Team 7- Myasthenia Gravis, Etiology, Pathophysiology & Therapeutic Approach

Team leader: Rozen Le Panse

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies directed against components of the neuromuscular junction and leading to abnormal muscle fatigability. In most cases, the autoantibodies are directed against the acetylcholine receptor (AChR). However, in a minority of cases, patients have antibodies directed against other molecules of the muscle endplate, including the muscle specific tyrosine kinase (MuSK) or the lipoprotein-related protein 4 (LRP4).

The thymus is most likely the site of initiation of the disease in patients with anti- AChR antibodies. Indeed thymic histological abnormalities are very common in this subgroup of patients: 50-60 % of patients have a thymic follicular hyperplasia with germinal centers, 10 to 15% have a thymic tumor, and thymectomy is a beneficial treatment for many patients.

MG as all autoimmune diseases, is a multifactorial disease involving genetic and hormonal predisposing background, abnormalities of the immune system, and is triggered by unidentified factors. Among these, environmental factors such as viral infections or endocrine disrupters are highly suspected.

The team uses many immunological, cellular and molecular techniques, including omics approaches to identify factors that are responsible for the initiation of the disease, its development and its chronicity. The team is also developing new therapeutic approaches based on immune modulation.

Main projects

Our research aims to better understand the pathophysiological mechanisms in myasthenia gravis and to elucidate the events involved in the initiation and chronicity of the disease, with the long-term objective to propose new therapies. Our specific objectives are to:

• Identify the triggering mechanisms that cause myasthenia. We study the role of genetic factors and sex hormones, and analyze how the activation of signaling pathways of innate immunity may lead to remodeling of the thymus. We also analyze the relative contribution of the environment and the genetics, namely by exploring epigenetic data in monozygotic twins that are discordant for MG.
• Analyze the pathophysiological mechanisms in the thymus and in the muscle. In the thymus, we study how the cytokines related to IL-17 and T follicular cells affect immune regulation processes. In the muscle, we study the effects of pathogenic antibodies on muscle function, and the ability of satellite cells to regenerate muscle after the autoimmune attack.
• Provide a proof of concept of new immunotherapeutic approaches. To overcome the immune dysregulation defects observed in patients, we test the therapeutic potential of mesenchymal stem cells and molecules that interfere with the IL-17 inflammatory pathway. To this end, we developed a new pre-clinical experimental model based on an immune-deficient mice grafted with thymic biopsies from MG patients. This model recapitulates very well the clinical observations of MG patients, including clinical symptoms and anti-acetylcholine receptor antibody production.
• Search for biomarkers in the serum of MG patients. The finding of such molecules is very important for the follow up of the patients and the analysis of their response to various treatments. To do so, in collaboration with clinicians, we investigate circulating micro-RNAs and various cytokines.

Team members