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Myasthenia gravis (MG) is a neuromuscular disease caused in most cases by anti-acetyl-choline receptor (AChR) autoantibodies that impair neuromuscular signal transmission and affect skeletal muscle homeostasis. Myogenesis is carried out by muscle stem cells called satellite cells (SCs). However, myogenesis in MG had never been explored. The aim of this study was to characterise the functional properties of myasthenic SCs as well as their abilities in muscle regeneration. SCs were isolated from muscle biopsies of MG patients and age-matched controls. We first showed that the number of Pax7+ SCs was increased in muscle sections from MG and its experimental autoimmune myasthenia gravis (EAMG) mouse model. Myoblasts isolated from MG muscles proliferate and differentiate more actively than myoblasts from control muscles. MyoD and MyoG were expressed at a higher level in MG myoblasts as well as in MG muscle biopsies compared to controls. We found that treatment of control myoblasts with MG sera or monoclonal anti-AChR antibodies increased the differentiation and MyoG mRNA expression compared to control sera. To investigate the functional ability of SCs from MG muscle to regenerate, we induced muscle regeneration using acute cardiotoxin injury in the EAMG mouse model. We observed a delay in maturation evidenced by a decrease in fibre size and MyoG mRNA expression as well as an increase in fibre number and embryonic myosin heavy-chain mRNA expression. These findings demonstrate for the first time the altered function of SCs from MG compared to control muscles. These alterations could be due to the anti-AChR antibodies via the modulation of myogenic markers resulting in muscle regeneration impairment. In conclusion, the autoimmune attack in MG appears to have unsuspected pathogenic effects on SCs and muscle regeneration, with potential consequences on myogenic signalling pathways, and subsequently on clinical outcome, especially in the case of muscle stress.

Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor-induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.

Myasthenia gravis (MG) is an autoimmune disease caused by an immunological response against the acetylcholine receptor (AChR) at the neuromuscular junction. Anti-AChR antibodies induce degradation of the receptor, activation of complement cascade and destruction of the post-synaptic membrane, resulting in a functional reduction of AChR availability. The pathophysiological role of autoantibodies (auto-Abs) and T helper lymphocytes has been studied in the experimental autoimmune MG (EAMG) models. EAMG models have been employed to investigate the factors involved in the development of MG and to suggest new therapies aimed to preventing or modulating the ongoing disease. EAMG can be induced in susceptible mouse and rat strains, which develop clinical symptoms such as muscular weakness and fatigability, mimicking the human disease. Two major types of EAMG can be induced, passive and active EAMG. Passive transfer MG models, involving the injection of auto-Abs, are helpful for studying the role of complement molecules and their regulatory proteins, which can prevent neuromuscular junction degradation. Active models, induced by immunization, are employed for the analysis of antigen-specific immune responses and their modulation in order to improve disease progression. In this review, we will concentrate on the main pathogenic mechanisms of MG, focusing on recent findings on EAMG experimental models.

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii) low-density lipoprotein receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and stimulating MuSK. Passive transfer studies in mice have shown that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components, suggesting that these MuSK antibodies cause disease by directly interfering with MuSK function. Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK dimerization or MuSK internalization. These results provide insight into the unique pathogenesis of MuSK MG and provide clues toward development of specific treatment options.

The ability of thymic histopathology to predict the long-term impact of thymectomy in non-thymomatous myasthenia gravis (NTMG) is mainly uncharted. We applied digital pathology to quantitatively characterize differences of thymic histology between early-onset (EOMG) and late-onset MG (LOMG) and to investigate the role of thymic changes for thymectomy outcomes in MG. We analyzed 83 thymic H&E slides from thymectomized NTMG patients, of which 69 had EOMG and 14 LOMG, using digital pathology open-access software QuPath. We compared the results to the retrospectively assessed clinical outcome at two years after thymectomy and at the last follow-up visit where complete stable remission and minimal use of medication were primary outcomes. The automated annotation pipeline was an effective and reliable way to analyze thymic H&E samples compared to manual annotation with mean intraclass correlation of 0.80. The ratio of thymic tissue to stroma and fat was increased in EOMG compared to LOMG (p = 8.7e-07), whereas no difference was observed in the ratio of medulla to cortex between these subtypes. AChRAb seropositivity correlated with the number of ectopic germinal centers (eGC; p = 0.00067) but not with other histological areas. Patients with an increased number of eGCs had better post-thymectomy outcomes at two years after thymectomy (p = 0.0035) and at the last follow-up (p = 0.0267). ROC analysis showed that eGC area predicts thymectomy outcome in EOMG with an AUC of 0.79. Digital pathology can thus help in providing a predictive tool to the clinician, the eGC number, to guide the post-thymectomy treatment decisions in EOMG patients.

Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.

