WHY WOULD OUR IMMUNE SYSTEM TURN AGAINST OUR OWN CELLS? THIS IS THE QUESTION THAT THE COMBINED INSERM/CNRS/ PIERRE AND MARIE CURIE UNIVERSITY/ASSOCIATION INSTITUT DE MYOLOGIE  HAVE STRIVED

TO ANSWER IN THEIR “THERAPIES FOR DISEASES OF STRIATED MUSCLE”, CONCENTRATING IN PARTICULAR ON THE AUTO-IMMUNE DISEASE KNOWN AS MYASTHENIA GRAVIS. THROUGH THE PROJECT KNOWN AS FIGHT-MG

(FIGHT MYASTHENIA GRAVIS), FINANCED BY THE EUROPEAN COMMISSION AND COORDINATED BY INSERM, SONIA BERRIH-AKNIN AND ROZEN LE PANSE HAVE CONTRIBUTED PROOF OF THE CONCEPT THAT A MOLECULE

IMITATING A VIRUS MAY TRIGGER AN INAPPROPRIATE IMMUNE RESPONSE, CAUSING MUSCULAR FUNCTION TO DETERIORATE. THESE RESULTS HAVE BEEN PUBLISHED IN _ANNALS OF NEUROLOGY__, _ACCESSIBLE ON LINE.

circulating AUTO-ANTIBODIES that block the ACETYLCHOLINE RECEPTORS (RACh), these neurotransmitters being necessary for transmitting the motor nerve signal to the neuro-muscular junction.

COULD A VIRAL INFECTION BE THE ORIGIN OF MYASTHENIA? Myasthenia is a multi-factorial disease in which environmental factors seem to play a key triggering role. VIRAL INFECTIONS ARE SUSPECTED

but it is hard to prove the role of a virus in triggering the condition. In fact, diagnosis of myasthenia is often made months, or even years, after the actual start of the illness when the

virus is no longer detectable, even though the signature left by the virus is visible long after the infection. PROOF OF THE CONCEPT OF A VIRAL ORIGIN CONTRIBUTED BY RESEARCHERS Under the

European FIGHT-MG project, the team of researchers managed to decode the trigger for the illness by using A MOLECULE THAT MIMICS THE RNA DOUBLE VIRAL STRAND (POLY(I:C)). To do this, they

concentrated on the organ that plays a central role in the disease – THE THYMUS. It is in this gland located in the thorax that the T-lymphocytes mature, these being the key players in

immune response that are normally programmed to avoid the development of any auto-immunity. The researchers were thus able to show _in vitro_ that the Poly(I:C) was capable of specifically

inducing an over-expression of RACh through thymal epithelial cells, while activating three proteins (the “toll-like” receptor 3 (TLR3), the protein kinase R (PKR) and interferon-beta

(IFN-â)); it is this last that produces inflammation in the thymus. At the same time, they analysed pathological thymus glands of myasthenia sufferers in whom they observed over-expression

of these same three proteins in the immune system, characteristic of a viral infection. Finally, the researchers also managed to identify the same molecular changes in the thymus glands of

mice, after they had been injected with Poly(I:C). After a prolonged injection period, they also observed a proliferation in the mice of B anti-RACh cells, the presence of auto-antibodies

blocking the RACh receptors and clinical signs synonymous with the muscular weakness found in myasthenia. THESE ORIGINAL RESULTS SHOW THAT MOLECULES THAT MIMIC A VIRAL INFECTION ARE CAPABLE

OF INDUCING MYASTHENIA IN THE MOUSE, SOMETHING THAT HAD NEVER BEEN DEMONSTRATED BEFORE. This set of papers published in the _Annals of Neurology_ provides proof of the concept that a VIRAL

