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Résumé: La myasthénie se caractérise par une faiblesse musculaire et une fatigabilité anormale à l’effort. C’est une maladie auto-immune due à la présence d’anticorps dirigés contre des composants de la membrane musculaire localisés au niveau de la jonction neuromusculaire. Dans la majorité des cas, il s’agit d’auto-anticorps dirigés contre le récepteur de l’acétylcholine (RACh). Récemment d’autres cibles ont été décrites, telles que les protéines muscle-specific kinase (MuSK) ou lipoprotein related protein 4 (LRP4). L’origine de la réponse auto-immune n’est pas connue, mais les anomalies thymiques et les défauts de régulation du système immunitaire jouent certainement un rôle majeur chez les patients avec anticorps anti-RACh. Une prédisposition génétique influence très probablement la survenue de la maladie. Quant aux hormones sexuelles, elles jouent vraisemblablement un rôle dans la forme précoce de la maladie. La faiblesse musculaire est fluctuante et s’aggrave avec l’effort. La classification de la myasthénie peut être faite en fonction de la localisation des muscles atteints (oculaire versus généralisée), l’âge de début des symptômes, les anomalies thymiques et le profil des auto-anticorps. Ces critères permettent d’optimiser la prise en charge et le traitement des patients. Dans cette revue, nous analyserons les derniers concepts de la physiopathologie de la myasthénie en fonction des différents sous-groupes de la pathologie, en décrivant notamment le rôle des facteurs immunologiques, génétiques et environnementaux dans le développement de cette maladie. L’origine potentiellement virale de cette maladie sera évoquée. Enfin, nous discuterons de l’importance des tests biologiques disponibles pour confirmer le diagnostic. [Copyright &y& Elsevier]

Desmoglein (Dsg) 1 is a transmembrane glycoprotein of the desmosome allowing cell–cell adhesion between keratinocytes, whose expression is restricted to stratified squamous epithelia-like epidermis. Dsg1 is the target autoantigen of pathogenic autoantibodies produced by pemphigus foliaceus and 50% of pemphigus vulgaris patients in a Dsg1-specific T-cell-dependent pathway. Herewith, we show that mRNA of the DSG1 gene is present in normal human thymus and show by quantitative real-time polymerase chain reaction analysis that the expression of DSG1 transcript increases with age. Although immunoblot analysis on human thymus extracts using different anti-Dsg1 antibodies did not allow to detect the protein, we show by double-immunofluorescence assay that Dsg1 is expressed at protein level by CD19+ CD63+ cells located in the medulla. These data provide another illustration of the thymic expression of a tissue-specific autoantigen involved in an organ-specific autoimmune disease, which may participate in the tolerance acquisition and/or regulation of Dsg1-specific T cells. [ABSTRACT FROM AUTHOR]

Thymic myoid cells correspond to a muscle-like cell population present in the thymic medulla. They are well conserved throughout species evolution, but their biological role is not known. We demonstrated that myoid cells protected thymocytes from apoptosis as evidenced by a strong decrease of annexin-V-FITC positive thymocytes. This effect was (1) specific of myoid cells compared to thymic epithelial cells; (2) dependent on direct cell-to-cell contacts and (3) triggered rapidly after 2 h in cocultures. This protective phenomenon was due to the activation of prosurvival mechanisms. Indeed, myoid cells activated extracellular-regulated kinases (ERK1/2) and Akt in thymocytes. Myoid cells also influenced thymocyte maturation. We observed an increase in CD4+ and a decrease in CD8+ single positive (SP) thymocytes when cocultured with myoid cells, independently of a CD8+SP increased death or a CD4+SP overproliferation. Consequently, thymic myoid cells protect thymocytes from apoptosis and could also modulate their differentiation process.Cell Death and Differentiation (2005) 12, 463–472. doi:10.1038/sj.cdd.4401611 Published online 18 March 2005 [ABSTRACT FROM AUTHOR]

Résumé: L’œdème aigu du poumon (OAP) à pression négative complique 0,1 % des anesthésies générales. Dans de rares cas, il s’accompagne d’hémoptysie, surtout chez des patients jeunes, athlétiques après une chirurgie des voies aérodigestives supérieures. Sa physiopathologie est celle d’un obstacle des voies aériennes supérieures induisant des efforts inspiratoires responsables de dépressions intrathoraciques importantes provoquant un saignement des voies aériennes. Nous rapportons le cas d’un adulte jeune ayant fait une hémoptysie et un OAP à pression négative, au réveil d’une anesthésie générale pour amygdalectomie. La résolution de l’épisode intervient généralement dans les 24 premières heures après la levée de l’obstacle et d’une aide ventilatoire en pression positive. [ABSTRACT FROM AUTHOR]

• Quality of life is reduced in myasthenia gravis. • The role of exercise therapy to improve quality of life has not been explored. • This is the first prospective randomized controlled trial of home-based, unsupervised exercise therapy in MG. • Home-based exercise therapy was well-tolerated but did not improve quality of life. The tolerance of exercise and its effects on quality of life in myasthenia gravis are not currently backed up by strong evidence. The aim of this study was to determine whether exercise as an adjunct therapy is well tolerated and can improve health-related quality of life (HRQoL) in stabilized, generalized autoimmune myasthenia gravis (gMG). We conducted a parallel-group, multi-center prospective RCT using computer-generated block randomization. Adults with stabilized, gMG, and no contra-indication to exercise, were eligible. Participants received usual care alone or usual care and exercise. The exercise intervention consisted of 3-weekly 40 min sessions of an unsupervised, moderate-intensity home rowing program over 3 months. The primary endpoint was the change in HRQoL from randomization to post-intervention. Assessor-blinded secondary endpoints were exercise tolerance and effects on clinical, psychological and immunological status. Of 138 patients screened between October 2014 and July 2017, 45 were randomly assigned to exercise (n = 23) or usual care (n = 20). Although exercise was well tolerated, the intention-to-treat analysis revealed no evidence of improved HRQoL compared to usual care (MGQOL-15-F; mean adjusted between-groups difference of -0.8 points, 95%CI -5.4 to 3.7). Two patients hospitalized for MG exacerbation were from the usual care group. [ABSTRACT FROM AUTHOR]

Using in situ hybridization, we analysed the immunoglobulin repertoire expressed by the B cells present in myasthenia gravis thymuses from four patients. B cells, mostly in activated state, were clustered in germinal centres, in which multiple isotypes were identified. A majority of cells expressed IgG as compared with IgM, with a roughly similar contribution of κ and λ chains. Hybridization with the six Vκ and the 4 Vκ human family probes was observed in serial sections, providing additional evidence that individual germinal centres were polyclonal. The thymic B ceil repertoire closely reflected the VH and the Vκ family usage of normal peripheral blood lymphocytes with the preferential utilization of VH3, Vκl and Vκ3. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~ 10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients. [ABSTRACT FROM AUTHOR]

Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed. [ABSTRACT FROM AUTHOR]

Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (~2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about a study that investigated antibodies to Epstein-Barr virus in patients with thymic tumor.