Cited by 694Multiple Sclerosis Research StudiesT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis

McMahon, Eileen J, Bailey, Samantha L, Castenada, Carol Vanderlugt, Waldner, Hanspeter, Miller, Stephen D·2005·Nature Medicine

Abstract

Chronic progression of two T cell-mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139-151-specific T cells in SJL mice undergoing PLP178-191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178-191-induced R-EAE shows that only F4/80-CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139-151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139-151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.

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Crossref · 10.1038/nm1202

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  • Elucidation of the temporal dynamics of immune cell recruitment in the brains of mice with EAE provides a valuable tool for studying the contribution of leukocyte trafficking to cytokine signalling and sickness/depression-like behaviour.

    “Elucidation of the temporal dynamics of immune cell recruitment in the brains of mice with EAE90,91 provides a valuable tool for studying the contribution of leukocyte trafficking to the activation of cytokine signalling in the brain and to the development of sickness and depression-like behaviour in this model.”

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Authors
McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H., & Miller, S. D.
Affiliations
  • Northwestern University (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Miller, Stephen D
Venue
Nature Medicine
Published
2005-02-27
Volume
11
Issue
3
Pages
335-339
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W1981688486
Cited by
694
References
30
Citations by year
2026: 10 · 2025: 17 · 2024: 23 · 2023: 13 · 2022: 19 · 2021: 22 · 2020: 18 · 2019: 18 · 2018: 21 · 2017: 28 · 2016: 34 · 2015: 47 · 2014: 44 · 2013: 38 · 2012: 44
FWCI
40.36
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (AI07476, T32AI007476)
  • National Institute of Neurological Disorders and Stroke (NS30871, NS-23349, P01NS023349, R01NS030871)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
epitope spreading, multiple sclerosis, T cell activation, dendritic cells, antigen presentation, microglia, macrophages, naive T cells, neuroinflammation, T cell receptor transgenic T cells, bone marrow chimeras
MeSH terms
Animals, Epitopes, Central Nervous System, Demyelinating Diseases, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Multiple Sclerosis, T-Lymphocytes, Theilovirus, Antigen Presentation, Cardiovirus Infections, Adoptive Transfer, Mice

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