INFECTION CAN CAUSE INFLAMMATION OF THE THYMUS AND LEAD TO THE DEVELOPMENT OF AUTO-IMMUNE MYASTHENIA. The next stages of the research will consist in determining which exogenous virus this

may be or whether it is a case of the abnormal activation of an anti-viral response by endogenous molecules. _© Inserm / R. Le Panse__ _ _The introduction of a double strand of RNA

(Poly(I:C) into the thymal epithelial cell induces the over-expression of the acetylcholine receptors (RACh), via the activation of the “toll-like” receptor 3 (TLR3) and the protein kinase R

(PKR),  as well as the production of interferon-beta (IFN-β)). These changes in the thymus gland cause the formation of B anti-RACh cells and the production of circulating auto-antibodies

that block the acetylcholine receptors present in the neuromuscular junction_. FIGHT-MG (FIGHTING MYASTHENIA GRAVIS) – A EUROPEAN COLLABORATION MAKING GIANT LEAPS FORWARD The FIGHT-MG

project seeks to determine the genetic and environmental risk factors associated with the occurrence of the illness and its development. The project aims also to identify the key

immunological molecules associated with its appearance, and to study the pathogenic mechanisms at the neuromuscular junction, establish new diagnostic tests, as well as new treatments

(cellular treatments, immuno-regulatory treatments, immuno-absorption of pathogenic auto-antibodies and other pharmacological treatments). _“WHEN ONE IS WORKING ON A RARE DISEASE, IT IS

ESSENTIAL TO WORK THROUGH NETWORKING, SO AS TO BE ABLE TO SHARE OUR FACILITIES AND RESOURCES TO PROMOTE FUNDAMENTAL AND CLINICAL RESEARCH. IT IS ALSO CRUCIAL TO COMMUNICATE PERMANENTLY WITH

PATIENT ASSOCIATIONS. IT IS THIS COMBINATION THAT ENABLES US TO TAKE GIANT STEPS IN THE TREATMENT OF RARE CONDITIONS,”_ explains Sonia Berrih-Aknin. FIGHT-MG : https://www.fight-mg.eu/ 

FIGHT-MG started in December 2009 and will last for four years, with a total budget of about six million euros funded by the European Union (FP7). The project involves 12 partners based in

seven European countries: THE 12 PARTNERS: Inserm (coordinator), France Hellenic Pasteur Institute (HPI), Greece Open University of Israel (OUI), Israel Fondazione Istituto Neurologico

“Carlo Besta” (INNCB), Italy Oslo University Hospital (OUS), Norway Hadassah Hebrew University Medical Center (HMO), Israel Israel Institute of Technology (TECHNION), Israel University of

Paris 6 Pierre and Marie Curie (UPMC), France University of Basel (UNIBAS), Switzerland ProteoSys (PSY), Germany Genopolis Consortium for Functional Genomics (GENOPOLIS), Italy INSERM

TRANSFERT SA (IT), France THE “MYASTHENIA” TEAM The “Myasthenia” team, headed by Sonia Berrih-Aknin joined the Institute of Myology directed by Professor T. Voit, just over a year ago in

order to get closer to the reference centre for neuromuscular diseases run by Prof B. Eymard, at the Pitié-Salpêtrière Hospital in Paris. The Institute of Myology is an international center

of expertise on the muscle and its diseases, a member of the Institute of Biotherapy of rare diseases created by the AFM-Telethon. The Sonia Berrih-Aknin’s team is interested in the

etiological and physio-pathological mechanisms of myasthenia and innovative treatments that could improve patients’ quality of life. Even though winning a European project is very

competitive, this team has exceptionally been granted three other projects since 2001, and was responsible for their coordination. Sonia Berrih-Aknin was the coordinator of the “Mechanisms

of Myasthenia” project (2001-2005) under FP5, the MYASTAID (2006-2010) project under  le cadre du FP6, as well as the Euromyasthenia Project (2006-2009) through the European Public Health 

Directorate. These projects brought a total of more than fifty teams of clinicians, researchers and associations of sufferers in Europe. THESE CONTENTS COULD BE INTERESTING :