Mouse study points to carbohydrate
By Edward Edelson
MONDAY, Jan. 29 (HealthScout) -- Identification of a gene in mice whose absence causes an autoimmune disease remarkably similar to systemic lupus erythematous (SLE, or lupus) in humans has given valuable new insights about a condition that affects 1 million Americans, researchers say.
In lupus, the human immune system somehow turns against the body's own tissues, causing progressive and potentially fatal damage to the kidneys, heart, lungs, spleen and other organs. The cause of the disease is unknown, as the reason why 90 percent of patients are women and why African-Americans and Hispanics are at higher risk.
Work with the mouse gene points a finger toward the role of carbohydrates in making the immune system run amok, says a report in the Jan. 30 issue of the Proceedings of the National Academy of Sciences by a group led by Jamey D. Marth, professor of cellular and molecular medicine at the University of California, San Diego School of Medicine.
Lack of an enzyme called alpha-mannosidase II causes the lupus-like disease in mice, the report says. That enzyme is essential for formation of carbohydrate structures called N-glycans, which are found on the surfaces of cells and that play a key role in the process by which cells of the immune system make the distinction between invaders that should be attacked and the body's own tissues.
Gene testing spurs research
Marth says he has long suspected that N-glycans play a role in autoimmune diseases such as lupus and multiple sclerosis, but that investigating that possibility became possible only in the last few years, when genes controlling their production have been identified and cloned.
His work focused on alpha-mannosidase II because it is a starting point for the variation in the structures of N-glycans. Marth and his team bred mice deficient in the gene for the enzyme, then made a detailed study of their organs and tissues. They found that the mice had not only abnormally low levels of the glycans but also abnormally shaped glycans that could produce an autoimmune response.
The lymphocytes that play a central role in the immune response were normal in these mice, Marth says. But there were elevated levels of the antibodies that attack bacteria and other foreign invaders. And the mice suffered kidney inflammation and scarring severe enough to be fatal in some cases. Other tissues also suffered damage from the autoimmune attack, although to a lesser extent than the kidneys.
"This is an entirely new manner by which autoimmune disease can occur, by a gene controlling carbohydrate formation," Marth says.
"This is very interesting work by a very good group published in a very good journal," says Dr. Evelyn V. Hess, professor of medicine at the University of Cincinnati Medical School and an advisor to the Lupus Foundation of America. It also turns attention toward the role of carbohydrates in autoimmune diseases, rather than the proteins, which have been of more interest to researchers, she says.
"I have noticed more interest in the last six months in research with carbohydrates rather than proteins, which opens up a whole new area of investigation," Hess says.
Carbohydrate research is applicable not only to lupus but also to other autoimmune conditions, Marth says. He calls it "an emerging area of biomedical research" that has a name all its own: glycobiology.
What To Do
The clinical payoff
from such a pioneering research effort may be years away.