Elsevier

Journal of Autoimmunity

Volume 52, August 2014, Pages 90-100
Journal of Autoimmunity

Review
Myasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms

https://doi.org/10.1016/j.jaut.2013.12.011Get rights and content

Highlights

  • Anti-AChR, -MuSK, and -LRP4 antibodies differentially affect neuromuscular transmission in MG.

  • The thymus is likely the source of chronic inflammation in early-onset MG.

  • T cells are impaired and a Th1 and Th17 signature is observed in the MG thymus.

  • Our data suggest that a virus-mediated mechanism is involved in the onset of MG.

  • Changes in miRNA expression might alter the regulation of immune cells in MG.

Abstract

Autoimmune myasthenia gravis (MG) is characterized by muscle weakness caused by antibodies directed against proteins of the neuromuscular junction. The main antigenic target is the acetylcholine receptor (AChR), but the muscle Specific Kinase (MuSK) and the low-density lipoprotein receptor-related protein (LRP4) are also targets. This review summarizes the clinical and biological data available for different subgroups of patients, who are classified according to antigenic target, age of onset, and observed thymic abnormalities, such as follicular hyperplasia or thymoma.

Here, we analyze in detail the role of the thymus in the physiopathology of MG and propose an explanation for the development of the thymic follicular hyperplasia that is commonly observed in young female patients with anti-AChR antibodies. The influence of the pro-inflammatory environment is discussed, particularly the role of TNF-α and Th17-related cytokines, which could explain the escape of thymic T cells from regulation and the chronic inflammation in the MG thymus. Together with this immune dysregulation, active angiogenic processes and the upregulation of chemokines could promote thymic follicular hyperplasia.

MG is a multifactorial disease, and we review the etiological mechanisms that could lead to its onset. Recent global genetic analyses have highlighted potential susceptibility genes. In addition, miRNAs, which play a crucial role in immune function, have been implicated in MG by recent studies. We also discuss the role of sex hormones and the influence of environmental factors, such as the viral hypothesis. This hypothesis is supported by reports that type I interferon and molecules mimicking viral infection can induce thymic changes similar to those observed in MG patients with anti-AChR antibodies.

Introduction

Myasthenia gravis (MG) is characterized by fluctuating muscle weakness and abnormal fatigability. MG is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane at the neuromuscular junction. In most cases, autoantibodies against the acetylcholine receptor (AChR) can be found. Recently, other targets, such as Muscle-Specific Kinase (MuSK) and Lipoprotein-Related Protein 4 (LRP4), have been described. MG is classified based on the location of the affected muscles (i.e., ocular versus generalized), the age of onset of symptoms, and the autoantibody profile. These criteria are required to optimize the management and treatment of MG patients.

The origin of the autoimmune dysfunction in MG patients is unknown, but thymic abnormalities, defects in immune regulation and sex hormones play major roles in patients with anti-AChR antibodies. Genetic predisposition is also likely to influence the occurrence of the disease.

In this review, we analyze the latest concepts related to the pathophysiology of MG according to the different subgroups of the disease and provide a description of the roles of immunological, genetic, hormonal and environmental factors in the development of this disease.

Section snippets

Classification

MG occurs in patients of all ages and both sexes. The incidence ranges from 1.7 to 21.3 per million, and the prevalence is between 15 and 179 per million inhabitants, depending on the location [1], [2]. Studies of large groups of patients show that there is a predominance of female cases (60–70%) before the age of 50 years but not after the age of 50 years.

The clinical presentation, the age of onset, the autoantibody profile, and the thymic pathology can differ among patients and are used to

The role of the thymus in MG

The thymus is essential for T-cell differentiation and for the establishment of central tolerance. Interactions between thymic stromal cells expressing self-antigens and developing thymocytes lead to the elimination of autoreactive T cells. The self-tolerant T cells continue their differentiation before being exported to the periphery. Thymic stromal cells include epithelial cells [34], mesenchymal cells [35], and a few myoid cells [36].

Under physiological conditions, most thymic cells are

Etiological mechanisms of MG

Regardless of the clinical form, MG is a multifactorial disease. The onset of the disease is not clearly defined and is likely linked to a combination of predisposing factors and environmental factors.

Conclusion

MG has been actively studied since the 1970s, especially following the discovery of anti-AChR autoantibodies. However, recent investigations have improved our understanding of MG and highlighted new questions related to the development of MG. New antigenic targets have been described, and an improved classification system for the different MG subtypes and their distinct physiopathological mechanisms has been delineated. Recent microarray analyses have revealed a number of mechanisms that are

Acknowledgments

This work is supported by the 7th Framework Programme of the European Union FIGHT-MG (Grant No. 242210), by INSERM, and by the Institute of Myology.

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