Gene mutation can spur autoimmunity

Two research groups working separately have discovered a gene on the X chromosome that, when mutated, can lead to a dangerous autoimmune disorder and sometimes diabetes.

One of the groups, led by scientists at the University of Washington in Seattle, reports in the January Nature Genetics that the gene, called FOXP3, can be mutated in many ways. By checking blood samples from members of families afflicted with the autoimmune disorder—known as IPEX, which stands for immune disregulation, polyendocrinopathy, enteropathy, X-linked syndrome—the researchers uncovered the problematic mutations.

Although the protein encoded by the normal form of FOXP3 influences the immune system, its mechanism remains unknown, says coauthor Hans D. Ochs, an immunologist at the University of Washington School of Medicine. The scientists learned from animal studies that some defective versions of the protein cause out-of-control proliferation of T cells and antibodies. These, in turn, attack the small intestine and cause diarrhea that can be fatal in babies, Ochs says.

Eczema, thyroid problems, allergies, and type I diabetes also turn up in people with IPEX. In type I diabetes, also called juvenile-onset diabetes, the immune system destroys insulin-making cells in the pancreas. This autoimmune reaction spurred another research team to investigate whether IPEX patients with type I diabetes are likely to have the FOXP3 mutation.

After studying two extended families with a history of the disease combination, Talal A. Chatila and his colleagues at Washington University in St. Louis found that five boys who had IPEX and type I diabetes indeed had a mutated version of FOXP3, also called JM2. The researchers report their findings in the December 2000 Journal of Clinical Investigation.

The mutation is probably only one of several genetic defects that lead to type I diabetes, Chatila says.

IPEX, also known as X-linked autoimmunity-allergic disregulation (XLAAD) syndrome, selectively affects boys because they have only one X chromosome. If a boy’s sole X chromosome carries the mutated FOXP3, he develops IPEX. Girls aren’t affected when they carry the mutation because their normal copy of the gene on the other X chromosome compensates for the abnormal one, Chatila reports.

Mutations in this particular gene may account for the observation that, in the general population, boys are nearly twice as likely as girls to get type I diabetes, Chatila adds.

He suspects that normally the gene encodes a protein that enables immune cells to discern the body’s own cells from foreign material. This protein may be essential to the maturation of the T cells that makes them tolerant of body components, he says.

Ochs suggests, instead, that the protein may activate or silence other genes that play as yet unidentified roles in the immune system. Or, he says, the protein may sustain the programmed cell death that helps keep T cells from proliferating excessively.