ReviewMyasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms
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.
References (142)
- et al.
Anti-acetylcholine receptor antibodies in myasthenia gravis. Part 1. Relation to clinical parameters in 250 patients
J Neurol Sci
(1983) - et al.
Complement associated pathogenic mechanisms in myasthenia gravis
Autoimmun Rev
(2013) - et al.
Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4
Autoimmun Rev
(2013) - et al.
Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: heterogeneity and pathogenic significance
J Autoimmun
(1991) - et al.
The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo
Cell
(1996) - et al.
Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice
Exp Neurol
(2011) - et al.
Lrp4 is a receptor for Agrin and forms a complex with MuSK
Cell
(2008) - et al.
A Comprehensive Analysis of the Epidemiology and Clinical Characteristics of Anti-LRP4 in Myasthenia Gravis
J Autoimmun
(2014) - et al.
The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes
Autoimmun Rev
(2013) - et al.
Thymoma-associated myasthenia gravis: on the search for a pathogen signature
J Autoimmun
(2014)