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<p>Involvement of the complement system in myasthenia gravis (MG) depends on the IgG subclass of the mediating antibody. LRP4 antibodies (LRP4-ab) are typically of the IgG1 or IgG2 subclass, implying distinct capacities to activate complement. The extent and pattern of complement involvement in LRP4-ab⁺ MG remain insufficiently characterized at the human neuromuscular junction (NMJ). We examined intercostal muscle biopsies from seven patients with LRP4-ab⁺ generalized MG using immunohistochemistry, immunofluorescence including IgG-subtyping, electron microscopy (EM), and qPCR for complement-associated gene expression. AChR-ab⁺ MG patients and non-disease controls served as comparators. C5b-9 deposition at NMJs was observed in all LRP4-ab⁺ biopsies, affecting 6–96% of identified endplates. Co-localization with IgG1 was consistently detected, whereas IgG2 and IgG4 were absent. One double-seropositive patient showed focal IgG3 staining. Complement transcript levels (<i>C1QC</i>, <i>C3</i>) were higher in LRP4-ab⁺ and AChR-ab⁺ MG compared with controls. Ultrastructural analysis revealed reduced and shortened postsynaptic clefts in 3/4 evaluable LRP4-ab⁺ patients. One therapy-refractory LRP-ab + MG patient with complement deposition and endplate destruction improved after targeted complement inhibition was introduced to his therapeutic regimen, which was based on the biopsy finding. Our findings provide in situ evidence of classical complement pathway activation and associated structural alterations at the human NMJ in LRP4-ab⁺ MG. These tissue-based data contribute to a better understanding of the pathophysiology in this rare MG subgroup.</p>

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Complement deposition, IgG subtyping and endplate destruction in LRP4-ab-positive myasthenia gravis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月21日

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  • Sarah Hoffmann,
  • Katharina Brokamp,
  • Andreas Meisel,
  • Paolo Doksani,
  • Lissy Helmig,
  • Markus Schuelke,
  • Jens-Carsten Rückert,
  • Matthias Pumberger,
  • Friederike Schömig,
  • Marlene Wolfsgruber,
  • Inga Koneczny,
  • Marie Mayrhofer,
  • Martin Blüthner,
  • Tobias Ruck,
  • Marc Pawlitzki,
  • Werner Stenzel,
  • Corinna Preusse

摘要

Involvement of the complement system in myasthenia gravis (MG) depends on the IgG subclass of the mediating antibody. LRP4 antibodies (LRP4-ab) are typically of the IgG1 or IgG2 subclass, implying distinct capacities to activate complement. The extent and pattern of complement involvement in LRP4-ab⁺ MG remain insufficiently characterized at the human neuromuscular junction (NMJ). We examined intercostal muscle biopsies from seven patients with LRP4-ab⁺ generalized MG using immunohistochemistry, immunofluorescence including IgG-subtyping, electron microscopy (EM), and qPCR for complement-associated gene expression. AChR-ab⁺ MG patients and non-disease controls served as comparators. C5b-9 deposition at NMJs was observed in all LRP4-ab⁺ biopsies, affecting 6–96% of identified endplates. Co-localization with IgG1 was consistently detected, whereas IgG2 and IgG4 were absent. One double-seropositive patient showed focal IgG3 staining. Complement transcript levels (C1QC, C3) were higher in LRP4-ab⁺ and AChR-ab⁺ MG compared with controls. Ultrastructural analysis revealed reduced and shortened postsynaptic clefts in 3/4 evaluable LRP4-ab⁺ patients. One therapy-refractory LRP-ab + MG patient with complement deposition and endplate destruction improved after targeted complement inhibition was introduced to his therapeutic regimen, which was based on the biopsy finding. Our findings provide in situ evidence of classical complement pathway activation and associated structural alterations at the human NMJ in LRP4-ab⁺ MG. These tissue-based data contribute to a better understanding of the pathophysiology in this rare MG subgroup.