Overabundance of Immune Cells Might Trigger Lupus

THURSDAY Feb. 14, 2008 -- Researchers from Saint Louis University report that a pile-up of superfluous immune cells might contribute to lupus, a finding which could point to new therapies for the autoimmune disease.

"We're on the precipice of finding new treatments for lupus," said Dr. Jill Buyon, a professor of medicine at New York University School of Medicine. "There are a myriad of targets at different levels of the immune system. What we're seeking are therapies that are targeted that would not cause patients to have overwhelming infection [as side effects]. This paper supports the notion that such therapeutic approaches might be possible."

More than 1.5 million Americans have lupus, a disease in which a hyperactive immune system assaults otherwise healthy organs, such as the kidney, brain, heart, lungs and skin, as well as joints and blood.

The current standard of treatment typically involves nonsteroidal anti-inflammatory drugs (NSAIDs), anti-malarials and steroids.

Immunosuppressive medications -- such as azathioprine and cyclosporine -- are also used to dampen an immune system gone haywire. However, such regimens, while effective, can provoke severe side effects.

"There hasn't been a drug approved [for lupus] by the FDA [U.S. Food and Drug Administration] for 40 years," Buyon said. "This is a time of major discovery, probably one of the most exciting times we'll ever see."

The current study, published in the Feb. 15 issue of Immunity, is a small one involving only 14 patients with lupus and an equal number of healthy controls.

Researchers did a genetic analysis of three different types of white blood cells and found that, in patients with more severe lupus, there was an increase in the activity of genes that normally would prevent the death of a cell, compared to the controls.

"There are essentially two death pathways in cells, one that takes signals from the outside of the cell and one from the inside," explained study senior author Harris Perlman, an associate professor of molecular microbiology and immunology at Saint Louis University, in St. Louis. Normal cells are given signals to die at certain points to make room for new cells.

Perlman and his colleagues knocked out one gene from each pathway in mice with lupus. "Lo and behold, these mice that have two death pathways knocked out developed massive lupus," he said. "They died at four to five months of age."

Individuals with lupus produce more immune cells that carry too many of the proteins that prevent death. The more immune system cells a patient had, the more severe the disease was.

The next step is to manipulate these genes, or the proteins they produce, to restore a natural life cycle to the cells.

"If you can somehow turn off these anti-death genes then you can restore the balance again," Perlman said. "We have dome preliminary work and seen some positive results. We're not trying to do gene therapy approach. We're going to try to look at protein levels and remove proteins from the equation by inactivating them."

Although it's not clear that this finding specifically will bring relief to some people suffering from lupus, it is emblematic of a new era in research.

"We have a smorgasbord of discovery," Buyon said. "The challenge to industry and clinical trialists is picking and choosing which target to go after, because it costs so much to bring a drug to market."

More information

Visit the Lupus Research Institute for more on what's being done in this field.

Posted: February 2008


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