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Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation

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Abstract

Autoimmune diseases such as multiple sclerosis (MS) result from complex and poorly understood interactions of genetic and environmental factors. A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA). Multiple environmental factors (vitamin D3 deficiency and metabolism) converge with multiple genetic variants (IL-7RA, IL-2RA, MGAT1, and CTLA-4) to dysregulate Golgi N-glycosylation in MS, resulting in T cell hyperactivity, loss of self-tolerance and in mice, a spontaneous MS-like disease with neurodegeneration. Here, we review the genetic and biological interactions that regulate MS pathogenesis through dysregulation of N-glycosylation and how this may enable individualized therapeutic approaches.

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Acknowledgments

Research was supported by the National Institutes of Health R01AI053331 and R01AI082266 to M.D. and F32AI081456 to A.G. through the National Institute of Allergy and Infectious Disease, F30 HL108451 to H.M. through the National Heart Lung and Blood Institute, as well as through a Collaborative Multiple Sclerosis Research Center Award to M.D.

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Authors and Affiliations

  1. Institute for Immunology, Department of Neurology, University of California, Irvine, Irvine, CA, USA

    Ani Grigorian, Carey F. Li & Barbara L. Newton

  2. Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA

    Haik Mkhikian & Raymond W. Zhou

  3. Departments of Neurology and Microbiology & Molecular Genetics, Multiple Sclerosis Research Center, Institute for Immunology, University of California, Irvine, 250 Sprague Hall, Irvine, CA, 92697, USA

    Michael Demetriou

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  1. Ani Grigorian
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This article is published as part of the Special Issue on Glycosylation and Immunity [34:3].

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Grigorian, A., Mkhikian, H., Li, C.F. et al. Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation. Semin Immunopathol 34, 415–424 (2012). https://doi.org/10.1007/s00281-012-0307-y

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