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Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen
In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911382/ https://www.ncbi.nlm.nih.gov/pubmed/27022743 http://dx.doi.org/10.1007/s00401-016-1559-8 |
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author | Kinzel, Silke Lehmann-Horn, Klaus Torke, Sebastian Häusler, Darius Winkler, Anne Stadelmann, Christine Payne, Natalie Feldmann, Linda Saiz, Albert Reindl, Markus Lalive, Patrice H. Bernard, Claude C. Brück, Wolfgang Weber, Martin S. |
author_facet | Kinzel, Silke Lehmann-Horn, Klaus Torke, Sebastian Häusler, Darius Winkler, Anne Stadelmann, Christine Payne, Natalie Feldmann, Linda Saiz, Albert Reindl, Markus Lalive, Patrice H. Bernard, Claude C. Brück, Wolfgang Weber, Martin S. |
author_sort | Kinzel, Silke |
collection | PubMed |
description | In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1559-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4911382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-49113822016-07-05 Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen Kinzel, Silke Lehmann-Horn, Klaus Torke, Sebastian Häusler, Darius Winkler, Anne Stadelmann, Christine Payne, Natalie Feldmann, Linda Saiz, Albert Reindl, Markus Lalive, Patrice H. Bernard, Claude C. Brück, Wolfgang Weber, Martin S. Acta Neuropathol Original Paper In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1559-8) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-03-29 2016 /pmc/articles/PMC4911382/ /pubmed/27022743 http://dx.doi.org/10.1007/s00401-016-1559-8 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper Kinzel, Silke Lehmann-Horn, Klaus Torke, Sebastian Häusler, Darius Winkler, Anne Stadelmann, Christine Payne, Natalie Feldmann, Linda Saiz, Albert Reindl, Markus Lalive, Patrice H. Bernard, Claude C. Brück, Wolfgang Weber, Martin S. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title | Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title_full | Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title_fullStr | Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title_full_unstemmed | Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title_short | Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen |
title_sort | myelin-reactive antibodies initiate t cell-mediated cns autoimmune disease by opsonization of endogenous antigen |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911382/ https://www.ncbi.nlm.nih.gov/pubmed/27022743 http://dx.doi.org/10.1007/s00401-016-1559-8 |
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