Apr. 23, 2002 In a finding that could lead to better treatments for lupus, a Princeton biologist has pinpointed what appears to be a central cause of the disease.
Martin Weigert and colleagues have discovered a point at which the immune system's procedure for making disease-fighting antibodies breaks down and allows antibodies to attack the body's own DNA, which is the hallmark of lupus.
Although the processes involved are complex and remain partly unexplained, the failure comes down to a relatively simple mechanism that may be an attractive target for drug developers, said Weigert. He already is developing molecules that would block the disease in mice and could be the starting-point for a drug for humans.
Lupus is part of a diverse group of disorders called autoimmune diseases, in which the immune system mistakenly attacks the body's own tissue. In lupus, the mistaken target is DNA, which is present throughout the body. The disease has various forms that range in severity from mild rashes to fatal complications. It affects about 1.4 million Americans, 90 percent of whom are women, according to the Lupus Foundation of America.
Doctors currently use essentially the same treatment for all autoimmune conditions: steroids or other drugs that suppress the immune system in a very broad way. Often this approach cannot control the disease without causing a dangerous immune deficiency.
"We are now in a position to be able to tailor our approach to very specific autoimmune diseases," said Weigert, a professor in the Department of Molecular Biology.
Weigert and collaborators at Princeton, the University of Pennsylvania and the University of Tennessee published their discoveries regarding lupus in a series of recent papers, including one in the December issue of Cell and another in the Jan. 21 issue of the Journal of Experimental Medicine.
The researchers started with mice that have lupus and isolated the gene responsible for making one section of their DNA-attacking antibodies. They introduced the gene into healthy mice and were surprised to find that it did not cause these mice to have lupus. The mice turned out to have a natural mechanism for "editing" the antibodies so they no longer reacted with DNA.
The most recent studies showed, again unexpectedly, that mice with lupus also successfully edit their antibodies. However, they then mistakenly "re-edit" them, restoring their attraction for DNA.
These editing processes occur in an immune system component called B cells, which produce antibodies. The researchers found that normal, healthy editing has the effect of covering or neutralizing certain DNA-attracting chemical units on the surface of the B cells. The re-editing in lupus mice re-exposes these chemical units, which have a strong chemical attraction for the phosphates that make up the backbone of all DNA.
Weigert believes the phosphate-attracting chemicals could be a prime target for a drug to treat lupus. He has begun to design small protein fragments, called peptides, that could bind to these chemicals and neutralize them, which may have the same effect as editing.
"I think it's quite important work," said David Nemazee, an immunologist at the Scripps Research Institute in California, who independently discovered the healthy editing process at the same time as Weigert several years ago. Nemazee said Weigert pioneered the use of genetically altered mice to explore how B cells are regulated and how that regulation relates to autoimmune disease.
Nemazee added, however, it is too early to say whether the processes Weigert discovered in mice will explain lupus in people, even though mouse and human immune systems are very similar. "As with all these diseases, we are using fairly artificial animal models," said Nemazee.
Weigert started his research with a longstanding quandary in immunology: How does the immune system distinguish viruses, bacteria and other disease-causing agents from its own tissue? "To me, it's one of the most fascinating questions in all of science," he said.
Weigert's discovery of B-cell editing showed one important way in which the body eliminates self-directed antibodies. He realized, however, that such a general mechanism could not completely answer the question. It required finding the precise mechanism of a particular disease in which self-tolerance failed, he said.
"The fundamental scientific questions that we set out to answer just came closer and closer to -- and, in fact, depended on -- the disease," said Weigert.
Weigert noted that the lupus finding probably is not directly applicable to other autoimmune diseases. In fact, it helps to show that each form of autoimmunity is likely to be caused by a specific and unique kind of failure. "The tendency has been to look for some general breakdown in self-tolerance that explains all autoimmune diseases," he said. Even though there may be no such universal mechanism, he said, "tracking down the unique aspects of each one is within our ability."
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