Molecule that destroys bone also protects it, new research shows

May 08, 2007

BUFFALO, N.Y. -- An immune system component that is a primary cause of bone destruction and inflammation in autoimmune diseases such as rheumatoid arthritis actually protects bone in the oral cavity from infectious pathogens that play a major role in periodontal disease in humans, research at the University at Buffalo has shown.

The component, IL-17, was recognized only in the past 18 months to be a primary cause of bone destruction and inflammation in autoimmune diseases. Therapies that target IL-17 or its cellular receptor currently are being developed.

However, a UB molecular biologist has discovered that, in contrast to its action in rheumatoid arthritis(RA), IL-17 actually protects bone in the oral cavity from infectious pathogens such as Porphyromonas gingivalis, a bacterium that plays a major role in most periodontal disease in humans.

The research findings appear in the current (May) issue of the journal Blood.

Sarah L. Gaffen, Ph.D., associate professor of oral biology in the UB School of Dental Medicine and associate professor of microbiology and immunology in the UB School of Medicine and Biomedical Sciences, is senior author. Jeffrey J. Yu, a medical student and doctoral candidate who is a researcher working in Gaffen's lab, is first author.

Gaffen and colleagues conducted the research in mice bred to have no receptors for IL-17. Other researchers had shown previously, using rats and mice as animal models, that blocking the receptor for IL-17 could be an effective therapy for RA and possibly for other autoimmune diseases such as multiple sclerosis, colitis, psoriasis and lupus.

The effects of an IL-17 deficiency in periodontal disease, however, were unknown, so Gaffen's lab set out to investigate.

"I predicted these mice without the IL-17 receptor were going to be protected from periodontal bone loss, just like they're protected from arthritic bone loss," Gaffen said. "In fact, we got the opposite result. The mice without IL-17 were much more susceptible to bone loss caused by periodontal disease, compared to normal mice.

"What's the difference between an autoimmune disease like RA and periodontal disease" Periodontal disease is an infectious disease, and as with most infectious diseases, white blood cells of the innate immune system called neutrophils play a critical role in fighting infections. In fact, humans with neutrophil defects usually lose all their teeth by the time they are 20 due to severe periodontal disease.

"It turns out that IL-17 is really important in regulating neutrophils by causing other cells in the vicinity to recruit these infection fighters to the infection site," Gaffen said.

IL-17 is a cytokine, a protein hormone made by "T helper" cells of the immune system that stimulate immunity. Gaffen noted that until recently, immunologists believed there were only two major types of "T helper" cells -- TH1 and TH2 -- which were believed to be responsible for nearly all immune system activities.

"This paradigm underwent a sea change in 2005 with the discovery of a new type of T cell that produces IL-17, now called TH-17," she said. "We know now that almost all autoimmune diseases, at least in the mouse model, are caused by TH-17 cells. This new information has forced scientists to revise completely how they view their favorite disease. Everyone now has to rethink the causative mechanism."

Gaffen said IL-17 likely would be toxic if given systemically, so it may not be a therapeutic candidate to increase immunity. But inhibitors of IL-17 are considered important targets for drugs to treat autoimmune diseases such as RA and psoriasis.

On the down side, however, this new finding indicates that inhibiting IL-17 too much could put people taking such a drug at risk for opportunistic infections such as periodontal disease and tuberculosis, she noted.

"Developing knowledge about the molecules that contribute to host defense versus pathology is very important for gaining a fundamental understanding of the immune system," Gaffen said, "but also because the consequences of therapies that target these cytokines need to be understood."
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Contributing authors, in addition to Gaffen and Yu, were Matthew J. Ruddy, Ph.D., a former graduate student in Gaffen's lab, now at the University of Chicago; Grace C. Wong, Cornelia Sfintescu and Richard Todd Evans, Ph.D., from the UB Department of Oral Biology; Pamela J. Baker, Ph.D., from Bates College, Lewiston, Maine; and Jeffrey B. Smith, M.D., from David Geffen School of Medicine, Los Angeles, Calif.

The research was supported by grants from the National Institutes of Health to Gaffen and Baker and by an oral biology training grant to Yu.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Dental Medicine and School of Medicine and Biomedical Sciences are two of five schools that constitute UB's Academic Health Center.

University at Buffalo

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