MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies

Nicolas Molnarfi, Ulf Schulze-Topphoff, Martin S Weber, Juan C Patarroyo, Thomas Prod'Homme, Michel Varrin-Doyer, Aparna Shetty, Christopher Linington, Anthony J Slavin, Juan Hidalgo, Dieter E Jenne, Hartmut Wekerle, Raymond A Sobel, Claude Charles Andre Bernard, Mark J Shlomchik, Scott S Zamvil

Research output: Contribution to journalArticleResearchpeer-review

162 Citations (Scopus)

Abstract

Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.
Original languageEnglish
Pages (from-to)2921 - 2937
Number of pages17
JournalJournal of Experimental Medicine
Volume210
Issue number13
DOIs
Publication statusPublished - 2013

Cite this

Molnarfi, N., Schulze-Topphoff, U., Weber, M. S., Patarroyo, J. C., Prod'Homme, T., Varrin-Doyer, M., ... Zamvil, S. S. (2013). MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. Journal of Experimental Medicine, 210(13), 2921 - 2937. https://doi.org/10.1084/jem.20130699
Molnarfi, Nicolas ; Schulze-Topphoff, Ulf ; Weber, Martin S ; Patarroyo, Juan C ; Prod'Homme, Thomas ; Varrin-Doyer, Michel ; Shetty, Aparna ; Linington, Christopher ; Slavin, Anthony J ; Hidalgo, Juan ; Jenne, Dieter E ; Wekerle, Hartmut ; Sobel, Raymond A ; Bernard, Claude Charles Andre ; Shlomchik, Mark J ; Zamvil, Scott S. / MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 13. pp. 2921 - 2937.
@article{6f904696e5c74ac69f5f9d7f17bb1528,
title = "MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies",
abstract = "Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.",
author = "Nicolas Molnarfi and Ulf Schulze-Topphoff and Weber, {Martin S} and Patarroyo, {Juan C} and Thomas Prod'Homme and Michel Varrin-Doyer and Aparna Shetty and Christopher Linington and Slavin, {Anthony J} and Juan Hidalgo and Jenne, {Dieter E} and Hartmut Wekerle and Sobel, {Raymond A} and Bernard, {Claude Charles Andre} and Shlomchik, {Mark J} and Zamvil, {Scott S}",
year = "2013",
doi = "10.1084/jem.20130699",
language = "English",
volume = "210",
pages = "2921 -- 2937",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "13",

}

Molnarfi, N, Schulze-Topphoff, U, Weber, MS, Patarroyo, JC, Prod'Homme, T, Varrin-Doyer, M, Shetty, A, Linington, C, Slavin, AJ, Hidalgo, J, Jenne, DE, Wekerle, H, Sobel, RA, Bernard, CCA, Shlomchik, MJ & Zamvil, SS 2013, 'MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies', Journal of Experimental Medicine, vol. 210, no. 13, pp. 2921 - 2937. https://doi.org/10.1084/jem.20130699

MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. / Molnarfi, Nicolas; Schulze-Topphoff, Ulf; Weber, Martin S; Patarroyo, Juan C; Prod'Homme, Thomas; Varrin-Doyer, Michel; Shetty, Aparna; Linington, Christopher; Slavin, Anthony J; Hidalgo, Juan; Jenne, Dieter E; Wekerle, Hartmut; Sobel, Raymond A; Bernard, Claude Charles Andre; Shlomchik, Mark J; Zamvil, Scott S.

In: Journal of Experimental Medicine, Vol. 210, No. 13, 2013, p. 2921 - 2937.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies

AU - Molnarfi, Nicolas

AU - Schulze-Topphoff, Ulf

AU - Weber, Martin S

AU - Patarroyo, Juan C

AU - Prod'Homme, Thomas

AU - Varrin-Doyer, Michel

AU - Shetty, Aparna

AU - Linington, Christopher

AU - Slavin, Anthony J

AU - Hidalgo, Juan

AU - Jenne, Dieter E

AU - Wekerle, Hartmut

AU - Sobel, Raymond A

AU - Bernard, Claude Charles Andre

AU - Shlomchik, Mark J

AU - Zamvil, Scott S

PY - 2013

Y1 - 2013

N2 - Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.

AB - Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B-MHC II(-/-)), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)-specific B cell receptor (BCR; IgH(MOG-mem)) but cannot secrete antibodies. B-MHC II(-/-) mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell- and B cell-dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B-MHC II(-/-) mice. In the absence of antibodies, IgH(MOG-mem) mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle-like structures were observed in IgH(MOG-mem) mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell-targeted therapies.

UR - http://jem.rupress.org/content/210/13/2921.full.pdf

U2 - 10.1084/jem.20130699

DO - 10.1084/jem.20130699

M3 - Article

VL - 210

SP - 2921

EP - 2937

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 13

ER -