Advances in research on acetylcholine receptor antibodies in myasthenia gravis_West China Medical Journal

Authors：

GUO Yuhe ¹ ,  TAN Song ²

1. School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, P. R. China;
2. Department of Neurology, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, P. R. China;

Corresponding author：

TAN Song, Email: tansong@med.uestc.edu.cn

Keywords：

Myasthenia gravis; acetylcholine receptor; autoantibodies; epitope specificity; immunoglobulin subclasses; pathogenic mechanisms

DOI：

10.7507/1002-0179.202504269

Video：

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Myasthenia gravis is an autoimmune neuromuscular junction disorder primarily mediated by autoantibodies against the acetylcholine receptor (AChR). It is now widely recognized that the total titer of anti-AChR antibodies does not correlate directly with clinical severity and shows significant interindividual variability. This review focuses on the structure of the AChR, the three major pathogenic mechanisms mediated by anti-AChR antibodies, the pathogenic differences associated with distinct antigenic epitopes, the characteristics of various immunoglobulin subclasses, and the limitations of current antibody detection methods. It further explores future directions in antibody profiling and functional assessment. By systematically analyzing the complexity and heterogeneity of anti-AChR antibodies, this article underscores the critical role of precision medicine in the management of myasthenia gravis.

Citation： GUO Yuhe, TAN Song. Advances in research on acetylcholine receptor antibodies in myasthenia gravis. West China Medical Journal, 2025, 40(6): 997-1002. doi: 10.7507/1002-0179.202504269 Copy

1.	Punga AR, Maddison P, Heckmann JM, et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol, 2022, 21(2): 176-188.
2.	Martyn JAJ, Sparling JL, Bittner EA. Molecular mechanisms of muscular and non-muscular actions of neuromuscular blocking agents in critical illness: a narrative review. Br J Anaesth, 2023, 130(1): 39-50.
3.	Huijbers MG, Lipka AF, Plomp JJ, et al. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody‐binding epitopes in myasthenia gravis. J Intern Med, 2014, 275(1): 12-26.
4.	Tzartos SJ, Sophianos D, Efthimiadis A. Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibody protects against antigenic modulation by human sera. J Immunol, 1985, 134(4): 2343-2349.
5.	Li H, Pham MC, Teng J, et al. Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures. Cell, 2025, 188(9): 2390-2406.e20.
6.	Vrolix K, Fraussen J, Losen M, et al. Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor. J Autoimmun, 2014, 52: 101-112.
7.	Verschuuren JJ, Huijbers MG, Plomp JJ, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev, 2013, 12(9): 918-923.
8.	Tüzün E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev, 2013, 12(9): 904-911.
9.	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.
10.	Huang YF, Sandholm K, Persson B, et al. Visualization and characterization of complement activation in acetylcholine receptor antibody seropositive myasthenia gravis. Muscle Nerve, 2024, 70(4): 851-861.
11.	Plomp JJ, Huijbers MGM, Verschuuren JJGM, et al. A bioassay for neuromuscular junction-restricted complement activation by myasthenia gravis acetylcholine receptor antibodies. J Neurosci Methods, 2022, 373: 109551.
12.	Obaid AH, Zografou C, Vadysirisack DD, et al. Heterogeneity of acetylcholine receptor autoantibody–mediated complement activity in patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm, 2022, 9(4): e1169.
13.	Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol, 2017, 16(12): 976-986.
