Autophagy-deficiency in bone marrow mononuclear cells from patients with myasthenia gravis: a possible mechanism of pathogenesis

Abstract

Myasthenia gravis (MG) is a chronic autoimmune disorder resulting from autoantibodies against neuromuscular junction components. Research shows that this disease might be a primary bone marrow (BM) stem cell disorder. Autophagy protects the dynamics and homeostasis of the host cells by removing damaged mitochondria, protein aggregates and other intercellular materials. Dysfunctional autophagy is associated with autoimmune diseases. However, the autophagy activity and mechanisms in BM stem cell from MG patients remain largely uncharacterized. We evaluated the autophagy activity in bone marrow mononuclear cells (BM-MNCs) and the effects of autophagy on cell survival from patients with MG and healthy controls. Our results revealed that autophagy was significantly decreased in patients with MG before immunomodulation treatment compared with that in age-/sex-matched controls, and was lower in generalized MG (GMG) patients than in ocular MG (OMG) patients. Immunomodulatory treatment partially increased autophagy activity of BM-MNCs in MG patients and improved the symptoms. Furthermore, defective BM-MNCs differentiation, proliferation and apoptosis were observed due to dysfunctional autophagy. These findings suggest for the first time that BM-MNCs autophagy is impaired in patients with MG before immunomodulation therapy, and that autophagy is indispensable for the survival of BM-MNCs, implicating autophagy might be a potential pathogenic mechanism of MG and a novel therapeutic strategy for MG treatment.

Highlights:

•   The BM microenvironment and autophagy were defective in patients with MG before immunomodulation therapy.

•   Autophagy-deficiency in BM stem cell may be a potential pathogenesis of MG, and may sensitize the cells to apoptosis.

•   Improved autophagy was accompanied by the amelioration of MG, indicating a new therapeutic strategy for MG treatment.

Keywords:

• Myasthenia gravis
• Autophagy
• Bone marrow mononuclear cells
• Haematopoietic stem cells

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the National Key R&D Program of China (No. 2017YFC1307500, 2017YFC1307502), the National Natural Science Foundation of China (No. 81860222) and the Key R&D Program of Guangxi, China (No. Guike AB16380204).