There is strong evidence that chronic permanent neurologic impairment in multiple sclerosis is the result of injury and potential loss of axons. We have shown in a viral model of multiple sclerosis induced by Theiler's virus that the immune response contributes to neurologic deficits and axonal dropout months following demyelination of the spinal cord. In this set of experiments we will test the hypothesis that axonal loss which follows demyelination can be the result of immune-mediated damage to axons. Although we have striking data demonstrating the expression of Class I molecules on neurons and axons under pathologic conditions, there is still significant controversy regarding the expression of MHC on CNS cells. Our hypothesis depends in part on the expression of these proteins in the CNS during chronic demyelination. Thereforethe first goal of this project is to examine, using double and triple labeling con-focal immunofluorescence, the expression of MHCClass I and MHCClass II on CNScells with a particular focus on neurons and axons. We will also examine the interaction of MHC molecules on CNS cells with CD8+ T cells, CD4+T cells, NK cells, macrophages, and perforin in the spinal cords of animals with chronic demyelination induced by Theiler's virus infection and in myelin mutant mice with denuded axons. The second goal is to quantify immune mediated axonal loss and changes in neurologic function by adoptive transfer experiments using purified populations of antigen-specific and non antigen-specific immune cells into mice with chronic demyelination either induced by virus or mutations that lead to spontaneous dysmyelination. The third goal is to develop transgenic mouse models in which neurons are specifically deficient in MHCclass I function or in which MHC class I function is only expressed on neurons, andto characterize axonal injury following Theiler's virus infection in these animals. These experiments will specifically address whether immune cells require the direct engagement of MHC molecules for induction of axonal injury. The findings are expected to provide new insights into the pathogenesis of axonal and neuronal injury in demyelinating disorders such as multiple sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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Mayo Clinic, Rochester
United States
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Watzlawik, Jens O; Painter, Meghan M; Wootla, Bharath et al. (2015) A human anti-polysialic acid antibody as a potential treatment to improve function in multiple sclerosis patients. J Nat Sci 1:
Paz Soldán, M Mateo; Novotna, Martina; Abou Zeid, Nuhad et al. (2015) Relapses and disability accumulation in progressive multiple sclerosis. Neurology 84:81-8
Painter, Meghan M; Morrison, James H; Zoecklein, Laurie J et al. (2015) Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity. PLoS Pathog 11:e1005311
Perschbacher, Katherine; Smestad, John A; Peters, Justin P et al. (2015) Quantitative PCR analysis of DNA aptamer pharmacokinetics in mice. Nucleic Acid Ther 25:11-9
Wootla, Bharath; Denic, Aleksandar; Rodriguez, Moses (2014) Polyclonal and monoclonal antibodies in clinic. Methods Mol Biol 1060:79-110
Tutuncu, Melih; Tang, Junger; Zeid, Nuhad Abou et al. (2013) Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 19:188-98
Xu, Xiaohua; Denic, Aleksandar; Warrington, Arthur E et al. (2013) Therapeutics to promote CNS repair: a natural human neuron-binding IgM regulates membrane-raft dynamics and improves motility in a mouse model of multiple sclerosis. J Clin Immunol 33 Suppl 1:S50-6
Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses (2013) PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLoS One 8:e55149
Waubant, Emmanuelle; Mowry, Ellen M; Krupp, Lauren et al. (2013) Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. Mult Scler 19:891-5
Denic, Aleksandar; Pirko, Istvan; Wootla, Bharath et al. (2012) Deletion of beta-2-microglobulin ameliorates spinal cord lesion load and promotes recovery of brainstem NAA levels in a murine model of multiple sclerosis. Brain Pathol 22:698-708

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