14.	Aguirre F, Manin A, Fernandez VC, et al. C3, C5a and anti-acetylcholine receptor antibody as severity biomarkers in myasthenia gravis. Ther Adv Neurol Disord, 2020, 13: 1756286420935697.
15.	Iacomino N, Vanoli F, Frangiamore R, et al. Complement activation profile in myasthenia gravis patients: perspectives for tailoring anti-complement therapy. Biomedicines, 2022, 10(6): 1360.
16.	Khani-Habibabadi F, Roy B, Pham MC, et al. Distribution and temporal changes of autoantibody-mediated pathogenic mechanisms among acetylcholine receptor-positive myasthenia gravis patients. Neurology, 2024: 1-28.
17.	Kang SY, Oh JH, Song SK, et al. Both binding and blocking antibodies correlate with disease severity in myasthenia gravis. Neurol Sci, 2015, 36(7): 1167-1171.
18.	Pham MC, Masi G, Patzina R, et al. Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathol, 2023, 146(2): 319-336.
19.	Fichtner ML, Hoarty MD, Vadysirisack DD, et al. Myasthenia gravis complement activity is independent of autoantibody titer and disease severity. PLoS One, 2022, 17(3): e0264489.
20.	Michail M, Zouvelou V, Belimezi M, et al. Analysis of nAChR autoantibodies against extracellular epitopes in MG patients. Front Neurol, 2022, 13: 858998.
21.	Morell SW, Trinh VB, Gudipati E, et al. Structural characterization of the main immunogenic region of the torpedo acetylcholine receptor. Mol Immunol, 2014, 58(1): 116-131.
22.	Masuda T, Motomura M, Utsugisawa K, et al. Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. J Neurol Neurosurg Psychiatry, 2012, 83(9): 935-940.
23.	Lazaridis K, Baltatzidi V, Trakas N, et al. Characterization of a reproducible rat EAMG model induced with various human acetylcholine receptor domains. J Neuroimmunol, 2017, 303: 13-21.
24.	Feferman T, Im SH, Fuchs S, et al. Breakage of tolerance to hidden cytoplasmic epitopes of the acetylcholine receptor in experimental autoimmune myasthenia gravis. J Neuroimmunol, 2003, 140(1): 153-158.
25.	Liu Y, Wang W, Li J. Evaluation of serum IgG subclass concentrations in myasthenia gravis patients. Int J Neurosci, 2011, 121(10): 570-574.
26.	Rispens T, Ooijevaar-de Heer P, Bende O, et al. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc, 2011, 133(26): 10302-10311.
27.	Guptill JT, Sleasman JW, Steeland S, et al. Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis. Autoimmunity, 2022, 55(8): 620-631.
28.	焦可馨, 赵重波. 重症肌无力患者血清致病性自身抗体的认识进展和诊断技术评述. 中华神经科杂志, 2024, 57(1): 5-9.
29.	Meisel A, Baggi F, Behin A, et al. Role of autoantibody levels as biomarkers in the management of patients with myasthenia gravis: a systematic review and expert appraisal. Eur J Neurol, 2023, 30(1): 266-282.
30.	Diogenes L, Dellavance A, Baldo DC, et al. Detection of autoantibodies against the acetylcholine receptor, evaluation of commercially available methodologies: fixed cell-based assay, radioimmunoprecipitation assay and enzyme-linked immunosorbent assay1. J Neuromuscul Dis, 2024, 11(3): 613-623.
31.	陈嘉欣, 黄鑫, 冯慧宇. 乙酰胆碱受体抗体浓度在重症肌无力病情评估中的应用. 中国神经精神疾病杂志, 2021, 47(5): 306-310.
32.	He T, Chen K, Zhou Q, et al. Immune repertoire profiling in myasthenia gravis. Immunol Cell Biol, 2024, 102(10): 891-906.
33.	Xu Y, Li Q, Pan M, et al. Interpretable machine learning models for predicting short-term prognosis in AChR-Ab+ generalized myasthenia gravis using clinical features and systemic inflammation index. Front Neurol, 2024, 15: 1459555.
34.	Zhong H, Ruan Z, Yan C, et al. Short-term outcome prediction for myasthenia gravis: an explainable machine learning model. Ther Adv Neurol Disord, 2023, 16: 17562864231154976.
35.	蒋露, 张志东, 吴建军, 等. 1990—2021 年我国精神障碍疾病负担分析与预测. 医学新知, 2025, 35(1): 14-21.
36.	徐瑞霞, 洪燕玲, 江吴霞, 等. 个体化综合护理模式辅助内镜下黏膜切除术治疗结肠息肉的效果观察. 中华全科医学, 2024, 22(12): 2167-2171.

