Complement deposition at the neuromuscular junction in seronegative myasthenia gravis

Höffmann, Sarah; Harms, Lutz; Schuelke, Markus; Rückert, Jens-Carsten; Goebel, Hans‐Hilmar; Stenzel, Werner; Meisel, Andreas

doi:10.1007/s00401-020-02147-5

Cited by 24 publications

(20 citation statements)

References 11 publications

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“…Seronegative MG patients are a heterogeneous group of patients and although we had stringent inclusion criteria, we cannot rule out that some seronegative patients have low-affinity antibodies or would be positive for complement deposition at the neuromuscular junction [ 10 , 11 ]. Especially the high portion of thymus hyperplasia in our cohort might argue for low-affinity antibodies since thymic pathologies in MG are known to produce AChR-antibodies [ 12 ], but 75% of double negative patients (AChR and MuSK) showed lymph node-type infiltrates in thymus similar to AChR-MG [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Seronegative myasthenic crisis: a multicenter analysis

et al. 2022

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Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10–15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs.

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Section: Discussionmentioning

confidence: 99%

Seronegative myasthenic crisis: a multicenter analysis

et al. 2022

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“…The involvement of the complement system in the pathogenesis of MG depends on the IgG subtype. MuSK is primarily derived from the IgG4 subtype that does not activate the complement system; hence, complement inhibitors do not exhibit reactions with MuSK antibody-positive MG ( 57 ). Defects in complement therapy have motivated the development of novel drugs to be used in the treatment of MG. B-cell-activating factors may also be considered a potential therapeutic target for MG. Belimumab is an immunoglobulin antibody that binds and blocks the B-cell activating factor, leading to a reduction in B-cell differentiation via direct reduction in the number of B cells to alleviate dysimmunity ( 58 ).…”

Section: Potential Alternative Complement-based Treatment Methodsmentioning

confidence: 99%

Clinical Efficacy and Safety of Eculizumab for Treating Myasthenia Gravis

Xiao

Liang

et al. 2021

Front. Immunol.

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Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.

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“…Similarly, both MuSK MG and LRP4 MG were identified by investigating novel antigenic targets in SNMG patients [11,12,47]. Complement deposition has been identified at motorendplates in muscle tissue biopsies [48]; positive staining included C1q, implicating activation of the Ab-dependent classical pathway. Although these results provide support for active Ab-mediated immunopathology, testing of this patient cohort with the clustered AChR CBA was not performed.…”

Section: Seronegative Myasthenia Gravismentioning

confidence: 99%

Novel pathophysiological insights in autoimmune myasthenia gravis

Masi

O’Connor

2022

Current Opinion in Neurology

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Purpose of reviewThis review summarizes recent insights into the immunopathogenesis of autoimmune myasthenia gravis (MG). Mechanistic understanding is presented according to MG disease subtypes and by leveraging the knowledge gained through the use of immunomodulating biological therapeutics. Recent findingsThe past two years of research on MG have led to a more accurate definition of the mechanisms through which muscle-specific tyrosine kinase (MuSK) autoantibodies induce pathology. Novel insights have also emerged from the collection of stronger evidence on the pathogenic capacity of low-density lipoprotein receptor-related protein 4 autoantibodies. Clinical observations have revealed a new MG phenotype triggered by cancer immunotherapy, but the underlying immunobiology remains undetermined. From a therapeutic perspective, MG patients can now benefit from a wider spectrum of treatment options. Such therapies have uncovered profound differences in clinical responses between and within the acetylcholine receptor and MuSK MG subtypes. Diverse mechanisms of immunopathology between the two subtypes, as well as qualitative nuances in the autoantibody repertoire of each patient, likely underpin the variability in therapeutic outcomes. Although predictive biomarkers of clinical response are lacking, these observations have ignited the development of assays that might assist clinicians in the choice of specific therapeutic strategies.

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Complement deposition at the neuromuscular junction in seronegative myasthenia gravis

Cited by 24 publications

References 11 publications

Seronegative myasthenic crisis: a multicenter analysis

Seronegative myasthenic crisis: a multicenter analysis

Clinical Efficacy and Safety of Eculizumab for Treating Myasthenia Gravis

Novel pathophysiological insights in autoimmune myasthenia gravis

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