Myasthenia gravis (MG) is an autoimmune disorder mediated by B-cells, characterized by muscle weakness and fatigue. Mitochondria, essential for energy production and muscle function, have been implicated in MG. Despite their importance, the exact relationship between mitochondrial proteins (MPs) and MG remains unclear. This study utilized two-sample Mendelian Randomization (TSMR) to investigate potential causal associations between MPs and MG. Data from the largest available genome-wide associated study (GWAS), comprising 1873 acetylcholine receptor (AchR) antibody-positive MG patients (1278 late-onset MG [LOMG] and 595 early-onset MG [EOMG]), were analyzed. A total of 66 MPs were selected as exposure variables, with MG and its subtypes as outcomes. Analyses employed inverse variance weighted (IVW), MR-PRESSO, MR-Egger, and weighted median methods, with heterogeneity assessed using Cochran’s Q statistic. Significant causal associations were found between MPs and MG subtypes. For LOMG, GrpE protein homolog 1, oligoribonuclease, protein SCO1 homolog, and rRNA methyltransferase 3 were linked to increased risk. Cytochrome c oxidase subunit 7A1 was associated with higher EOMG risk, while [pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, dihydrolipoyl dehydrogenase, and NFU1 iron-sulfur cluster scaffold were linked to reduced EOMG risk. MPs such as dihydrolipoyl dehydrogenase and NAD-dependent protein deacylase sirtuin-5 showed protective effects against MG, while GrpE protein homolog 1, mitochondrial glutamate carrier 2, oligoribonuclease, and protein SCO1 homolog were associated with increased risk. This MR analysis suggests potential causal relationships between MPs and MG, highlighting the need for further research to validate these findings and explore the mechanisms underlying these associations.

Background The literature lacks consistent information on the correlation between baseline body mass index (BMI), clinical presentation, and prognosis in patients with myasthenia gravis (MG). This observational multicenter prospective cohort study included patients with MG from February 2017 to June 2023, categorizing them by baseline BMI. The primary outcome was the time to generalization of ocular MG. Secondary outcomes included the time to Activities of Daily Living (ADL) response and Minimal Symptom Expression (MSE). Kaplan-Meier curves and multivariable Cox proportional hazards regression models were used to assess the impact of BMI on these outcomes. Results Out of 940 MG patients (510 women) included, 524 had a low BMI and 416 had a high BMI, with a median age of 50.00 years. Patients in the high BMI group were significantly older ( p  < 0.001), had a lower percentage of females ( p  < 0.001), and had a shorter disease duration ( p  = 0.014) compared to those with a low BMI. They also had higher rates of ocular onset ( p  < 0.001), ocular MG classification ( p  = 0.001), and acetylcholine receptor antibody seropositivity ( p  = 0.007), but a lower incidence of thymectomy ( p  = 0.027). During a median follow-up of 33.00 months, the adjusted Cox models revealed that a higher baseline BMI was associated with an increased risk of ocular MG generalization (HR 1.06; 95% CI 1.01–1.11; p  = 0.026), but not with ADL response (HR 0.99; 95% CI 0.95–1.04; p  = 0.779) or MSE (HR 0.97; 95% CI 0.92–1.02; p  = 0.240). Conclusions A higher baseline BMI was associated with an increased risk of ocular MG generalization but not with ADL response or MSE.

Background To identify the associations between thymic pathology and the prognosis of myasthenia gravis (MG) patients. Methods In this multicenter retrospective study, 1,254 myasthenia gravis (MG) patients who underwent thymectomy across four clinical centers were included. Participants were categorized by thymic pathology into thymomatous and non-thymomatous groups. Primary outcome was postoperative deterioration. Secondary outcomes comprised the proportion of patients achieving minimal manifestation status (MMS) within the first year after surgery and conversion from ocular MG (OMG) to generalized MG (GMG) within 2 years of symptom onset. Subgroup analyses assessed associations between world health organization (WHO) pathological type (both groups) or Masaoka stage (thymoma patients) and prognosis. Results Thymomas were associated with an increased risk of deterioration in both Cox regression (adjusted HR = 1.40 [1.18, 1.66], p  < 0.001) and logistic regression analyses (1-year deterioration: adjusted OR = 1.59 [1.15, 2.20], p  = 0.005; 3-year deterioration: adjusted OR = 1.40 [1.01, 1.94], p  = 0.047). Additionally, thymomas were linked to a higher conversion rate (adjusted OR = 2.37 [1.15, 4.86], p  = 0.019). However, thymoma showed no significant association with MMS (adjusted p  = 0.682). In the thymoma subgroup, neither pathological type nor Masaoka stage was significantly associated with deterioration (pathological type: 1-year p  = 0.069, 3-year p  = 0.220; Masaoka stage: 1-year p  = 0.944, 3-year p  = 0.909), first-year MMS attainment (pathological type: p  = 0.067; Masaoka stage: p  = 0.579), or conversion rate (pathological type: p  = 0.606; Masaoka stage: p  = 0.163). Similarly, in the nonthymomatous group, WHO pathological type was not significantly correlated with deterioration (1-year p  = 0.806, 3-year p  = 0.654), MMS achieved ( p  = 0.940), or conversion ( p  = 0.755). Conclusions This study demonstrated an association between thymoma and higher risks of clinical deterioration, which was independent of WHO pathological type or Masaoka stage.