Autoimmune Disease Triggered If T Cells Miss A Single Protein Early On

Scientists have discovered that autoimmunity can be triggered in the 
thymus, where the immune system's T cells develop, if T cells fail to 
recognize just one of the body's thousands of proteins as "self." The 
research confirms an emerging view that autoimmunity can start in 
this cradle of the immune system, and not only at the sites where 
autoimmune diseases emerge, such as the pancreas in the case of type 
1 diabetes, or the joints in rheumatoid arthritis.

The discovery, from a mouse model of a human autoimmune condition, 
suggests that effective strategies to treat autoimmune disease should 
target not only the "peripheral" sites where autoimmune disease is 
active, but also the thymus -- the organ where T cells and self-
proteins, or self-antigens, first interact.

The research was led by investigators at the University of 
California, San Francisco (UCSF). It was published online November 20 
by the Journal of Experimental Medicine and will appear in the 
journal's print edition November 27.

T cell soldiers encounter the body's full array of proteins in the 
thymus, and those T cells with receptors that recognize "self" 
proteins, or antigens, normally are purged to avoid autoimmune 
attacks in the body later on. The new research showed that if just 
one of the body's antigens is not recognized as "self," this single 
failure can lead to a severe autoimmune disease in the retina.

"The thymus is like a filter," said Mark Anderson, MD, PhD, assistant 
professor of medicine at the UCSF Diabetes Center, and senior author 
of a scientific paper describing the discovery. "It is removing or 
pulling out autoreactive T cells. What this new study shows is if 
just one self-antigen is missing as the T cells go through the 
filter, it looks like this alone can lead to an autoimmune disease."

"The finding supports the promise of treatments targeting individual 
body proteins or antigens since we have shown that a single self-
antigen can trigger disease," he added.

A similar mechanism may be at play involving other autoimmune 
diseases such as type 1 diabetes, Anderson said. Immunologists have 
demonstrated that insulin is expressed in the thymus -- not just in 
the pancreas. Studies have shown that people who are protected from 
diabetes express high levels of insulin in the thymus, while those 
who are predisposed express lower levels of insulin in this organ.

"What we think is that 'more is better' in the thymus," Anderson 
says. "If you have more insulin in the thymus, then there is a better 
chance that potentially destructive insulin-specific T cells will 
encounter insulin as self and be filtered out."

In the thymus, immature T cells display on their surface many 
thousands of unique receptors, generated by random gene 
rearrangements. This strategy allows the receptors to recognize the 
tremendous diversity of invading pathogens. In the process, however, 
they also develop receptors that bind to the body's own proteins. 
These T cells are normally eliminated, avoiding the plague of 
autoimmunity.

A clue to how the elimination process is controlled came from 
previous work involving a protein in the cell nucleus called Aire 
(for autoimmune regulator), which regulates the expression of some 
300 to 1,000 antigens in the thymus. Humans and mice lacking the 
normal Aire gene suffer from multiple autoimmune diseases including 
diseases that target the thyroid, adrenal, ovary, and eye.

In 2002, Anderson, then at Harvard Medical School, and colleagues 
there demonstrated that knocking out the Aire gene in the mouse 
thymus led to failures of expression of a number of genes in 
peripheral tissues, resulting in autoimmune diseases in those tissues 
-- the first direct evidence linking gene knockouts in the thymus to 
autoimmune defects in body tissues. The study, however, did not link 
a specific organ autoimmune attack with a specific protein missing in 
the thymus.

In the new study, the researchers carried out a detailed analysis of 
the autoimmune attack that is directed against the eye in Aire-
deficient mice. What the team found was that the immune system was 
mainly targeting a single eye protein called IRBP despite the fact 
that several eye-specific proteins were missing in the thymus of Aire 
knockout mice. The team then went on to show that IRBP was expressed 
in the thymus under the control of Aire and that knockout mice 
lacking the IRBP protein were protected from the disease because they 
don't express the protein that the immune system is targeting.

In a key, final part of the new study, Anderson and his colleagues 
showed that if mice without a thymus gland -- so-called "nude" mice 
-- received a normal thymus lacking only IRBP, they developed the 
autoimmune eye disease. The autoimmune attack occurred even though 
the mice had normally functioning IRBP in their retinas. The final 
finding demonstrated that failure of T cells in the thymus to 
recognize IRBP as a self-protein was sufficient to cause the 
autoimmune disorder in the retina.

The scientists hope that better understanding of interactions in the 
thymus can lead to earlier, more effective treatment of autoimmune 
diseases.

"When we see autoimmune disease in the clinic, we are usually looking 
at it in a relatively late stage. Tissue is already damaged, antigen 
expression is ramped up and the immune response is spreading to other 
self-antigens," Anderson said. "If we can also train our focus on the 
thymus, where we know at least some of the autoimmune disease is 
triggered, we may be able to determine just what self-antigens are 
important and shut down the autoimmune process targeting those self -
antigens."

The team is collaborating with Jeffrey Bluestone, PhD, director of 
the UCSF Diabetes Center, in preclinical studies to see if T cell 
autoimmune attacks on IRBP can be modulated to prevent the autoimmune 
eye disease.



The research is supported in part by the National Institutes of Health.