1. Punga AR, Maddison P, Heckmann JM, et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol, 2022, 21(2): 176-188.
2. Martyn JAJ, Sparling JL, Bittner EA. Molecular mechanisms of muscular and non-muscular actions of neuromuscular blocking agents in critical illness: a narrative review. Br J Anaesth, 2023, 130(1): 39-50.
3. Huijbers MG, Lipka AF, Plomp JJ, et al. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody‐binding epitopes in myasthenia gravis. J Intern Med, 2014, 275(1): 12-26.
4. Tzartos SJ, Sophianos D, Efthimiadis A. Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibody protects against antigenic modulation by human sera. J Immunol, 1985, 134(4): 2343-2349.
5. Li H, Pham MC, Teng J, et al. Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures. Cell, 2025, 188(9): 2390-2406.e20.
6. Vrolix K, Fraussen J, Losen M, et al. Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor. J Autoimmun, 2014, 52: 101-112.
7. Verschuuren JJ, Huijbers MG, Plomp JJ, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev, 2013, 12(9): 918-923.
8. Tüzün E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev, 2013, 12(9): 904-911.
9. 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.
10. Huang YF, Sandholm K, Persson B, et al. Visualization and characterization of complement activation in acetylcholine receptor antibody seropositive myasthenia gravis. Muscle Nerve, 2024, 70(4): 851-861.
11. Plomp JJ, Huijbers MGM, Verschuuren JJGM, et al. A bioassay for neuromuscular junction-restricted complement activation by myasthenia gravis acetylcholine receptor antibodies. J Neurosci Methods, 2022, 373: 109551.
12. Obaid AH, Zografou C, Vadysirisack DD, et al. Heterogeneity of acetylcholine receptor autoantibody–mediated complement activity in patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm, 2022, 9(4): e1169.
13. Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol, 2017, 16(12): 976-986.
14. Aguirre F, Manin A, Fernandez VC, et al. C3, C5a and anti-acetylcholine receptor antibody as severity biomarkers in myasthenia gravis. Ther Adv Neurol Disord, 2020, 13: 1756286420935697.
15. Iacomino N, Vanoli F, Frangiamore R, et al. Complement activation profile in myasthenia gravis patients: perspectives for tailoring anti-complement therapy. Biomedicines, 2022, 10(6): 1360.
16. Khani-Habibabadi F, Roy B, Pham MC, et al. Distribution and temporal changes of autoantibody-mediated pathogenic mechanisms among acetylcholine receptor-positive myasthenia gravis patients. Neurology, 2024: 1-28.
17. Kang SY, Oh JH, Song SK, et al. Both binding and blocking antibodies correlate with disease severity in myasthenia gravis. Neurol Sci, 2015, 36(7): 1167-1171.
18. Pham MC, Masi G, Patzina R, et al. Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathol, 2023, 146(2): 319-336.
19. Fichtner ML, Hoarty MD, Vadysirisack DD, et al. Myasthenia gravis complement activity is independent of autoantibody titer and disease severity. PLoS One, 2022, 17(3): e0264489.
20. Michail M, Zouvelou V, Belimezi M, et al. Analysis of nAChR autoantibodies against extracellular epitopes in MG patients. Front Neurol, 2022, 13: 858998.
21. Morell SW, Trinh VB, Gudipati E, et al. Structural characterization of the main immunogenic region of the torpedo acetylcholine receptor. Mol Immunol, 2014, 58(1): 116-131.
22. Masuda T, Motomura M, Utsugisawa K, et al. Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. J Neurol Neurosurg Psychiatry, 2012, 83(9): 935-940.
23. Lazaridis K, Baltatzidi V, Trakas N, et al. Characterization of a reproducible rat EAMG model induced with various human acetylcholine receptor domains. J Neuroimmunol, 2017, 303: 13-21.
24. Feferman T, Im SH, Fuchs S, et al. Breakage of tolerance to hidden cytoplasmic epitopes of the acetylcholine receptor in experimental autoimmune myasthenia gravis. J Neuroimmunol, 2003, 140(1): 153-158.
25. Liu Y, Wang W, Li J. Evaluation of serum IgG subclass concentrations in myasthenia gravis patients. Int J Neurosci, 2011, 121(10): 570-574.
26. Rispens T, Ooijevaar-de Heer P, Bende O, et al. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc, 2011, 133(26): 10302-10311.
27. Guptill JT, Sleasman JW, Steeland S, et al. Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis. Autoimmunity, 2022, 55(8): 620-631.
28. 焦可馨, 赵重波. 重症肌无力患者血清致病性自身抗体的认识进展和诊断技术评述. 中华神经科杂志, 2024, 57(1): 5-9.
29. Meisel A, Baggi F, Behin A, et al. Role of autoantibody levels as biomarkers in the management of patients with myasthenia gravis: a systematic review and expert appraisal. Eur J Neurol, 2023, 30(1): 266-282.
30. Diogenes L, Dellavance A, Baldo DC, et al. Detection of autoantibodies against the acetylcholine receptor, evaluation of commercially available methodologies: fixed cell-based assay, radioimmunoprecipitation assay and enzyme-linked immunosorbent assay1. J Neuromuscul Dis, 2024, 11(3): 613-623.
31. 陈嘉欣, 黄鑫, 冯慧宇. 乙酰胆碱受体抗体浓度在重症肌无力病情评估中的应用. 中国神经精神疾病杂志, 2021, 47(5): 306-310.
32. He T, Chen K, Zhou Q, et al. Immune repertoire profiling in myasthenia gravis. Immunol Cell Biol, 2024, 102(10): 891-906.
33. Xu Y, Li Q, Pan M, et al. Interpretable machine learning models for predicting short-term prognosis in AChR-Ab+ generalized myasthenia gravis using clinical features and systemic inflammation index. Front Neurol, 2024, 15: 1459555.
34. Zhong H, Ruan Z, Yan C, et al. Short-term outcome prediction for myasthenia gravis: an explainable machine learning model. Ther Adv Neurol Disord, 2023, 16: 17562864231154976.
35. 蒋露, 张志东, 吴建军, 等. 1990—2021 年我国精神障碍疾病负担分析与预测. 医学新知, 2025, 35(1): 14-21.
36. 徐瑞霞, 洪燕玲, 江吴霞, 等. 个体化综合护理模式辅助内镜下黏膜切除术治疗结肠息肉的效果观察. 中华全科医学, 2024, 22(12): 2167-2171.

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