Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

23.11.2006
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.

Wallace Ravven | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung

nachricht A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>