Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of uncertain etiology. It is a complex disease in which one or more environmental agents predispose genetically susceptible individuals to develop immunologically mediated CNS demyelination and axonal injury. In 80-90% of cases, MS starts with a relapsing-remitting course (RR-MS), but most patients develop progressive neurological deficits (i.e. secondary progressive MS;SP-MS). In 10-20% of cases, MS patients exhibit a more progressive disease without remission, namely primary progressive MS (PP-MS). Despite intense investigation into the pathological changes of MS, many questions regarding the nature of immunological dysregulation that lead to the development of MS remain unanswered. Most of our understanding of the pathogenesis of multiple sclerosis comes from investigations using experimental autoimmune encephalomyelitis animal model. In this model, both CD4+ T helper type 1 (TH1) and T helper type 17 (TH17) cells contribute to the pathogenesis of the disease. The transcription factor T-bet (encoded by the Tbx21 gene) drives the development of TH1 cells and inhibits the differentiation of TH17 cells. Interestingly, despite its role as a negative regulator of TH17 differentiation program in naive CD4+ T cells, T-bet is critical for the function of mature TH17 cells. T-bet is re-expressed in TH17 cells in response to IL-23, which drives the pathogenesis of several autoimmune diseases. T-bet deficient TH17 cells treated with IL-23 are not pathogenic in the setting of neuroinflammation. This observation raised important questions: (a) What makes TH17 cells pathogenic? (b) Is it the genetic program regulated by T-bet in response to IL-23 signaling? To answer these questions, we have performed genome-wide profiling of wild-type and T-bet deficient TH17 cells. In the process, an intriguing panel of candidate genes has been uncovered. Identifying the T-bet target genes in CD4+ T cells responsible for conferring pathogenicity and understanding how these gene products lead to CNS damage will lead to novel therapeutic targets. Treatment strategies directed at a specific subset of T-bet target genes, rather than T-bet itself, will provide selective intervention without causing global impairment of Type 1 immunity. Ultimately, the goal of this research is to lead to the development of new therapies for multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011431-02
Application #
8763519
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2013
Total Cost
$358,028
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
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State
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