Abstract
B linage cells are versatile players in multiple sclerosis (MS) and neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO). New potential targets of autoantibodies have been described recently. Pathogenic mechanisms extend further to antigen presentation and cytokine production, which are increasingly recognized as therapeutic targets. In addition to pro-inflammatory effects of B cells, they may act also as anti-inflammatory via production of interleukin (IL)-10, IL-35, and other mechanisms. Definition of regulatory B cell subsets is an ongoing issue. Recent studies have provided evidence for a loss of B cell self-tolerance in MS. An immunogenetic approach demonstrated exchange of B cell clones between CSF and blood. The central nervous system (CNS) of MS patients fosters B cell survival, at least partly via BAFF and APRIL. The unexpected increase of relapses in a trial with a soluble BAFF/APRIL receptor (atacicept) suggests that this system is involved in MS, but with features that are not yet understood. In this review, we further discuss evidence for B cell and Ig contribution to human MS and NMO pathogenesis, pro-inflammatory and regulatory B cell effector functions, impaired B cell immune tolerance, the B cell-fostering microenvironment in the CNS, and B cell-targeted therapeutic interventions for MS and NMO, including CD20 depletion (rituximab, ocrelizumab, and ofatumumab), anti-IL6-R (tocilizumab), complement-blocking (eculizumab), inhibitors of AQP4-Ig binding (aquaporumab, small molecular compounds), and BAFF/BAFF-R-targeting agents.
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Abbreviations
- MS:
-
Multiple sclerosis
- PP-MS:
-
Primary progressive MS
- RR-MS:
-
Relapsing-remitting MS
- SP-MS:
-
Secondary progressive MS
- NMO:
-
Neuromyelitis optica/neuromyelitis optica spectrum disorder
- RA:
-
Rheumatoid arthritis
- CNS:
-
Central nervous system
- IL:
-
Interleukin
- TNF:
-
Tumor necrosis factor
- TGF-β:
-
Transforming growth factor β
- LTα:
-
Lymphotoxin α
- EAE:
-
Experimental autoimmune encephalomyelitis
- AQP4:
-
Aquaporin 4
- MOG:
-
Myelin oligodendrocyte glycoprotein
- mAb:
-
Monoclonal antibody
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Acknowledgments
The work of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB TR128), the Verein zur Therapieforschung für Multiple-Sklerose-Kranke, the Bundesministerium für Bildung und Forschung (“Krankheitsbezogenes Kompetenznetz Multiple Sklerose”), and the Gemeinnützige Hertie Stiftung.
Conflict of interest
E. Meinl has received compensations from TEVA and Novartis. E. Meinl and M. Krumbholz have received grant support from Novartis.
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Disclaimer: For all compounds mentioned (marked as asterisks): indication, approval by local regulatory authorities, combination therapy, disease, severity, contraindications, prerequisites, and individual patient characteristics have to be independently verified for each compound by the treating physician.
This article is a contribution to the special issue on B cell-mediated autoimmune diseases - Guest Editors: Thomas Winkler and Reinhard Voll
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Krumbholz, M., Meinl, E. B cells in MS and NMO: pathogenesis and therapy. Semin Immunopathol 36, 339–350 (2014). https://doi.org/10.1007/s00281-014-0424-x
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DOI: https://doi.org/10.1007/s00281-014-0424-x