The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics

Abstract

T regulatory cells (Tregs) are crucial for the development of self-tolerance and are the major focus in many studies interpreting the pathogenesis of myasthenia gravis (MG), an autoimmune-based disease. In normal conditions, Tregs regulate the immune responses, while impaired regulatory function of these cells can lead to autoimmunity. Recent studies have confirmed that the thymic and peripheral blood CD4⁺CD25⁺ Tregs of MG are defective in functions and/or in numbers, which are associated with disease severity; approaches to correct the defects of these Tregs may be promising in the treatment of MG. This review discusses recent studies on characteristics, quantitative and qualitative changes of Tregs and possible mechanisms that are involved in the impairment of these cells in MG pathogenesis. In addition, new approaches inducing Treg generation that are currently being investigated as therapies for MG, will be discussed as well as proposed approaches for future therapies.

Keywords:

• autoimmunity
• EAMG
• FOXP3
• GM-CSF
• myasthenia gravis
• T regulatory cells
• vitamin D

Acknowledgements

We apologize to those researchers whose works, because of space restrictions, have not been cited in this review. The authors would like to thank Ethan Cieslewicz for critical reading.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Severe defects in the function of the thymus and peripheral blood CD4⁺CD25⁺ Tregs are observed in EAMG/AChR-MG patients; the actual etiology of this defect has not been clearly defined yet.

• Abnormal thymus environment (hyperplasia, neoplastic and inflammatory conditions), increased inflammatory condition, decreased FOXP3 level and alteration of surface molecules can disrupt the development/function of Tregs in AChR-MG patients; Tregs disruption is associated with MG pathogenesis.

• The reconstitution of functional ability of Tregs may have positive roles in AChR-MG pathogenesis, including inhibitory effects on autoreactive T cells and suppressing autoreactive B cells as well as autoantibody production, leading to the reduction of disease severity and progression.

• The regulatory defect observed in MG patients suggests the use of Tregs in appropriate treatment for MG patients.

• Administration of 1,25-dihydroxy vitamin D3 can overcome the impairment of Tregs; besides routine treatments, vitamin D supplement approaches could be useful in MG.

• Use of immunomodulatory agents related to Tregs function, including, anti-IL-6, -TNF-α antibodies as well as GM-CSF have shown promising results in EAMG and MG patients.

Notes