Like many common diseases, autoimmune disorders generally result from a complex mix of pathogenic factors that are environmental and genetic in nature. Among these factors, are likely to be processes that govern the control of immune tolerance which can be broadly separated into central and peripheral tolerance mechanisms. Until recently, however, the role of central tolerance in the pathogenesis of autoimmune disease was unclear. Our laboratory group and others have uncovered a direct link between autoimmunity and central tolerance through the detailed study of the AIRE (for AutolmmuneRegulator) gene. This gene was originally identified through the study of patients with the clinical autoimmune disorder APECED. These patients develop multi-organ autoimmunity, mainly involving the endocrine organs. We have generated AIRE-deficient mice and our previous work with these animals has demonstrated that these animals have a defect in the ability of the thymus to tolerize developing T cells to self-antigens whose expression is controlled by AIRE. This finding has helped establish that central tolerance in the thymus is important in the prevention of autoimmune disease and has provoked us to hypothesize how the central tolerance defect present in these animals interacts with other modifying factors and that this process can be used as a tool to prevent autoimmune disease. This work has important implications for the more detailed understanding of how autoimmune disease(s) occur and how they can be prevented. The model system that is utilized in these studies has a direct link to an existing clinical disorder whose symptoms include autoimmunity to the pancreatic islets, thyroid, adrenal, parathyroid, and liver. The proposed work is designed to learn more about how these important diseases unfold and also how they can potentially be prevented.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035297-19
Application #
8133786
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
19
Fiscal Year
2010
Total Cost
$294,039
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Proekt, Irina; Miller, Corey N; Lionakis, Michail S et al. (2017) Insights into immune tolerance from AIRE deficiency. Curr Opin Immunol 49:71-78
Sanchez Rodriguez, Robert; Pauli, Mariela L; Neuhaus, Isaac M et al. (2014) Memory regulatory T cells reside in human skin. J Clin Invest 124:1027-36
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142
Stumpf, Melanie; Zhou, Xuyu; Chikuma, Shunsuke et al. (2014) Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur J Immunol 44:1737-46
Bailey-Bucktrout, Samantha L; Martinez-Llordella, Marc; Zhou, Xuyu et al. (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949-62
Zikherman, Julie; Parameswaran, Ramya; Hermiston, Michelle et al. (2013) The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity. J Immunol 190:2527-35
Jeker, Lukas T; Bluestone, Jeffrey A (2013) MicroRNA regulation of T-cell differentiation and function. Immunol Rev 253:65-81
de Kouchkovsky, Dimitri; Esensten, Jonathan H; Rosenthal, Wendy L et al. (2013) microRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol 191:1594-605
Gratz, Iris K; Truong, Hong-An; Yang, Sara Hsin-Yi et al. (2013) Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol 190:4483-7
Baumjohann, Dirk; Kageyama, Robin; Clingan, Jonathan M et al. (2013) The microRNA cluster miR-17?92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol 14:840-8

Showing the most recent 10 out of 117 publications