European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe

Encefalomielitis miàlgica/síndrome de fatiga crònica; Cura; DiagnòsticMyalgic encephalomyelitis/chronic fatigue syndrome; Care; DiagnosisEncefalomielitis miálgica/síndrome de fatiga crónica; Cuidado; DiagnósticoDesigned by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)—COST action 15111—from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.This research received no external funding. EUROMENE receives funding for networking activities from the COST programme (COST Action 15111), via the COST Association

Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth

Once escaped from the quiescence niche, precursor cells interact with stromal components that support their survival, proliferation, and differentiation. We examined interplays between human myogenic precursor cells (mpc) and monocyte/macrophages (MP), the main stromal cell type observed at site of muscle regeneration. mpc selectively and specifically attracted monocytes in vitro after their release from quiescence, chemotaxis declining with differentiation. A DNA macroarray–based strategy identified five chemotactic factors accounting for 77% of chemotaxis: MP-derived chemokine, monocyte chemoattractant protein-1, fractalkine, VEGF, and the urokinase system. MP showed lower constitutive chemotactic activity than mpc, but attracted monocytes much strongly than mpc upon cross-stimulation, suggesting mpc-induced and predominantly MP-supported amplification of monocyte recruitment. Determination of [3H]thymidine incorporation, oligosomal DNA levels and annexin-V binding showed that MP stimulate mpc proliferation by soluble factors, and rescue mpc from apoptosis by direct contacts. We conclude that once activated, mpc, which are located close by capillaries, initiate monocyte recruitment and interplay with MP to amplify chemotaxis and enhance muscle growth

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe.

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS

Macrophagic myofasciitis: characterization and pathophysiology.

International audienceAluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain

Mécanismes moléculaires impliqués dans la fusion des cellules précurseurs myogéniques humains

Les cellules musculaires striées squelettiques, sont des cellules multinucléées, formées par la prolifération, l'agrégation etla fusion de cellules précurseurs myogéniques (myogenic precursor cells, mpc) mononucléées. La caractérisation des mécanismes moléculaires impliqués dans le processus de fusion des cellules myogéniques humaines apparaît nécessaire à l'amélioration des biothérapies des maladies musculaires. Nous avons choisi d'évaluer in vitro l'implication de deux systèmes dans la fusion des mpc humaines l'ADAM12 et son partenaire intégrine alpha9betal et le récepteur purinergique P2X7. Nous avons montré l'expression du P2X7 par les mpc humaines et une partie de ses fonctions. Le récepteur P2X7 semble intervenir dan les mécanismes de régulation de la mort cellulaire plutôt que dans la fusion des mpc. Nous avons montré que les mpc humaines expriment constitutivement l'ADAM12 et l'intégrine alpha9betal in vitro et que les deux molécules interagissent entre elles aux zones de contact intercellulaire. L'inhibition du système ADAM12/ alpha9betal montre une diminution significative de l'index de fusion global. Cet effet n'est pas du à un détachement des mpc de leur support, et intervient principalement dans l'élongation des myotubes. Nous avons démontré in vivo chez l'homme une forte expression des 2 isoformes membranaire et secrétée d'ADAM 12 lors du processus de nécrose/régénération myocytaire; les cellules exprimant ADAM12 étant d'origine myogénique, hématopoïétique et interstitielle potentiellement myogénique. Le contrôle de la fusion des mpc avec les myocytes existants s'inscrit dans le développement de thérapies cellulaires efficaces des maladies musculaires.Cell therapy using transplantation of exogenous myogenic precursor cell (mpc) aimed at fusing with mature muscle fibres may help treating devastating muscle diseases. Characterization of molecular systems involved in mpc is a major goal to improve cell therapy. Fusion does not depend on the engagement of a single molecule, but rather on the coordinated recruitment of several molecules mediating ceIl aggregation, close cell-to-cell contact and, finally, the actual fusion event. Among the different human fusion systems, molecules from the ADAM family and the purinoceptor P2X7 could play a direct role in the cell fusion process itself. We showed in human mpc cultures, expression and partial functionality of P2X7. It seems to be implicated in cell death regulation during differentiation process more than in mpc fusion. We showed that human mpc constitutively express ADAMI2 and its integrin partner alpha9betal. Both molecuîes interact atcell-ceII contact areas. Inhibition strategies induce a significant decrease of fusion index. This effect is not due to ceIl de-adhesion from their support, and interaction of ADAM12 and alpha9betal s mainly operative in nascent myotube growth. We showed, in vivo, that in human the necrosislregeneration process is associated with high expression of both isoforms of ADAM1 2 (membrane-bound and secreted). Cells expressing ADAM12 are from myogenic, haematopoietic and interstitial origin. We believe that there is great interest in understanding mpc fusion, because of both ifs central role in muscle development and adult muscle repair, and the relevance of influencing muscle cell fusion for designing future therapeutic strategies.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Rôle de l'endocytose et du compartiment endosomal dans la cytotoxicité de la toxine du choléra (implication de la cathepsine D)

