| Résumé : | The involvement of the complement system in the pathogenesis of myasthenia gravis (MG) depends on the IgG subtype. The serum anti-acetylcholine receptor antibody (AChR-ab, present in about 80% of all MG patients) essentially belongs to the IgG1 subtype and can, therefore, activate the classical complement pathway. In contrast, serum antibodies against the muscle-specific tyrosine kinase (MuSK-ab, present in about 3% of all MG patients) are mostly from the IgG4 subtype that do not activate the complement system [6, 12]. Other previously identified antibodies are directed against the lipoprotein-related protein 4 (LRP4-ab, present in 2% of all MG patients) [2]. Approximately, 15% of MG patients are termed “seronegative” (SNMG), meaning that no known serum antibodies can be detected. Clinicoserological diagnosis alone carries the risk of under-diagnosis, which may exclude SNMG patients from modern therapies: targeted complement inhibition (eculizumab) has recently been introduced in the treatment of AChR-ab-positive generalized MG patients who do not respond to standard treatment [5]. The aim of this study was to identify a reliable biomarker to justify complement-targeting therapies in SNMG.
To investigate the role of the complement system in SNMG, we performed a cross-sectional study in 11 patients with treatment-refractory SNMG who prospectively underwent external intercostal muscle biopsy. Furthermore, we retrospectively analyzed previously performed biopsies of deltoid muscles from two patients with SNMG. Diagnosis of SNMG was established as follows: (i) typical clinical presentation with fatigable muscle weakness that improves with rest and (ii) absence of detectable autoantibodies against AChR, MuSK (measured by enzyme-linked immunosorbent assay, ELISA) and LRP4 (measured by indirect immunofluorescence test, IIFT) in patients’ sera and (iii) abnormal results in repetitive nerve stimulation and/or single-fiber electromyography and/or (iv) clinical response to intravenous or oral acetylcholinesterase inhibitors. Generalized, treatment-refractory disease course was defined as follows: (i) Myasthenia Gravis Foundation of America (MGFA) classification ≥ II despite (ii) standard therapy consisting of acetylcholinesterase inhibitors, steroids, and long-term immunosuppressants and/or (iii) repeated need for intravenous immunoglobulins and/or plasmapheresis/immunoadsorption. Muscle specimens were analyzed by conventional and immunostaining, immunofluorescence and electron microscopy. The results were compared to ‘disease controls’ (i.e. patients with AChR-ab-positive MG) and ‘non-disease controls’ (i.e. patients with non-specific muscle complaints who had no morphological or serological abnormalities). In all patients, stains were done under standardized conditions using the same batches of antibodies. Endplates could be identified in all patients by staining with non-specific esterase (NSE), acetylcholine esterase (AChE) and CD56 (a neural cell adhesion molecule on the pre- and postsynaptic membrane). All patients gave written informed consent. All procedures were approved by the official institutional ethics review committee (EA2/163/17) at the Charité—University Hospital Berlin... |
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