Upsetting a Delicate Balance: One gene may underlie various immune diseases

One form of an immune-system gene shows up more frequently in people with three different diseases than in people free of those illnesses, a new study shows. The findings suggest that this subtle genetic difference plays a role in two thyroid diseases and diabetes.

The gene in question encodes a protein that normally moderates the aggressiveness of immune cells called T cells against an invading pathogen. In an autoimmune disease, such as the two thyroid diseases and diabetes, a person’s immune system attacks the body’s own tissues.

Linda S. Wicker of the University of Cambridge in England and her colleagues report that the presence of one variant of the gene corresponds with lowered production of the protein called cytotoxic T lymphocyte antigen-4 (CTLA-4). That, in turn, may explain why some immune reactions go unchecked and cause damage in people with that variant, she says.

In one part of the study, the researchers recorded the form of the CTLA-4 gene in blood samples from 1,110 people in British families with abnormally high incidences of either Graves’ disease or autoimmune hypothyroidism. Both disorders are caused by immune-system attacks on the thyroid. Graves’ disease is marked by an enlarged, overactive gland and, sometimes, protruding eyeballs. In contrast, autoimmune hypothyroidism kills cells in the thyroid. Another 844 blood samples, from people without thyroid problems, served as a comparison.

The scientists identified one particular version of the CTLA-4 gene, called CT60, that was much more common in families prone to one of the autoimmune thyroid diseases than in healthy people. They report the finding in an upcoming issue of Nature.

The researchers also analyzed blood samples from 3,671 families with a history of type I, or juvenile-onset, diabetes. Although the data were not as convincing as those from the thyroid group, there were hints that CT60 crops up more often in families marked by this form of diabetes than in people without the disease.

Together, the results provide evidence that these autoimmune diseases are caused in part by one form of CTLA-4, Wicker and her colleagues conclude.

In the immune system, the CTLA-4 protein works by competing directly with its alter ego, a molecule called CD28. These two signaling molecules bind to the same docking sites on cells, but CD28 enhances immune responses whereas CTLA-4 slows them, says Jeffrey A. Bluestone of the University of California, San Francisco.

When less CTLA-4 is available, CD28 can gain the upper hand and rev up an immune response, contributing to autoimmune disease, Wicker and her colleagues hypothesize. The new findings suggest that “the immune system is on a fine balance,” she says.

Despite its apparent disadvantages, the genetic variant identified in this study may have conferred an evolutionary advantage, Wicker says. Perhaps the revved-up immune systems of people producing less CTLA-4 more aggressively attack viruses and other disease pathogens, she speculates. In the “hyperclean” environments of some of today’s developed countries, however, immune agents may attack people’s own cells instead of legitimate foes, Wicker says (SN: 8/14/99, p. 108:

“If we could harness the profound regulatory attributes of CTLA-4 or effectively block CD28, we might be able to modify the immune response” in people with autoimmune diseases, Bluestone says.

Wicker says that the next logical step would be tests in diabetes-prone mice to see whether genetically engineering the animals to make extra CTLA-4 enables them to overcome the disease.


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