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.
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.
|Permanent position||Non permanent position|
|Rozen Le Panse, DR2 CNRS, Team leader
Sonia Berrih-Aknin, DR2 INSERM, Emeritus
Jean-Thomas Vilquin, DR2 CNRS
Nadine Dragin, Researcher, Inovarion
Frédérique Truffault, Engineer, AIM
|Julien Verdier, Post-doct
Jose Adolfo Villegas, Post-doct
Odessa-Maud Fayet, Engineer
Axel You, Engineer
Cloé Payet, PhD student
Alexandra Bayer, PhD student
- C.MJ. Lefeuvre, C.A. Payet, O-M. Fayet, S. Maillard, F. Truffault, V. Bondet, D. Duffy, V. de Monpreville, M-R. Ghigna, E. Fadel, A. Mansuet-Lupo, M. Alifano, P. Validire, D. Gossot, A. Behin, B. Eymard, S. Berrih-Aknin, R. Le Panse. Risk factors associated with myasthenia gravis in thymoma patients: the potential role of thymic germinal centers. Journal of Autoimmunity, 2020 Jan;106:102337.
- M.A. Cron, S. Maillard, F. Truffault, A.M. Gualeni, A. Gloghini, E. Fadel, J. Guihaire, A. Behin, S. Berrih-Aknin and R. Le Panse. Cause and consequences of miR-150-5p dysregulation in myasthenia gravis. Frontiers in Immunology 10; 539, 1-14, 2019.
- J.A. Villegas, A.C. Bayer, K. Ider, J. Bismuth, F. Truffault, R. Roussin, N. Santelmo, R. Le Panse, S. Berrih-Aknin and N Dragin. Role of IL-23/Th17 cell pathway: a promising target to alleviate thymic inflammation maintenance in myasthenia gravis. J. Autoimmunity (Epub ahead of print).
- Birnbaum S, Hogrel JY, Porcher R, Portero P, Clair B, Eymard B, Demeret S, Bassez G, Gargiulo M, Louët E, Berrih-Aknin S, Jobic A, Aegerter P, Thoumie P, Sharshar T; MGEX Study Group. The benefits and tolerance of exercise in myasthenia gravis (MGEX): study protocol for a randomised controlled trial. Trials. Jan 18;19(1):49, 2018.
- Crahès M, Bories MC, Vilquin JT, Marolleau JP, Desnos M, Larghero J, Soulat G, Bruneval P, Hagège AA, Menasché P. Long-Term Engraftment (16 Years) of Myoblasts in a Human Infarcted Heart. Stem Cells Transl Med. 7(10):705-708. 2018.
- V. Yilmaz, S. Maillard, F. Truffault, F. Bolgert, A. Behin, J.F. Reignard, S. Berrih-Aknin and R. Le Panse. Regulatory B cells in myasthenia gravis are differentially affected by therapies. Annals of Clinical Translational Neurology, 2018.
- J.A. Villegas, A. Gradolatto, F. Truffault, R. Roussin, S. Berrih-Aknin, R. Le Panse and N Dragin. Cultured Human Thymic-Derived Cells Display Medullary Thymic Epithelial Cell Phenotype and Functionality. Frontiers in Immunology 23; 9:1663, 2018.
- M.A. Cron, S. Maillard, F. Delisle, N. Samson, F. Truffault, M. Foti, E. Fadel, J. Guihaire, S. Berrih-Aknin and R. Le Panse. Analysis of microRNA expression in the thymus of Myasthenia Gravis patients opens new research avenues. Autoimmunity Review 17(6): 588-600, 2018.
- Praud C, Vauchez K, Zongo P, Vilquin JT. Modelling human myoblasts survival upon xenotransplantation into immunodeficient mouse muscle. Exp Cell Res.; 364(2):217-223, 2018.
- V. Mariot, R. Joubert, C. Hourdé, L. Féasson, M. Hanna, F. Muntoni, T. Maisonobe, L. Servais, R. Le Panse, O. Benvensite, T. Stojkovic, P.M. Machado, T. Voit, A. Buj-Bello, J. Dumonceaux. Reversible endogenous downregulation of myostatin pathway in muscle wasting neuromuscular diseases explains challenges of anti-myostatin therapeutic approaches. Nature communications 30; 8 (1): 1859, 2017.
- Mamrut S, Avidan N, Truffault F, Staun-Ram E, Sharshar T, Eymard B, Frenkian M, Pitha J, de Baets M, Servais L, Berrih-Aknin S, Miller A. Methylome and transcriptome profiling in Myasthenia Gravis monozygotic twins. J Autoimmun. Aug;82:62-73. doi: 10.1016/j.jaut.2017.05.005. Epub 2017 May 24, 2017.
- M. Robinet, S. Maillard, B. Villeret, M.A. Cron, S. Berrih-Aknin and R. Le Panse. Use of Toll-Like Receptor agonists to induce ectopic lymphoid structures in myasthenia gravis mouse models. Frontiers in Immunology, 25; 8: 1029 2017.
- M. Attia, M. Maurer, M. Robinet, F. Le Grand, E. Fadel, R. Le Panse, G. Buttler-Browne and S. Berrih-Aknin. Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration. Acta Neuropathologica – 134(6):869-888, 2017.
- N. Dragin, P. Nancy, J. Villegas, R. Roussin and R. Le Panse, and S. Berrih-Aknin. Balance between estrogens and proinflammatory cytokines regulates chemokine production involved in thymic germinal center formation. Scientific reports – 7 (1), 7970, 1-13, 2017.
- M. Sudres, M. Maurer, M. Robinet, J. Bismuth, F. Truffault, D. Girard, N. Dragin, M. Attia, E. Fadel, N. Santelmo, C. Sicsic, T. Brenner, S. Berrih-Aknin. Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model. JCI Insight. Apr 6;2(7):e89665, 2017.
- N. Dragin, J. Bismuth, G. Cizeron-Clairac, M.G. Biferi, C. Berthault, A. Serraf, R. Nottin, D. Klatzmann, A. Cumano, M. Barkats, R. Le Panse, S. Berrih-Aknin. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126(4):1525-37, 2016.
- J. M. Weiss, M. Robinet, R. Aricha, P. Cufi, B. Villeret, F. Lantner, I. Shachar, M.C. Souroujon, S. Fuchs, S. Berrih-Aknin, R. Le Panse. Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis. Oncotarget 16-7(7):7550-62, 2016.
- S. Mamrut, N. Avidan, E. Staun-Ram, E. Ginzburg, F. Truffault, S. Berrih-Aknin and A. Miller. Integrative Analysis of Methylome and Transcriptome in Human Blood Identifies Extensive Sex- and Immune Cell-Specific Differentially Methylated Regions. Epigenetics 10 (10), 943-57, 2015.