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J Autoimmun. 2014 Aug;52:101-12. doi: 10.1016/j.jaut.2013.12.008. Epub 2014 Jan 16.

Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor.

Author information

1
Department of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
2
Neuroimmunology group, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, Diepenbeek, Belgium.
3
Department of Biochemistry, Hellenic Pasteur Institute, GR 11521 Athens, Greece.
4
Centre Superior d'Investigació en Salut Pública (CSISP), Àrea de Genòmica i Salut, Conselleria de Sanitat, Generalitat Valenciana, València, Spain; Institut "Cavanilles" de Biodiversitat i Biologia Evolutiva (ICBiBE), Universitat de València, València, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Ministerio de Ciencia e Innovación, Spain.
5
UPMC UM 76/INSERM U974/CNRS UMR7215/Institute of Myology, 105 Bd de l'hôpital, Paris, France.
6
Department of Cardiothoracic Surgery, University Hospital, Maastricht, The Netherlands.
7
Department of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands; Neuroimmunology group, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, Diepenbeek, Belgium.
8
Department of Neuroscience, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: p.martinez@maastrichtuniversity.nl.

Abstract

Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR-MG) is considered as a prototypic autoimmune disease. The thymus is important in the pathophysiology of the disease since thymus hyperplasia is a characteristic of early-onset AChR-MG and patients often improve after thymectomy. We hypothesized that thymic B cell and antibody repertoires of AChR-MG patients differ intrinsically from those of control individuals. Using immortalization with Epstein-Barr Virus and Toll-like receptor 9 activation, we isolated and characterized monoclonal B cell lines from 5 MG patients and 8 controls. Only 2 of 570 immortalized B cell clones from MG patients produced antibodies against the AChR (both clones were from the same patient), suggesting that AChR-specific B cells are not enriched in the thymus. Surprisingly, many B cell lines from both AChR-MG and control thymus samples displayed reactivity against striated muscle proteins. Striational antibodies were produced by 15% of B cell clones from AChR-MG versus 6% in control thymus. The IgVH gene sequence analysis showed remarkable similarities, concerning VH family gene distribution, mutation frequency and CDR3 composition, between B cells of AChR-MG patients and controls. MG patients showed clear evidence of clonal B cell expansion in contrast to controls. In this latter aspect, MG resembles multiple sclerosis and clinically isolated syndrome, but differs from systemic lupus erythematosus. Our results support an antigen driven immune response in the MG thymus, but the paucity of AChR-specific B cells, in combination with the observed polyclonal expansions suggest a more diverse immune response than expected.

KEYWORDS:

B-cell immortalization; Clonal expansion; Myasthenia gravis; Striational autoantibodies

PMID:
24439114
DOI:
10.1016/j.jaut.2013.12.008
[Indexed for MEDLINE]
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