Some Harvard University researchers have found a key piece of the puzzle about how the body prevents the immune system from attacking the self. One can easily imagine how a deficiency of one kind of protein in the thymus could cause an auto-immune disorder when T cells encounter the same protein in some organ of the body:
Building on work of other groups, first author Mark Anderson, a research fellow in medicine at Joslin; Emily Venanzi, a Harvard Medical School graduate student in immunology; Christophe Benoist, a professor of medicine at Joslin; Mathis, and colleagues, reported that a small network of thymic cells -- the medullary epithelial cells -- expresses hundreds of genes usually associated with organs such as the pancreas, brain, and liver.
"No one would think you would encounter your big toe protein in the thymus, but in fact proteins from the eye, the liver, from all over the place are specifically expressed in a small population of stromal cells in the thymus," said Benoist.
A majority of these expressed proteins are used by the peripheral organs to tell T cells to stay away. Indeed, the researchers believe the proteins are used in the thymus to foreshadow the very self-antigens that the T cells will encounter once they travel out into the body.
"There is a foretelling of these proteins in the thymus, which is why we call it an immunological self-shadow," said Mathis.
In a critical step, the Joslin team discovered that the transcription factor aire plays a critical role in producing these self-shadow proteins in the thymus (hence its name, which is formed from two letters in each word of autoimmune regulator). Mutant mice lacking aire exhibited in their thymus only a fraction of the peripheral self-proteins found in the thymus of normal mice. And the mutants exhibited widespread autoimmunity. In fact, their condition was reminiscent of a condition found in humans carrying a defective AIRE gene, autoimmune polyglandular syndrome.
It is not yet clear how the shadow proteins educate developing T cells inside the thymus, though Benoist suspects the processes are similar to those used to eliminate T cells that react to ubiquitous or circulating proteins. Nor is it clear how aire controls the expression of so many shadow proteins. One possibility is that it works by binding to other transcription factors.
"It is going to be interesting to figure out what the mechanism really is," Mathis said. While novel, the mechanism is probably only one of many that the immune system uses to educate peripheral T cells about the self-vs.-foreign distinction.
"It is very dangerous for the immune system to have self-reactive T cells," Anderson said. "It takes advantage of any mechanism to get rid of these cells. So there is a whole net of mechanisms."
A better understanding of the role of the thymus in prevention of auto-immune response will open up avenues for the development of therapies to treat auto-immune disorders. Also, it may become possible to add cells or do gene therapy to the thymus in order to teach immune cells not to attack transplanted organs. Plus, this information may even turn out to be useful for inducing immune responses against cancers and infectious diseases.
|Share |||Randall Parker, 2002 October 14 10:38 AM Biotech Immunology|