Protein Found that Can Prevent Autoimmune Attacks

The finding was reported in the April 2004 issue of Immunity.

"This protein may be one of the components that goes awry when the immune system's normal inflammatory processes malfunction, leading some T cells to attack the body,” said Scott Lovitch, an M.D./Ph.D. student at Washington University (St. Louis, MO, USA) and a member of the research team.

Distinguishing between foreign and native tissue is one of the immune system's most important tasks. Failure to make this distinction can lead the immune system to attack the body, resulting in autoimmune conditions such as diabetes, lupus, arthritis, and multiple sclerosis.

Lovitch works in the laboratories of the study's principal investigator, Emil R. Unanue, M.D., professor and head of the department of pathology and immunology at Washington University. Dr. Unanue's team is studying a group of T cells known as type B T cells. The body builds an arsenal of T cells to attack invaders, and these are supposed to delete any T cells that might attack the body's own tissues. However, the researchers have found that some of these self-reactive T cells do not get destroyed. These are the cells they call type B T cells.

Normally, T cells go on the attack when antigen-presenting cells show evidence of a foreign invasion. This evidence takes the form of protein bits on the surface of the cells. Based on its inspection of the protein bits, a T cell will either start multiplying to prepare for an attack or remain inactive. The protein bits are displayed in molecules collectively known as the major histocompatibility complex (MHC).

The researchers found evidence that type B T cell attacks on the body's own tissue were linked to slight changes in ways the MHC displays bits of proteins. Normally, a piece of one of the body's own proteins displayed in the MHC might not provoke a type B T cell, but that same protein part displayed in a slightly altered form of the MHC changes what the T "sees,” possibly leading the T cell to attack.

Using a test tube approach for inserting proteins into specific compartments of antigen-presenting cells, Lovitch found that when the proteins were given to a compartment in the cell known as an endosome, the proteins were displayed by the MHC in a way that could provoke type B T cells. However, when they were given to another compartment known as a lysosome, the MHC protein display did not provoke the type B T cells.

The scientists then tried the experiment in cells in which the gene for the H2-DM protein had been removed. HD-DM is common in lysosomes but rare in endosomes, and other scientists have shown that high-acidity environments such as the lysosome can increase H2-DM's activity levels. In this experiment, they found antigen-presenting cells could provoke a reaction in type B T cells regardless of which compartment received the protein.

"These results suggest that H2-DM appears to be playing an editing role in the lysosome, blocking the pathway that leads to an MHC-protein complex that can cause a response from type B T cells,” said Lovitch.

To further investigate the links between H2-DM, type B T cells, and autoimmune disease, Lovitch and others in Unanue's lab have produced a genetically altered mouse that only has type B T cells. They plan to study these mice to determine whether normal inflammation can provoke an autoimmune reaction in the T cells, leading to conclusions similar to diabetes.




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