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Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review

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Abstract

The most common form of Myasthenia gravis (MG) is due to anti-acetylcholine receptor (AChR) antibodies and is frequently associated with thymic pathology. In this review, we discuss the immunopathological characteristics and molecular mechanisms of thymic follicular hyperplasia, the effects of corticosteroids on this thymic pathology, and the role of thymic epithelial cells (TEC), a key player in the inflammatory thymic mechanisms. This review is based not only on the literature data but also on thymic transcriptome results and analyses of pathological and immunological correlations in a vast cohort of 1035 MG patients without thymoma. We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women. The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies. The degree of hyperplasia is not dependent upon the time from the onset, implying that either the antigen is chronically expressed and/or that the mechanisms of the resolution of the GC are not efficiently controlled. Glucocorticoids, a conventional therapy in MG, induce a significant reduction in the GC number, together with changes in the expression of chemokines and angiogenesis. These changes are likely related to the acetylation molecular process, overrepresented in corticosteroid-treated patients, and essential for gene regulation. Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients.

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Abbreviations

AChR:

Acetylcholine receptor

AIRE:

Autoimmune regulator

BAFF:

B cell-activating factor

BCR:

B cell receptor

EOMG:

Early-onset MG

ER:

Estrogen receptor

FDC:

Follicular dendritic cells

GC:

Germinal center

HEV:

High endothelial venules

IFN:

Interferon

IL:

Interleukin

IRF:

IFN-regulatory factor

KO:

Knock-out

MG:

Myasthenia gravis

MS:

Multiple sclerosis

PBMCs:

Peripheral blood mononuclear cells

PLP:

Proteolipid protein

PTPN22:

Protein tyrosine phosphatase, non-receptor type 22

TCR:

T cell receptor

TEC:

Thymic epithelial cell

Tfh:

T follicular helper

TLR3:

Toll-like receptor 3

TREC:

T cell receptor excision circles

Treg:

Regulatory T cells

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Authors and Affiliations

  1. INSERM U974, Paris, France

    Frédérique Truffault, Rozen Le Panse & Sonia Berrih-Aknin

  2. CNRS FRE3617, Paris, France

    Frédérique Truffault, Rozen Le Panse & Sonia Berrih-Aknin

  3. Sorbonne Universités, UPMC Univ Paris 06, Paris, France

    Frédérique Truffault, Rozen Le Panse & Sonia Berrih-Aknin

  4. AIM, Institut de myologie, Paris, France

    Frédérique Truffault, Rozen Le Panse & Sonia Berrih-Aknin

  5. Department of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, 92350, France

    Vincent de Montpreville

  6. Department of Neuromuscular Disorders, CHU Salpêtrière, Paris, France

    Bruno Eymard

  7. General Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, 92380, Garches, France

    Tarek Sharshar

  8. UMRS 974 UPMC, INSERM, FRE 3617 CNRS, AIM, Center of Research in Myology, 105 Boulevard de l’Hôpital, Paris, 75013, France

    Sonia Berrih-Aknin

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  1. Frédérique Truffault
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  2. Vincent de Montpreville
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  3. Bruno Eymard
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  4. Tarek Sharshar
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  6. Sonia Berrih-Aknin
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Correspondence to Sonia Berrih-Aknin.

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This work was supported by the FIGHT-MG (Heath-2009-242-210) grant from the European Community and a grant from the “Association Francaise contre les Myopathies” obtained by Dr S. Berrih-Aknin.

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Truffault, F., de Montpreville, V., Eymard, B. et al. Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review. Clinic Rev Allerg Immunol 52, 108–124 (2017). https://doi.org/10.1007/s12016-016-8558-3

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