PHILADELPHIA - The body's immune system has sophisticated safeguards in place to prevent it from turning its destructive power against the body's own cells. Immune cells with the capability of attacking the self are readily identified in healthy individuals, and these cells are typically purged from the system. Autoimmune disorders, such as lupus, arthritis, and diabetes, are understood to result from breakdowns in those protections - they are seen as departures from the healthy norm.
New findings from researchers at The Wistar Institute, however, suggest that autoimmunity may result from the rare confluence of entirely normal events. A report on the results appears in the December 18 issue of the Journal of Experimental Medicine and is featured on the journal's cover.
The study tracked a mildly self-reactive subset of the body's so-called memory B cells - long-lived immune cells that stand ready to respond to pathogens the immune system has previously encountered. This B cell subset apparently evades detection by the immune system's screening against cells that attack self. Then, under certain circumstances, a subsequent viral infection can activate this group of cells to begin producing antibodies against self, perhaps triggering full-blown autoimmunity and disease.
"One thing this study tells us is that there doesn't appear to be any process that prevents memory B cells from generating responses to self," says Wistar associate professor Andrew J. Caton, Ph.D., senior author on the study. "It also tells us that a subsequent infection with a virus is quite capable of activating these self-reactive immune cells. It's not difficult to see how these events could lead to autoimmunity. The question then becomes how common this might be - could it explain a substantial proportion of autoimmune disease?"
Immunologists have long suspected that viral infections may be able to initiate autoimmune responses, but it has been difficult to design an experiment that would clearly and convincingly differentiate the immune system's responses to a virus from those to self.
As part of their solution this problem, the Wistar team developed a transgenic mouse that incorporates an important influenza gene into its DNA, so that the flu gene becomes self. The gene codes for a protein called hemagglutinin, responsible for much of flu's virulence. The hemagglutinin gene undergoes constant mutation that results in the appearance of several dangerous new influenza strains each year. The researchers then immunized the transgenic mice with influenza virus. The result was an autoimmune response.
"The simplest prediction was that the mouse's immune system would be blind to the virus, that it wouldn't respond to the flu infection because it recognized elements of the flu virus as self," says Caton. "But that's not what happened. The mice responded to the virus - not as vigorously as ordinary mice, perhaps, but they responded nonetheless - even though it also represented a response against self."
The reason became clear after Caton and his colleagues dissected the various stages of immune response to infection in the mice. Normally, a powerful first wave of antibodies is produced by B cells in response to a new infection, with concentrations rising rapidly in the blood over the first five to seven days. This response dominates the immune landscape initially and helps to clear the infection from the body quickly. Caton and others had previously shown that self-reactive cells are effectively eliminated from this group of cells.
The surprise, however, came when Caton's team examined a set of B cells that participate in a second wave of the immune response to infections. It has long been known that some of the B cells less vigorously involved in the first-wave infection response congregate in the spleen and in lymph nodes, joining dendritic cells and T cells to form structures known as germinal centers. (One such center is pictured on the cover of the December 18 Journal of Experimental Medicine.) Here, the B cells enter into a process called hypermutation, which creates a population of long-lived memory B cells able to even more aggressively counter future infections similar to the one just vanquished. This process underlies the effectiveness of vaccines, and the result is an improved capacity to fight off infections that come later in life.
Because the mutations that produce memory B cells are largely random, immunologists have for some time recognized that this process could potentially produce memory B cells able to react with self and assumed that a screening process of some kind must exist to eliminate the self-reactive cells. The new work from the Wistar scientists, however, shows that this is not the case. This fact would set the stage for later infections by pathogens resembling elements of self to initiate autoimmunity, and this is precisely what was seen in the transgenic mice in Caton's laboratory.
The lead author on the Journal of Experimental Medicine study is doctoral student Amy J. Reed, and Michael P. Riley, Ph.D. is a co-author. Support for the research was provided by the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1968, and one of only ten focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation. News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.wistar.upenn.edu), and to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.