Shaikh Ullahansari

Background: MG is an autoimmune disease, with a prevalence of 150-250 cases per million people, in which autoantibodies target muscle-specific kinase (MuSK), lipoprotein-related peptide 4 (LRP4), and mainly the nicotinic acetylcholine receptor (nAChR) at the postsynaptic membrane (PSM) of the neuromuscular junction (NMJ).^1,2 Both environmental and genetic components play a role in MG, and dysfunction of negative selection in the thymus can lead to aberrant T-cells that activate B cells, which produce the autoantibodies.² MicroRNAs and JAK-STAT pathways have also been studied that can lead to and worsen MG through autoantibodies as well.^3,4 Further, autoantibody deposition can then induce the complement system.^5,6 The exacerbation of downstream effects of MG, including autoantibody production, is worsened through the recycling of IgG.⁷This involves IgG binding to FcRn and is recycled in the bloodstream. Efgartigomod is a promising therapeutic because it inhibits the recycling of IgG, thus preventing the multiple mechanisms implicated in the exacerbation or onset of MG.⁷

Objective: Within the framework of this review, the pathogenesis and symptoms of MG were elucidated, and strengthens the rationale for why Efgartigomod is a promising treatment for the condition.

Search Methods: Articles were gathered from 2018-2024 using PubMed and Nature with the following search queries: “Myasthenia Gravis”, “Nicotinic acetylcholine receptor”, “Monoclonal Antibody” and “Neuromuscular Junction”.

Results: Results from experimentally induced MG rats (EAMG) indicate that Natural Killer (NK) cells that expressed CXCR5(+) and migrated toward the germinal center of lymph nodes, led to the production of cells that release IL-17 which activates B cells that release IgG.⁸ Further, CXCR5(-) cells led to a decreased amount of CD4+ Helper T cells, indicating a decreased immune response.⁸ When IgG is released, it can induce the complement system by binding at the nAChR at the PSM. The synergism of different subclasses of IgG, most prominently aG101 and bG402-G1 led to an increased C3 deposition and decreased NMJ size which worsens the prognosis of MG.⁵ A potential physiological response to increased C3 deposition is CD59, which inhibits complement-mediated destruction at the NMJ.⁶ Patients with MG were shown to have increased levels of CD59 mRNA and decreased quality of life.⁶ In another EAMG model, it was found that miR-29a/b-1 deficient mice led to an increase in pro-inflammatory cytokines, such as IL-6, IL-17a, and IL-2, which can exacerbate the immune response in MG.³ The JAK-STAT pathway was also studied in EAMG, and an inhibitor of this pathway decreased complement activity and led to the preservation of the size of the NMJ.⁴ Efgartigomod inhibits the production and downstream effects of autoantibodies and was well-tolerated as there was a 7% decrease in treatment-emergent adverse events compared to a placebo.⁷

Conclusion: MG is a complicated disease that is affected by various pathological processes: complement system, microRNAs, JAK-STAT, as well as B and T cell interaction. A common downstream effect is the formation of autoantibodies, such as IgG. By inhibiting the recycling of IgG in plasma, Efgartigomod is a biological therapy that can improve the quality of life of those with MG.⁷

Works Cited:

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4. Lu Y, Ma Q, Yu L, et al. JAK2 inhibitor ameliorates the progression of experimental autoimmune myasthenia gravis and balances Th17/Treg cells via regulating the JAK2/STAT3-AKT/mTOR signaling pathway. Int Immunopharmacol. 2023;115:109693. doi:10.1016/j.intimp.2023.109693
5. Rose N, Holdermann S, Callegari I, et al. Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities. Acta Neuropathol. 2022;144(5):1005-1025. doi:10.1007/s00401-022-02493-6
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