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Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by pathogenic autoantibodies targeting components of the neuromuscular junction, most commonly the nicotinic acetylcholine receptor (nAChR). In AChR seropositive (AChR+) MG, autoantibody binding to nAChRs can activate the complement cascade, leading to membrane attack complex (MAC) formation, loss of nAChRs, and impaired neuromuscular transmission. MG is heterogeneous with multiple subgroups, and reliable circulating biomarkers and mechanistic insights into skeletal muscle pathology remain limited. This thesis investigates MG-associated circulating blood biomarkers and complement-associated pathogenic mechanisms using an in vitro human skeletal muscle model.

Papers I-II demonstrated that serum miR-150-5p and miR-30e-5p were elevated in MG, with miR-30e-5p correlating with disease course. Additionally, they exhibited good temporal stability. Paper III identified an altered inflammatory protein profile in AChR+ MG, in which CCL28, FGF-23, FGF-5, TGF-α, TNFSF14, and uPA exhibited the highest differences between MG and HC. Papers IV-V demonstrated complement activation in MG. Increased C1s/C1-INH complexes indicated proximal classical pathway activation, while elevated plasma C3a and soluble C5b-9 reflected downstream and terminal pathway activation. C3a exhibited the highest diagnostic performance. Papers V-VI established a human skeletal muscle model of AChR+ MG, in which pathogenic antibodies bound to nAChRs, causing receptor loss, MAC deposition, and impaired cholinergic calcium signaling. Similar effects induced by AChR α-subunit-specific monoclonal antibodies were restored by C3 inhibition, indicating complement activation as a key driver of antibody-mediated pathogenic effects.

Taken together, these studies identify candidate circulating miRNA, inflammatory, and complement-related biomarkers in MG and demonstrate the pathogenic effects in vitro. These findings provide a broader view of immune and inflammatory activation in MG, as well as mechanistic insights into complement-associated skeletal muscle pathology, including proximal complement C3 inhibition as a promising therapeutic strategy.