Subunit-Specific Immunodominance in Clinically Distinct Populations With AChR+ Myasthenia Gravis: A Multiparametric Cross-Sectional Analysis.
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BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is a chronic antibody-mediated autoimmune neuromuscular disorder causing fluctuating muscle weakness due to autoantibodies that target the acetylcholine receptor (AChR) in the neuromuscular junction (NMJ). Despite extensive research, MG remains unpredictable and heterogeneous, underscoring the need for better insight into disease pathogenesis and clinical course. The objective of this study was to identify clinical and immunologic disease-related parameters that correlate with disease severity. METHODS: This large-scale, multicenter, cross-sectional study included prospectively recruited patients with MG and MG serum samples procured from reputable biobanks. Inclusion criteria required an MG clinical presentation and a positive anti-AChR immunoglobulin G (IgG) titer (≥0.5 nM), confirmed by 2 independent tests. Enrolled patients underwent profiling of subunit-specific anti-AChR IgG titers. Disease severity patterns and their relation to age, sex, disease onset, thymic involvement, anti-AChR titer, and anti-AChR subunit immunodominance were investigated. RESULTS: The study included 513 patients with MG (50.5% female) with a median age of 64 years (range 14-98.5). Extended clinical data were available for 232 patients. Anti-AChR titers increased monotonically with disease severity (ρ = 0.31, 95% CI 0.17-0.44, p < 0.0001) and were higher in female patients (median 14.6 nM vs 7.7 nM, 95% CI for Δ 2.1-7.3 nM, p < 0.0001) in whom higher antibody titers decreased monotonically with age. Male patients' titers were predominantly alpha-immunodominant (male 23.2% vs female 16.6%, 95% CI for Δ 0%-7.6%, p = 0.031), while female patients' titers were gamma-immunodominant (female 30% vs male 24.5%, 95% CI for Δ 2%-11%, p = 0.0027). Gamma immunodominance correlated with higher anti-AChR titer (ρ = 0.25, 95% CI 0.16-0.33, p < 0.0001) and severe (Myasthenia Gravis Foundation of America IV-V) disease (44% vs 27%, 95% CI for Δ 4%-34%, p = 0.0141). Unsupervised principal component analysis disclosed 2 distinct disease endotypes: female patients with moderate to severe early-onset MG, gamma subunit immunodominance, high anti-AChR titers, and frequent thymic hyperplasia (endotype A) and the remaining patients, mostly patients with late-onset MG, alpha subunit immunodominance, and low anti-AChR titers (endotype B). DISCUSSION: Two distinct MG endotypes emerge based on sex, age, thymic involvement, autoantibody titer, and immunoglobulin AChR subunit immunodominance-suggesting different underlying etiologies with potential implications for sex-dependent precision medicine, women's health, and the development of new therapeutic modalities for MG.