Stephen D. Miller, PhD Congressman John Edward Porter Professor Microbiology-Immunology Immunoregulation of T Cell-Mediated Autoimmune and Virus Diseases Curricula: Immunology and Microbial Pathogenesis E-mail:   s-d-miller@northwestern.edu

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Our laboratory investigates cellular and molecular mechanisms of the immunopathogenesis and specific immunoregulation of CD4+ T cell-mediated autoimmune responses employing two mouse models of multiple sclerosis (MS) - Theiler's virus-induced demyelinating disease (a virus-induced model of MS) and relapsing experimental autoimmune encephalomyelitis (R-EAE) (an autoimmune model of MS).

MS is a T cell-mediated autoimmune CNS demyelinating disease thought to be initiated by a virus infection. Theiler’s virus, a natural mouse pathogen, is a picornavirus which induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic-progressive MS. This model is being employed to elucidate the contributions of two different mechanisms, epitope spreading and molecular mimicry, to the induction and progression of the virus-induced demyelinating disease process.

R-EAE is characterized by a relapsing-remitting clinical course and this system is being used to determine the role and mechanisms of epitope spreading to the pathogenesis and intrinsic regulation of a Th1-mediated autoimmune disease. The R-EAE model is also being used to study the efficacy and molecular mechanisms of various immunoregulatory strategies, including peripherally-induced immunologic tolerance and blockade of the CD40-CD40L and B7-CD28/CTLA-4 costimulatory pathways, as potential therapies for human autoimmune diseases. These studies include determination of the relative contributions of clonal deletion, clonal anergy, and induction of specific immunoregulatory T cells) to the tolerogenic process.

Lastly, we are studying the molecular mechanisms of antigen processing and presentation of self myelin epitopes by CNS-resident antigen presenting cells (i.e., astrocytes, microglia, and cerebrovascular endothelial cells).

Publications:

Vanderlugt, C.L., T.N. Eagar, K.L. Neville, K.M. Nikcevich, J.A. Bluestone, and S.D. Miller. (2000) Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. Journal of Immunology 164:670-678.

Katz-Levy, Y., K.L. Neville, A.M. Girvin, C.L. Vanderlugt, J.G. Pope, L.J. Tan, and S.D. Miller. (1999) Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus-infected mice. Journal of Clinical Investigation 104:599-610.

Miller, S.D., C.L. Vanderlugt, W.S. Begolka, W. Pao, R.L. Yauch, K.L. Neville, Y. Katz-Levy, A. Carrizosa and B.S. Kim. (1997) Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nature Medicine 3:133-1136.