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Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response

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Abstract

While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the meninges of a subset of MS patients and were suggested to be correlates of late-stage and more aggressive disease in this patient population. However, whether these aggregates actually exist has subsequently been questioned and their functional significance has remained unclear. Here, we studied myelin basic protein (MBP)–proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which is one of the few animal models for MS that is dependent on B cells. We provide evidence that B cell aggregation is reflective of lymphoid neogenesis in the central nervous system (CNS) in MBP–PLP-elicited EAE. B cell aggregation was present already few days after disease onset. With disease progression CNS B cell aggregates increasingly displayed the phenotype of tertiary lymphoid organs (TLOs). Our results further imply that these TLOs were not merely epiphenomena of the disease, but functionally active, supporting intrathecal determinant spreading of the myelin-specific T cell response. Our data suggest that the CNS is not a passive “immune-privileged” target organ, but rather a compartment, in which highly active immune responses can perpetuate and amplify the autoimmune pathology and thereby autonomously contribute to disease progression.

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Abbreviations

cLN:

Cervical lymph node

CNS:

Central nervous system

drLN:

Draining lymph node

EAE:

Experimental autoimmune encephalomyelitis

FDC:

Follicular dendritic cell

HEV:

High endothelial venule

MAdCAM:

Mucosal addressin cell adhesion molecule

MBP:

Myelin basic protein

MOG:

Myelin oligodendrocyte glycoprotein

MP4:

MBP–PLP fusion protein

MS:

Multiple sclerosis

OVA:

Ovalbumin

PNAd:

Peripheral node addressin

PLP:

Proteolipid protein

TLO:

Tertiary lymphoid organ

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Acknowledgments

We thank Jolanta Kozlowski, Jil Pochmann and Esra Kücüksarioglan for help with the experiments. This work was supported by research grants from the German Research Foundation (DFG) (project KU 2760/2-1), the Köln Fortune Programm, the Imhoff-Stiftung, a Jaqueline Du Pré grant [grants to S.K.] and a grant from the National Multiple Sclerosis Society RG 4126-A-7 [N.H.R.]. A.S. and C.K contributed equally to this work.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Anatomy I, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany

    Stefanie Kuerten, Achim Schickel, Christian Kerkloh, Mascha S. Recks & Klaus Addicks

  2. Departments of Epidemiology and Public Health and Immunobiology, Yale University, 300 George St, New Haven, CT, 06520-8034, USA

    Nancy H. Ruddle

  3. Department of Pathology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH, 44106-7288, USA

    Paul V. Lehmann

  4. Cellular Technology Limited, 20521 Chagrin Blvd., Shaker Heights, OH, 44122-5350, USA

    Paul V. Lehmann

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  1. Stefanie Kuerten
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  2. Achim Schickel
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Correspondence to Stefanie Kuerten.

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Kuerten, S., Schickel, A., Kerkloh, C. et al. Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response. Acta Neuropathol 124, 861–873 (2012). https://doi.org/10.1007/s00401-012-1023-3

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  • DOI: https://doi.org/10.1007/s00401-012-1023-3

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