An Immune Killer's Modus Operandi

Scientists appear to have unraveled a mysterious chain of biochemical events that leads to scleroderma, a sometimes-fatal immune disease. But experts disagree about whether the findings, reported in the current issue of the Journal of Experimental Medicine, might lead to earlier diagnosis and better treatments for the disease. Scleroderma, a thickening of the connective tissue of the skin, kidneys, lungs, and heart, attacks mainly women between 30 and 60 years of age.

A team led by Johns Hopkins University rheumatologist Antony Rosen set out to discover why the immune systems of scleroderma patients attack several of the body's own proteins. They speculated that one feature of the disease--intermittent poor blood flow--might abet a chemical reaction that produces oxygen radicals. They think the proteins bind to metals such as iron and copper in the bloodstream, generating oxygen radicals. These unstable forms of oxygen would be "so reactive that they would break the protein," Rosen says, warping familiar structural proteins into forms that the immune system views as foreign.

To test this scenario, Rosen and his colleagues added iron and cooper to cell cultures and monitored the effect on blood proteins. The result: The proteins were disfigured in the same manner seen in scleroderma. Rosen believes specific protein-cleavage patterns might serve as harbingers of scleroderma, providing a way to diagnose the disease early on. His group is also exploring potential drugs or dietary treatments that would block the metal-protein interactions and thus prevent the proteins from being cleaved.

Some experts caution, however, that Rosen's theory remains unproven. Although the study is "quite provocative," says Sergio Jimenez, director of rheumatology at Thomas Jefferson University in Philadelphia, it raises "false hope for treatment." Further research is needed, he says, to show that the peculiar protein-cleavage patterns are the cause of scleroderma and not simply a symptom.

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