The Effect of NOD2 Mutation On T Regulatory Cell Function in Patients With Crohn's Disease

William Faubion, Jr.

Mayo Clinic (Minnesota)

Funded in September, 2005: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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The Effect of NOD2 Mutation On T Regulatory Cell Function in Patients With Crohn's Disease

Researchers will collaborate to see whether autoimmune inflammatory bowel disease (called Crohn's disease) is related to alterations of a specific gene, which results in impaired regulation of immune T cells that cannot differentiate harmful from harmless bacteria.

Crohn's disease is characterized by a chronic inflammation of the small and large intestine. This inflammatory response is produced by patients' immune T cells which mistake all bacteria as harmful and forge a relentless attack. Prior population-based studies have linked Crohn's disease with three types of alterations in the "NOD2" gene. This gene produces a receptor on T cells that enables the T cells to recognize a constituent of the outer wall of bacteria. In the case of harmless bacteria, certain regulatory T cells keep other T cells from attacking these bacteria.

In Crohn's disease patients, however, the investigators hypothesize that the NOD2 gene alterations render regulatory T cells unable to receive a signal they need to survive. Without the signal, the regulatory T cells literally grow themselves to death. Without sufficient surviving regulatory T cells, Crohn's disease patients' errant T cells are unrestrained and constantly attack the harmless bacteria, producing chronic inflammation. The collaborators will test this hypothesis in the cells of Crohn's disease patients.

Significance: If the study unearths the way in which genetic alterations result in chronic inflammatory bowel disease, the results could lead to a new diagnostic test of regulatory T cell dysfunction, a new method for measuring disease activity, and new approaches to treating deficiencies in regulatory T cells.

ABSTRACT

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The Effect of NOD2 Mutation On T Regulatory Cell Function in Patients With Crohn's Disease

Crohn's disease is a common incurable inflammatory bowel disease that causes great suffering and expense. While the cause of Crohn's disease is unknown, genetic epidemiological studies have strongly linked this disease with single nucleotide polymorphisms of the NOD2/CARD15 gene. NOD2 is an intracellular pattern recognition receptor for muramyl dipeptide, a bacterial wall component. NOD2 activates the anti-apoptotic transcription factor NF-κB.

We hypothesize that immune-suppressing T regulatory cells of patients with Crohn's disease and variant NOD2 alleles fail to appropriately engage NF-κB-mediated survival signals upon activation, resulting in their apoptosis and a consequent loss of suppressor function. This hypothesis will be addressed through an experimental model in which NOD2-defined T regulatory cells isolated from patients with Crohn's disease will be analyzed for NF-κB-dependent functions and suppressor functions. The results of these studies will provide insight into mechanisms of variant NOD2-mediated immune activation and will point towards novel therapeutic strategies to arrest inappropriate immune activity in Crohn's disease.

INVESTIGATOR BIOGRAPHIES

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William Faubion, Jr.

William Faubion, M.D., is an Assistant Professor of Medicine and of Pediatrics at the Mayo Clinic in Rochester, Minnesota. He trained at Harvard Medical School, with a fellowship in Pediatric and Adult Gastroenterology at the Mayo Clinic, and as a Gastrointestinal Fellow in the laboratory of Gregory J. Gores, M.D. Center for Basic Research in Digestive Diseases at the Mayo Clinic. His residency as well as his M.D. was in Internal Medicine/ Pediatrics at Texas Medical Center, University of Texas, Houston,

Dr. Faubion's laboratory focus is primarily on the relationship between cells of the innate immune system, regulatory T cells, and commensal bacteria. They use animal models of inflammatory bowel disease to understand how macrophages and dendritic cells signal regulatory T cells to control chronic gastrointestinal inflammation. They also study the response of human regulatory T cells from patients with inflammatory bowel disease to bacterial products. As their clinical focus is Crohn's disease and ulcerative colitis, they hope their research leads to improved understanding of mechanisms and novel therapy.

Larry Egan, M.D., is an Assistant Professor of Medicine and of Pharmacology in the Division of Gastroenterology at the Mayo Clinic, Rochester, Minnesota. He trained at the University of California, San Diego and won a Fellowship in Gastroenterology and Hepatology and Clinical Pharmacology at the Mayo Graduate School of Medicine. He attended Medical School at University College in Ireland, earning his M.D. and M.Sc. degrees there, and did his residency in Internal Medicine at the Mayo Graduate School of Medicine. As a trainee he was part of the Pre-Membership Internal Medicine Training Scheme at University College Hospital and Mayo General Hospital. He also held a Medical and Surgical Internship at University College Hospital and Mayo General Hospital.

Dr. Egan's laboratory focus is the relationship of inflammation and the nuclear transcription factor NF-κB. Patients with inflammatory bowel disease have an increased risk of colorectal cancer. They study the role NF-κB plays in cell survival and programmed cell death potentially leading to neoplasia. Their clinical focus is Crohn's disease and ulcerative colitis, and therefore they believe their research will lead to an improved understanding of how inflammation may lead to cancer and to developing novel therapy for these diseases.

SELECTED PUBLICATIONS

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Bell M.P., Svingen P.A., Rahman M.K., Xiong Y., and Faubion W.A. Jr.   FOXP3 regulates TLR10 expression in human T regulatory cells.  J Immunol. 2007 Aug 1;179(3):1893-900.