Genetic Evidence Points to Potential Therapeutic Bypass for Autoimmune Process

Tuesday, March 02, 2010

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 edition PLoS (Public Library of Science) 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, PhD, 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.

Funding support for the research came from the National Institutes of Health.
Cincinnati Children's Hospital Medical Center is one of America's top three children's hospitals for general pediatrics and is highly ranked for its expertise in digestive diseases, respiratory diseases, cancer, neonatal care, heart care and neurosurgery, according to the annual ranking of best children's hospitals by U.S. News & World Report. One of the three largest children's hospitals in the U.S., Cincinnati Children's is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health.

For its achievements in transforming healthcare, Cincinnati Children's is one of six U.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize ® for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases, so that children with the most difficult-to-treat diseases and conditions receive the most advanced care leading to better outcomes.