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21 June 2010

Genetic defect tied to autoimmune diseases

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Rare variations in a single gene can lead to a wide variety of autoimmune disorders, including diabetes, lupus and rheumatoid arthritis, a new study shows.

The gene in question encodes an enzyme called sialic acid acetylesterase or SIAE, which regulates the activity of the immune system’s antibody-producing B cells. About 2 percent to 3 percent of people with autoimmune disorders have defects in the enzyme that allow B cells to run amok and make antibodies that attack the body, a team led by Shiv Pillai of Massachusetts General Hospital in Charlestown and Harvard Medical School reports online June 16 in Nature.

“It’s a seminal paper because it is so applicable to a wide variety of autoimmune diseases, says Judy Cho, a Yale geneticist not associated with the study. The finding suggests that enhancing the enzyme’s activity could help treat disease in people with autoimmune disorders.

Previously, Pillai’s group showed that mice lacking SIAE develop a lupuslike disease in which high levels of antibodies attack the body’s own proteins. The researchers decided to examine the enzyme in people who, like the mice, make high levels of autoimmune antibodies. “One hundred percent, I was confident that we would find nothing,” Pillai says.

Instead, in a small study of 19 people, including 13 with autoimmune disorders and a comparison group of six healthy people, the researchers found that a person with Crohn disease and one with rheumatoid arthritis had genetic mutations inactivating the enzyme. The team expanded the study and eventually identified variants of the enzyme in 27 of 923 people with autoimmune disease and in 17 of 648 healthy people.

Tests showed that most SIAE variants found in people with autoimmune disorders disrupt the enzyme’s normal function, while all but two of the healthy people were found to carry variants that don’t interfere with the enzyme’s activity.
The study estimated, albeit with a wide range of uncertainty, that people with defects in the enzyme have nine times greater odds of developing autoimmune disease than those with functioning versions of SIAE.


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