Autoimmune disease triggered if T cells miss a single protein early on

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Public release date: 21-Nov-2006

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Contact: Wallace Ravven

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University of California - San Francisco

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 , 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, 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, "

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, , 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, 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, " 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 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.

###

Lead author is DeVoss, PhD, a postdoctoral scientist in

's laboratory.

Co-authors include Lawrence Fong, MD, PhD, UCSF assistant professor

of hematology and oncology; Yafei Hou, PhD, a postdoc in Fong's lab;

Wen Lu, BS, and Kellsey Johannes, BA, both research assistants in

's lab.

Also: Liou, PhD, associate professor of ophthalmology at the

Medical College of Georgia; Chang, MD, PhD, assistant

professor dermatology at Stanford University School of Medicine;

Rinn, PhD, a postdoctoral scientist in Chang's lab; and Caspi,

PhD, section head, Laboratory of Immunology, National Eye Institute.

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

UCSF is a leading university that advances health worldwide by

conducting advanced biomedical research, educating graduate students

in the life sciences and health professions, and providing complex

patient care.

http://www.eurekalert.org/pub_releases/2006-11/uoc--adt112106.php