UCSD discovery may help humans
By Jeff Ristine
UNION-TRIBUNE STAFF WRITER
January 30, 2001

A University of California San Diego lab has identified a genetic cause of an autoimmune disease in mice that is similar to the most common form of lupus in humans.

In findings published today, researchers say the discovery is a first step in determining how much a similar genetic defect may be responsible for human autoimmune disorders.

The work establishes a cause-and-effect relationship between problems with the carbohydrates that form a coating on the outside of cells and an autoimmune disease, said Jamey D. Marth, a professor of cellular and molecular medicine at UCSD's School of Medicine.

Researchers determined a particular gene is part of an enzyme essential to the proper formation of carbohydrate structures that cover cell surfaces.

The structures control the development and function of the immune system. When the enzyme is missing, the mice usually develop the lupus syndrome.

UCSD's findings are published in Proceedings of the National Academy of Sciences.

The lupus syndrome involved in the mouse research is a close counterpart to systemic lupus erythematosus, or SLE, in humans. Lupus is a chronic inflammatory disease in which the body's immune system mistakenly attacks normal tissue.

SLE is the most common form of lupus. When left untreated, it can cause life-threatening damage to organs and tissues.

But the human disease does not yet have a defined genetic cause.

"The big question that this work opens up is, are there humans that have autoimmune disease due to the same genetic defect," said Marth, a Howard Hughes Medical Institute associate investigator and senior author of the journal report.

The mouse findings, he said, give researchers at least a lead in finding a new target for diagnostic tests in humans: carbohydrate deficiency.

Marth said the study of genes controlling the formation of carbohydrate structures on cell surfaces is a frontier in biomedical research, only five to six years old. Scientists want to know how the structures can alter metabolism or cause disease when they change, which can affect how they interact with other cells.

The UCSD lab bred mice without a specific enzyme called alpha-monnosidase II. Researchers found that loss of the enzyme interferes with the production of a cell-surface carbohydrate structure called complex-type N-glycans.

The abnormal N-glycans formation, in turn, produced kidney inflammation, eventual loss of kidney function, premature death in some cases and other hallmarks of the mouse lupus syndrome.

"That type of a cause for autoimmune disease has never been identified before," Marth said.

More than 5 percent of the adult population has some variety of autoimmune disease, including many forms of diabetes and arthritis. Some autoimmune conditions are believed to have hormonal or environmental causes, rather than genetic underpinnings.

Lupus affects nearly 1 million people in the United States, mostly women. Symptoms can include rashes, arthritis, skin ulcers and painful breathing.

Researchers from the Department of Biochemistry at London's Imperial College of Science, Technology & Medicine contributed to the journal report. The work was supported by grants from the National Institutes of Health and the Hughes Institute.



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