The Wistar Institute
(PHILADELPHIA - April 16, 2002) - Scientists know that the potential to generate dangerous antibodies that attack our own cells and tissues - one of the defining characteristics of autoimmune disorders like lupus - exists in everyone. That potential is unrealized in healthy individuals, but spins out of control in those who develop disease. So, what are the factors that push the potential for producing these antibodies into action and cause autoimmunity in some individuals? A new study from researchers at The Wistar Institute suggests that health depends on maintaining a balance of normal, but countervailing processes in the immune system. New approaches to developing treatments for autoimmunity might focus on influencing this balance.
In lupus and other autoimmune diseases, antibodies against our own cells and tissues are produced by B cells. The body contains billions of B cells that can make antibodies that target infecting viruses and bacteria, but these antibodies can also include ones that can react with "self" - an immunologist's term for our own bodies. One process that normally prevents these B cells from causing harm is that their activity depends on receiving "help" from T helper cells that also become stimulated when an infection occurs. However, another kind of T cell, called a regulatory T cell, may be important in preventing T helper cells from activating B cells with the potential to generate self-reactive antibodies.
Under normal circumstances, according to the Wistar study, a critical balance may exist between T helper cells and regulatory T cells. The researchers saw that providing T helper cells to healthy mice could cause autoreactive B cells to become active, and that removing T helper cells could alleviate disease in lupus-prone mice. They also found that regulatory T cells could stop T helper cells from activating the B cells, suggesting that the presence of self-reactive T helper cells with too few regulatory T cells may be crucial for the activation of B cells producing self-reactive antibodies in lupus. A report on the research appears in the April issue of Immunity.
"We first established in the laboratory that auto-reactive B cells do respond to stimulation from T helper cells by producing antibodies against self," explains Wistar associate professor Jan Erikson, Ph.D., senior author on the study. "This was not in itself unexpected because studies by others had suggested this might be the case. We were, however, somewhat surprised at how easy it was to trigger this potentially damaging production of auto-reactive antibodies in the lab."
"When we looked to see how the process might unfold in mice predisposed to develop lupus, we saw that, while the same thing happened, it was delayed. What was exciting to us was that a class of immune cells called T regulatory cells appeared to actively suppress the development of autoimmunity in these lupus-prone mice, at least for a time."
Erikson notes that lupus is a disease that primarily affects women in their reproductive years, suggesting that a similar delaying process may be at work in people who will later in life develop the disease. In terms of possible new therapies for autoimmune disorders, the new findings also shift attention from the antibody-generating B cells to the T cells that interact with them.
"One approach to lupus that has been considered is to delete from the circulation the subset of B cells that are self-reactive," Erikson says. "Our work suggests that knowing more about the specificity of the T cells that stimulate and suppress B cells might be an important path to explore too."
The Wistar study focused on some of the precursor events that lead to autoimmunity. To make eventual use of findings of this kind in a clinical setting, it would be critical to know if findings made in these animal models predict whether a particular person might be at risk for developing lupus or a similar disorder.
"The work we're doing looks at the beginnings of disease, before there
are clinical symptoms," Erikson says. "Other researchers are working to
iron out the genetics of predisposition to autoimmune diseases such as
lupus. That work and ours may come together at some point in the future."
The lead author on the Immunity study is Su-jean Seo at The Wistar Institute. The other Wistar-based coauthors are Michele L. Fields, Jodi L. Buckler, Amy J. Reed, Laura Mandik-Nayak, and Simone A. Nish. Wistar associate professor Andrew J. Caton, Ph.D., collaborated on the study, as did Randolph J. Noelle at Dartmouth Medical School, Laurence A. Turka at the University of Pennsylvania Medical Center, and Fred D. Finkelman at the University of Cincinnati College of Medicine.
Funding for the research was provided by the National Institutes of Health, the Arthritis Foundation, and, with support for Michele L. Fields, the Howard Hughes Medical Institute.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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