UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My research focuses on the genetic factors involved in the pathogenesis of autoimmune endocrine disease. One area of current interest involves an animal model of the human autoimmune disease called APECED. This is a clinical disease that is inherited in an autosomal recessive fashion and is characterized by autoimmunity involving multiple endocrine organs. The causative gene for this disorder called Aire was cloned by positional cloning. We have generated an animal model of this disease by knocking out the murine homologue of this gene. Aire-deficient mice exhibit immune cell infiltrates in multiple organs, and recent studies in my laboratory have shown that the general defect responsible for this disease involves thymic selection of T cells. This selection defect appears to involve the inability of thymic medullary epithelial cells to transcribe self-antigens in the thymus for presentation to self-antigen specific thymocytes. Studies are ongoing examining how this process affects immune tolerance in a number of disease models, including autoimmune diabetes. In addition, the genetic background in which the knockout gene is expressed alters the pattern and severity of the autoimmune disease in the mouse model. Studies are underway to map the genes that specifically influence these differences. We are also generating other animal models of autoimmunity using similar gene targeting techniques. Specifically, we are interested in targeting genes in an animal model of type I diabetes, the NOD mouse strain.

A second area of interest is the examination of candidate genes responsible for the risk to develop type I diabetes. The approach in these studies has been to use case-control collections and testing of SNPs in candidate genes for their potential contribution to disease risk. Studies are currently ongoing, but several excellent candidates have been identified, and confirmatory testing in a second case-control population is underway. Mechanistic experiments for the identified risk genes are also planned to follow up these findings.

Selected References

M.S. Anderson, E. Venanzi, L. Klein, Z. Chen, S. Berzins, S. Turley, H. von Boehmer, R. Bronson, A. Dierich, C. Benoist, and D. Mathis. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395-1401, 2002.

M.S. Anderson and J. Bluestone. The NOD mouse - a model of immune dysregulation. Annual Review in Immunology 23: 447-485, 2005.

M.S. Anderson, E. Venanzi, Z. Chen, S. Berzins, C. Benoist, and D. Mathis. The cellular mechanism of aire control of T cell tolerance. Immunity (in press).

Website: http://anderson.diabetes2.ucsf.edu/

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