Navigation Links
Genetic evidence points to potential therapeutic bypass for autoimmune process
Date:3/2/2009

CINCINNATI Bypassing a molecular breakdown that helps trigger autoimmunity could lead to new treatments for autoimmune disorders and chronic infections that sicken or kill thousands of children annually, according to researchers.

A study in the March 2 PLoS Biology has discovered genetic evidence that two distinct molecular pathways control the formation of regulatory T cells (Treg), a vitally important cell type in limiting undesirable immune responses. Autoimmunity is where the immune system mounts a self attack on the body, destroying vital tissues and organs.

Treg cells control the vigor of T cell responses. If the body lacks sufficient numbers of Treg cells, it loses the ability to tone down immune responses once invading pathogens are cleared. In addition, the body is unable to suppress T cell responses that recognize and target "self" antigens in the body. The latter can lead to autoimmunity.

Under normal healthy conditions, the majority of Treg cells are derived from an organ called the thymus. However, the study shows that in the functional absence of a gene called Carma1, Treg development is impaired in the thymus. Mutations in Carma1 can result in a failure of the thymus to produce Treg cells, said senior investigator Kasper Hoebe, Ph.D., a researcher in the Division of Molecular Immunology at Cincinnati Children's Hospital Medical Center.

But the study also points to a second molecular pathway occurring in the peripheral lymphoid system that can result in development of Treg cells. This means if the process in the thymus breaks down, as in the case with Carma1 mutations, inducing Treg cells through the peripheral lymphoid system may fill the void, according to the investigators.

"We show there are essentially two independent pathways for Treg development, and that it can occur quite well in the peripheral lymphoid system, independent of the thymic process," Dr. Hoebe said. "This is important because it shows the flexibility of the immune system to regulate T cell responses. If we understand the molecular requirements of these pathways we can potentially use these as targets for therapeutic intervention which is the eventual goal."

This may include repressing immune response in autoimmune disease by increasing Treg development, or doing the opposite in chronic infectious diseases by inhibiting Treg development and promoting activation of T cells, said Dr. Hoebe, who started this study with the first author, Michael J. Barnes, a graduate student at The Scripps Research Institute in La Jolla, Calif. The department of Genetics and Immunology at Scripps was the key collaborator on the study.

Dr. Hoebe's lab uses a unique experimental approach, where they randomly introduce genetic mutations in mice that reflect genetic changes in humans. This is done to discover essential genes required for a normal immune system, in this case that of Treg development. With this approach, the researchers identified a mouse that almost completely lacked Treg cells. The researchers determined the cause of this Treg deficiency to be caused by a specific point mutation in the Carma1 gene, which they named the king mutation.

The researchers took the Carma1-deficient mice and infected them with a mouse variant of human cytomegalovirus which is related to herpes and chickenpox viruses and can remain dormant or cause serious illness in people with compromised immune systems. Although the mice lacked thymus-derived Treg cells, they still had small pools of peripheral Treg cells that greatly expanded after the animals were infected with the virus.

To further investigate the requirements for Treg development in these mice, the researchers were able to induce Treg cells in external laboratory cell cultures from Carma1-deficient, peripheral T lymphocyte white blood cells. They determined these cells could still be transformed into Treg cells by incubation with a combination of immune system molecules cytokines (Transforming Growth Factor-beta and Interleukin-2) and specific ligands for activating the T cell receptor.

Besides the molecular requirements for Treg development, the study also provides new insight into the way pathogens, in this case mouse CMV, hijack the host immune system by deliberately inducing Treg cells. This reduces protective anti-viral T cell responses, increasing the survival and replication of viral pathogens in infected individuals.


'/>"/>

Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

Related medicine news :

1. Interleukin Genetics Announces Conference Call to Discuss Fourth Quarter 2008 Results
2. Cascade of Studies, New Clinical Tests Build the Case for Genetic Testing in Pharmacy Care Says Medco Expert
3. Big-hearted fish reveals genetics of cardiovascular condition
4. Six Questions Consumers Should Ask About Genetic Tests
5. Proteasome inhibition affects epigenetic mechanisms
6. Knowledge of genetics improves uncertain medication
7. Genetic Mutations Linked to Deadly Brain Cancer
8. Genetics May Help Fine-Tune Warfarin Dosage
9. Exploring Genetic Link Between Migraines, Cardiovascular Trouble
10. Researchers identify novel genetic markers linked to increased risk of heart attack
11. Genetic Code of Common Cold Cracked
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/9/2016)... ... February 09, 2016 , ... Cirracore Enterprise ... enterprises move workloads to the cloud. Cirracore provides a secure VMware® vCloud ... traversing the Internet. Transformation Solutions (TSL Partners) provides a full range of ...
(Date:2/9/2016)... (PRWEB) , ... February 09, 2016 , ... ... specialty pharmacies, announces today the continuation of the ‘Pay It Forward’ program into ... prescription referral received at our specialty pharmacy. , “Since our Pay It ...
(Date:2/9/2016)... ... February 09, 2016 , ... On January 12, 2016 Paul ... appointment after they noticed their furnace not producing any heat. Shortly after entering the ... cracked heat exchanger was leaking dangerous levels of carbon monoxide into the home, at ...
(Date:2/9/2016)... ... February 09, 2016 , ... The ... Herberger’s and Younkers department stores, announced it has raised $176,000 to benefit the ... Holden Comprehensive Cancer Center at the University of Iowa, The Lynn Sage Cancer ...
(Date:2/9/2016)... ... 09, 2016 , ... ZipHearing.com is proud to ... hearing aids , increase industry transparency, and promote awareness of hearing solutions ... “For the average consumer, the hearing aid industry is esoteric and difficult to ...
Breaking Medicine News(10 mins):
(Date:2/9/2016)... N.J. , Feb. 9, 2016  Bluestar Silicones ... (LSR) product line for long-term implant applications and ... Medical Design & Manufacturing (MD&M) West Conference (Booth ... --> --> ... Silbione® Biomedical LSRs offer outstanding physical properties enabling ...
(Date:2/8/2016)... Respiratory Devices - Medical Devices Pipeline ... sector report, " Respiratory Devices - Medical Devices ... Respiratory Devices currently in pipeline stage. The ... with comparative analysis of the products at various ... involved in the pipeline product development. It also ...
(Date:2/8/2016)... 8, 2016 CBG Technologies, a U.S. ... Solvent Recycling Systems, specifically designed for precision parts ... new and existing vapor degreasers, parts washers and ... through continuous recycling and recovers 100% of the ... --> Precision parts manufacturers benefit from ...
Breaking Medicine Technology: