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January 31, 2000

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Salmonella's Molecular Mimics May Spark Arthritis

Scientists at Johns Hopkins have uncovered an important link between getting specific bacterial infections and developing autoimmune diseases such as arthritis.

In a study reported in this month's edition of the journal Nature Medicine, the researchers show clearly that immune system cells which fight bacteria can also attack normal cells carrying a specific mimic molecule -- one that closely resembles a bacterial protein.

Further, they show that as long as there's been a previous bacterial infection, immune cells can attack "innocent bystander" cells -- body cells that bacteria have never infected. This occurs when the cells are stressed by exposure to irradiation, environmental toxins or the body's stress chemicals.

"We've found this evidence that the immune system can be fooled," says Mark Soloski, Ph.D, who led the research team, "and it suggests subtle changes that could underlie many autoimmune diseases." The study also offers a starting place for scientists to investigate environmental or genetic triggers to autoimmune diseases.

The team focused on infections by Salmonella, bacteria well known for food poisoning but also long thought to trigger arthritis in some people. "As many as 10 percent of those who get Salmonella develop a ‘reactive' kind of arthritis which lasts a few weeks," says Soloski. "But a smaller, significant number of those patients get a severe, debilitating type of arthritis that's long-lasting."

To investigate bacteria/arthritis connections, the scientists observed behavior of a typical bacteria-fighting immune cell, the cytotoxic lymphocyte (CTL), as it approached infected body cells. Cells invaded by bacteria normally give clear signals that they're infected. "They display small pieces of bacterial proteins on their surface that say, in effect, ‘Hey, here's a sick cell,'" says Soloski. Attracted by this protein "flag," CTLs dock with the infected cells and trigger their rapid self-destruction.

The Hopkins scientists first identified the protein "flag" in mouse cells infected with Salmonella as one common to certain bacteria associated with human arthritis, including Borrelia -- the cause of Lyme disease.

But they also found the bacterial "flag" was almost identical to parts of a "universal housekeeping molecule" found in humans, mice and all living organisms. This "housekeeping molecule" helps proteins keep their shape.

When researchers artificially coaxed mouse body cells to display the Salmonella "flag," the mouse CTLs would readily attack them. But CTLs also went into attack mode if the cells displayed a piece of the mouse's own housekeeping molecule or the identical human version. "This shows us the immune cells readily respond to a molecular mimic," says Soloski.

In a normal Salmonella infection in mice, Soloski says "at least half of the CTLs are stirred up to recognize the mouse's own protein as well as the bacterial one. That's a huge immune response." Based on the similarity of the set-up in humans, he adds, the response is likely the same. Now the scientists are trying to find why and how this immune response translates into arthritis in some mice and humans.

In a small side study, the team also found that normal, uninfected body cells could be attacked by CTLs if the cells were stressed in some way, such as being exposed to higher temperature or radiation or general infection. "We don't know what's going on here," says Soloski, "but it's a good place to study other triggers of autoimmune diseases."

Other researchers were lead author Wei-Feng Lo, M.D., Ph.D., Amy DeCloux, Ph.D., Amina S. Woods, Ph.D., and Robert J. Cotter, Ph.D., of Hopkins, as well as Eleanor S. Metcalf, Ph.D., of the Uniformed Services University of the Health Sciences in Bethesda, Md.

The research was funded by NIH grants and by an award from the Maryland Chapter of The Arthritis Foundation.

Related Web site: http://www.med.jhu.edu/gradweb/immunology/faculty/soloski.html


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