Regulation of innate immune responses to viruses.
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Regulation of virus-induced innate immunity.
Pattern recognition receptors (PRRs) expressed on cells are important for detecting pathogen-associated molecular patterns (PAMPS) during virus infections and promoting innate inflammatory immune responses to the virus. While these responses are essential for eradication of a virus from the host, these responses may lead to extensive immunopathogenic tissue damage if not properly regulated. Among the myriad of proteins that regulate these responses in cells, the most critical is the protein tyrosine phosphatase SHP-1. As such, SHP-1 has been shown to be a key negative regulator of signaling intensiity through both PRRs and proinflammatory cytokine receptors expressed on cells. Our current goal is to determine the mechanisms by which SHP-1 appropriately controls the biological activities of these receptors during pathogen-induced inflammatory responses in various tissues and how these controls might be disrupted during severe inflammatory diseases particularly within the central nervous system.
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Christophi, G.P., Hudson, C.A., Gruber, R.C., Christophi, C.P., Mihai, C., Mehico, L.J., Jubelt, B., and Massa, P.T. 2008 SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Lab. Invest. 88: 243-255.
Christophi, G.P., Hudson, C.A., Gruber, R., Christophi, C.P., and Massa, P.T. 2008 Promoter-specific induction of the phosphatase SHP-1 by viral infection and cytokines in CNS glia. J. Neurochem.105: 2511-2523.
Hudson, C.A., Christophi, G.P., Gruber, R.C., Wilmore, J.R., Lawrence, D.A., and Massa, P.T. 2008 Induction of IL-33 expression and activity in central nervous system glia. J. Leuk. Biol. 84: 631-643.
Christophi, G.P., Hudson, C.A., Panos, M., Gruber, R.C. and Massa, P.T. 2009 Modulation of macrophage infiltration and inflammatory activity by the phosphatase SHP-1 in virus-induced demyelinating disease. J. Virol. 82: 522-539.
Christophi, G. P., M. Panos, C. A. Hudson, R.L. Christophi, R. C. Gruber, A. T. Mersich, S. D. Blystone, B. Jubelt, and P. T. Massa. 2009. Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhance inflammatory phenotype. Lab. Invest. 89: 742-759.
Christophi, G.P., Panos, M., Hudson, C.A., Tsikkou,C., Mihai, C., Mejico, L.J., Jubelt, B., Massa, P.T. 2009 Interferon–beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1. Clin. Immunol. 133: 27-44
Christophi, G.P. and Massa, P.T. 2009 Central neuroinvasion and demyelination by inflammatory macrophages following peripheral virus infection is controlled by SHP-1. Viral Immunol. 22: 371-387.
CHRISTOPHI, G. P., CHRISTOPHI, J. A., GRUBER, R. C., MIHAI, C., MEJICO, L. J., MASSA, P. T. & JUBELT, B. 2011. Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-beta 1a treated multiple sclerosis patients. J Neurol Sci, 307, 41-5.
CHRISTOPHI, G. P., GRUBER, R. C., PANOS, M., CHRISTOPHI, R. L., JUBELT, B. & MASSA, P. T. 2012. Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol, 142, 308-19.
KUMAGAI, C., KALMAN, B., MIDDLETON, F. A., VYSHKINA, T. & MASSA, P. T. 2012. Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol, 246, 51-7.
Christophi, G.P., Rong, R., Holtzapple, P.G., Massa, P.T., and Landas, S.K. 2012 Immune markers and differential signaling networks in ulcerative colitis and Crohn’s disease. Inflamm. Bowel Dis. 18: 2342-2356.
Christophi, G.P., Caza, T., Curtiss, C., Gumber, D., Massa, P.T. and Landas, S.K. 2014 Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis. Exp. Mol. Pathol. 96: 393-399.
Watson, N.B., Schneider, K. M., and Massa, P.T. 2015 SHP-1-dependent macrophage differentiation exacerbates virus-induced myositis. J. Immunol. 194: 2796-2809.
Gruber, R.C., LaRocca, D., Minchenberg, S.B., Christiophi, G.P., Hudson, C.A., Ray, A.K., Shafit-Zagardo, B., and Massa, P.T. 2015 The control of reactive oxygen species production by SHP-1 in oligodendrocytes. GLIA (In press).
Iulia G. Movileanu
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