Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen

Silke Kinzel, Klaus Lehmann-Horn, Sebastian Torke, Darius Hausler, Anne Winkler, Christine Stadelmann, Natalie Payne, Linda Feldmann, Albert Saiz, Markus Reindl, Patrice H Lalive, Claude C Bernard, Wolfgang Bruck, Martin S Weber

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 naive 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.
Original languageEnglish
Pages (from-to)43-58
Number of pages16
JournalActa Neuropathologica
Volume132
Issue number1
DOIs
Publication statusPublished - 1 Jul 2016

Keywords

  • Auto-antibodies
  • Opsonization
  • Myeloid antigen-presenting cells
  • Fc receptor
  • Experimental autoimmune encephalomyelitis
  • Multiple sclerosis

Cite this

Kinzel, S., Lehmann-Horn, K., Torke, S., Hausler, D., Winkler, A., Stadelmann, C., ... Weber, M. S. (2016). Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. Acta Neuropathologica, 132(1), 43-58. https://doi.org/10.1007/s00401-016-1559-8
Kinzel, Silke ; Lehmann-Horn, Klaus ; Torke, Sebastian ; Hausler, Darius ; Winkler, Anne ; Stadelmann, Christine ; Payne, Natalie ; Feldmann, Linda ; Saiz, Albert ; Reindl, Markus ; Lalive, Patrice H ; Bernard, Claude C ; Bruck, Wolfgang ; Weber, Martin S. / Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. In: Acta Neuropathologica. 2016 ; Vol. 132, No. 1. pp. 43-58.
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abstract = "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 naive 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.",
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Kinzel, S, Lehmann-Horn, K, Torke, S, Hausler, D, Winkler, A, Stadelmann, C, Payne, N, Feldmann, L, Saiz, A, Reindl, M, Lalive, PH, Bernard, CC, Bruck, W & Weber, MS 2016, 'Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen', Acta Neuropathologica, vol. 132, no. 1, pp. 43-58. https://doi.org/10.1007/s00401-016-1559-8

Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. / Kinzel, Silke; Lehmann-Horn, Klaus; Torke, Sebastian; Hausler, Darius; Winkler, Anne; Stadelmann, Christine; Payne, Natalie; Feldmann, Linda; Saiz, Albert; Reindl, Markus; Lalive, Patrice H; Bernard, Claude C; Bruck, Wolfgang; Weber, Martin S.

In: Acta Neuropathologica, Vol. 132, No. 1, 01.07.2016, p. 43-58.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen

AU - Kinzel, Silke

AU - Lehmann-Horn, Klaus

AU - Torke, Sebastian

AU - Hausler, Darius

AU - Winkler, Anne

AU - Stadelmann, Christine

AU - Payne, Natalie

AU - Feldmann, Linda

AU - Saiz, Albert

AU - Reindl, Markus

AU - Lalive, Patrice H

AU - Bernard, Claude C

AU - Bruck, Wolfgang

AU - Weber, Martin S

PY - 2016/7/1

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N2 - 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 naive 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.

AB - 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 naive 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.

KW - Auto-antibodies

KW - Opsonization

KW - Myeloid antigen-presenting cells

KW - Fc receptor

KW - Experimental autoimmune encephalomyelitis

KW - Multiple sclerosis

UR - http://www.ncbi.nlm.nih.gov/pubmed/27022743

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DO - 10.1007/s00401-016-1559-8

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