| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Mironova, Yevgeniya Kulkarni, Deven Carbajal, Kevin S. Shrager, Peter Segal, Benjamin M. Ulrich-Lewis, Justin T. Grifka-Walk, Heather M. Huber, Amanda K. Giger, Roman J. |
| Description |
Author Affiliation: Carbajal KS ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109); Mironova Y ( Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109); Ulrich-Lewis JT ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109); Kulkarni D ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109); Grifka-Walk HM ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109); Huber AK ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109); Shrager P ( Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642); Giger RJ ( Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109); Segal BM ( Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan, Ann Arbor, MI 48109) |
| Abstract |
Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4(+) Th cells. IL-12-polarized Th1 cells, IL-23-polarized Th17 cells, and Th17 cells that acquire Th1 characteristics were each implicated in autoimmune pathogenesis. It is debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study, we assessed the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFN-γ- or IL-17-skewed responses to myelin basic protein over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFN-γ and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of experimental autoimmune encephalomyelitis. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th-polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1501097 |
| Journal |
The Journal of Immunology |
| Issue Number |
6 |
| Volume Number |
195 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2015-09-15 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Encephalomyelitis, Autoimmune, Experimental Immunology Multiple Sclerosis Th1 Cells Th17 Cells Adoptive Transfer Animals Autoimmunity Brain Cell Differentiation Demyelinating Diseases Interferon-gamma Biosynthesis Interleukin-12 Interleukin-17 Interleukin-23 Magnetic Resonance Imaging Mice Mice, Inbred C57bl Mice, Knockout Myelin Basic Protein Optic Nerve Pathology Radiography Cytology Transplantation Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, Non-p.h.s. Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