La toxine du choléra (CT) est le principal facteur de virulence sécrété par Vibrio cholerae, responsable de diarrhées sévères. Sous sa forme hétéropentamérique AB5, la CT est inactive. Dans ce travail nous avons démontré l implication du compartiment endosomal dans l étape d activation de la CT. Au moyen d une approche de fractionnement subcellulaire du parenchyme hépatique de rat, nous avons démontré dans la lumière des endosomes une interaction entre la CT et la cathepsine D (CD), favorisée par l augmentation de la vitesse d acidification dépendante de l ATP. La protéolyse de la CT par la CD s est accompagnée d une ADP-ribosylation de la protéine Gsa (son substrat) co-internalisé avec la CT, en présence du cofacteur ARF6 recruté à la membrane endosomale. Ces résultats démontrent que la protéolyse de la CT par la CD et l acidification endosomale sont deux étapes limitantes pour l activation endosomale de la CT.Cholera toxin (CT) is produced by Vibrio cholerae and is the major virulence factor responsible for the massive secretory diarrhea of infected humans. CT is composed of one activating A subunit and five identical B subunits. The CTA subunit is comprised of two domains termed the A1 and A2 peptides. For full cytotoxicity, a production of A1 peptide must occur intracellularly. We demonstrated that proteolysis of cholera toxin within endosomes required an acidic pH and was sensitive to pepstatin A, an inhibitor of aspartic acid proteases. Hydrolysates of cholera toxin at acidic pH by cathepsin D displayed ADP-ribosyltransferase activity towards exogenous Gsa. Gsa and ARF proteins were immunodetected in rat liver endosomes prepared various times after toxin injection. Internalized CT displayed an ADP-ribosyltransferase activity towards endogenous Gsa protein. These data identify endosomal cathepsin D as a key enzyme responsible for cholera toxin cytotoxic activation.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Myofascite à macrophages (étude clinique et paraclinique de 82 patients)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les myosites à éosinophiles idiopathiques

Les myosites à éosinophiles appartiennent au groupe des myopathies inflammatoires idiopathiques et sont définies par un infiltrat inflammatoire musculaire composé de polynucléaires éosinophiles. Il n’existe pas à ce jour de consensus concernant le diagnostic et le traitement de ces patients. Grâce à une revue exhaustive de la littérature, les principales caractéristiques cliniques et histologiques, ainsi que le traitement et l’évolution des patients, ont été résumés dans cette synthèse. Cette revue a permis de distinguer trois sous-groupes de myosites à éosinophiles : la forme focale, la forme diffuse et les périmyosites à éosinophiles. Un algorithme de traitement et de prise en charge est proposé, et les principaux diagnostics différentiels sont discutés

Méthode automatisée d’analyse d’images appliquée à la dermatomyosite

L’analyse histologique du tissu musculaire est un élément déterminant pour le diagnostic et la compréhension physiopathologique des myopathies. Le développement d’outils numériques et informatiques permet des analyses d’images quantifiées à grande échelle applicable aux biopsies musculaires. L’analyse d’images automatisée permet de déterminer la taille de l’ensemble des myofibres sur un échantillon de muscle et d’évaluer l’atrophie myocytaire. Le codage couleur selon la taille permet de visualiser directement la topographie de l’atrophie myocytaire. Cette approche morphométrique appliquée à la dermatomyosite permettra une meilleure stratification des patients

Distinct interferon signatures stratify inflammatory and dysimmune myopathies

International audienceWhat is already known about this subject? ► among inflammatory/dysimmune myopathies (iDMs), dermatomyositis (DM) is the only associated with type i-interferon signature. ► Most iDMs are associated with myofiber expression of major histocompatibility complex (MHc)-class i. MHc-i is induced by interferons suggesting a possible role for type ii-interferon in iDMs other than DM. What does this study add? ► in this study, we showed that myofiber MHc-ii expression is observed in inclusion body myositis (iBM) and antisynthetase myositis (aSM), but not in DM and necrotizing autoimmune myopathy (naM). ► in accordance with this finding, we showed that iBM and aSM are specifically associated with type-ii iFnγ signature, DM only with type-i iFn signature, and naM with neither type-i nor type-ii iFn signature. How might this impact on clinical practice? ► Distinct iFn signatures allow a more distinct segregation of iDMs and therefore a more accurate diagnosis. ► Deciphering iFn signatures in iDMs will also lead to develop new therapeutic approaches targeting iFns pathways. AbstrAct Objective the role of interferons (iFn) in the pathophysiology of primary inflammatory and dysimmune myopathies (iDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. in present work we analysed the muscular expression of specific iFnα/β and iFnγ-stimulated genes in patients with various types of iDM. Methods 39 patients with iDM with inclusion body myositis (iBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (naM, n=10) and antisynthetase myositis (aSM, n=10), and 10 controls were included. Quantification of expression levels of iFnγ, iSg15, an iFnα/β-inducible gene and of six iFnγ-inducible genes (gBP2, Hla-DOB, Hla-DPB, ciita, Hla-DrB and Hla-DMB) was performed on muscle biopsy samples. Results DM usually associated with strong type i iFnα/β signature, iBM and aSM with prominent type ii iFnγ signature and naM with neither type i nor type ii iFn signature. immunofluorescence study in aSM and iBM showed myofibre expression of major histocompatibility class 2 (MHc-2) and ciita, confirming the induction of the iFnγ pathway. Furthermore, MHc-2-positive myofibres were observed in close proximity to cD8+ t cells which produce high levels of iFnγ. Conclusion Distinct iFn signatures allow a more distinct segregation of iDMs and myofibre MHc-2 expression is a reliable biomarker of type ii iFn signature