that destroy tissues, such as the kidney, joints and skin which are the major organs affected in Lupus and Rheumatoid Arthritis." In normal individuals these B cells are tightly controlled and prevented from making autoantibodies.
Shlomchik said the scientific community has known for 15 years that autoantibodies undergo the same processes that generate memory immune responses to viruses. The most important of these processes is called somatic hypermutation, which refers to changes in the genetic code that produces the antibodies. As a result, every immune response contains many subtle variations that critically increase the breadth and strength of the response. There is no other similar process in any cell in mammals, and in B cells it is thought to occur normally in a unique site called the germinal center. However, until now no one had shown where autoantibodies were generated.
The researchers used a strain of mice that were prone to autoimmune diseases to visualize autoreactive B cells. They found that the autoantibody reaction does not take place in the germinal center as previously thought, but in an unusual area of the spleen.
The team also demonstrated that somatic hypermutation of autoantibodies occurs outside of the germinal center in this unusual part of the spleen. These findings suggest that in lupus and other autoimmune diseases, B cells that create autoantibodies escape normal controls by proliferating and undergoing somatic hypermutation outside of the germinal center, which is the normal location for these processes.
Other authors on the study included Jacqueline William and Sean Christensen, both MD/Ph.D. students at Yale; and Chad Euler who was a research technician in the Shlomchik lab.
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