Research Information System
15th International Conference on Myasthenia and Related Disorders, The Hague, Netherlands, 13 - 15 May 2025, (Unpublished)
INTRODUCTION: In MuSK myasthenia gravis, pathogenic IgG4 autoantibodies targeting MuSK are strongly linked to IL-4 signaling, which drives class switching to IgG4 and influences B cell activation. IL-4Ra, a pivotal component of IL-4 and IL-13 signaling, plays essential roles in B cell activation, IgG isotype switching, and antibody production. IL-4 drives class switching to IgG4 and IgE, enhances antigen presentation by upregulating MHC class II and CD23 on B cells, and facilitates the differentiation of plasma cells that secrete antibodies. Given the critical role of IL-4Ra signaling in autoimmune processes, we sought to determine whether silencing IL-4Ra could influence disease severity in experimental autoimmune myasthenia gravis (EAMG).
OBJECTIVE: To assess the effects of IL-4Ra silencing on disease progression, IgG isotype distribution, and immune responses in MuSK-induced EAMG.
METHODS: C57BL/6 mice were subcutaneously immunized with MuSK antigen on days 0 and 28 to induce EAMG. They were subsequently treated with lentiviral particle-delivered IL-4Ra shRNA, scrambled shRNA, or left untreated. Disease progression was monitored using clinical scoring, body weight measurements, and grip strength assessments. ELISA quantified serum IgG subclasses to assess isotype switching effects. NMJ integrity was evaluated via immunofluorescence staining, while flow cytometry analyzed immune cell populations and inflammatory responses.
RESULTS: IL-4Ra silencing significantly reduced disease severity, stabilized grip strength, and prevented excessive weight loss. ELISA analysis revealed elevated MuSK-specific IgG autoantibodies in immunized but untreated mice, whereas IL-4Ra shRNA treatment resulted in a reduction of IgG levels. Muscle immunofluorescence staining and Flow cytometry studies indicated alterations in B cell activation and changes in immune cell populations in response to IL-4Ra shRNA treatment. Ongoing studies, including the CFSE-based proliferation assay, are being conducted to further investigate the effects on lymph node cell dynamics.
SUMMARY/CONCLUSION: Preliminary results indicate that IL-4Ra may play a significant role in modulating B cell responses and antibody production in MG. IL-4Ra silencing appears to reduce disease severity, potentially through the modulation of IgG isotype switching. Targeting IL-4Ra could hold promise as a therapeutic approach for MG, though further studies are needed to confirm these findings.
DISCLOSURES: The authors have no conflicts of interest.