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gMG: A chronic, debilitating, IgG-mediated autoimmune disease1-3
In gMG, pathogenic IgG autoantibodies attack key components of the NMJ. This can cause4,5:
gMG=generalized myasthenia gravis; IgG=immunoglobulin G; NMJ=neuromuscular junction.
IgG autoantibodies are a key driver of gMG5-9*
IgG autoantibodies target multiple components of the NMJ, including AChR, MuSK, and LRP4.5
- 85% of patients have autoantibodies against AChR3
- ~5% of patients have autoantibodies against MuSK1,3
- ~1-~3% of patients have autoantibodies against LRP41
- ~10% of patients are seronegative with no identifiable autoantibodies1
- <p><b>1. Functional blockade</b></p>
- <p>2. Cross-linking</p>
- <p><b>3. Complement activation</b></p>
KEY
IgG autoantibodies disrupt neurotransmission in 3 ways:
1. Functional blockade
IgG autoantibodies bind to AChR, MuSK, and LRP4 receptors, creating a functional blockade. Acetylcholine is unable to bind to AChR, disrupting the interaction between MuSK and LRP4, which decreases the clustering of AChR5-10
2. Cross-linking
IgG autoantibodies cross-link AChR and LRP4 receptors, leading to internalization and degradation5-9
3. Complement activation
IgG autoantibodies activate the autoantibody dependent complement system (C1 complex)5-9
*AChR autoantibodies are a subtype of IgG autoantibodies.5,8
AChR=acetylcholine receptor; C1=complement component 1; gMG=generalized myasthenia gravis; IgG=immunoglobulin G; LRP4=low-density lipoprotein receptor-related protein 4; MuSK=muscle-specific tyrosine kinase; NMJ=neuromuscular junction.
FcRn plays a critical role in IgG regulation3,6,7,9,11,12
FcRn plays a critical role in enabling damage at the NMJ by:
- Binding IgG antibodies, including autoantibodies
- Rescuing them from lysosomal degradation
- Recycling them back into circulation
In doing so, FcRn helps maintain high levels of circulating IgG antibodies, including IgG autoantibodies.
FcRn=neonatal Fc receptor; IgG=immunoglobulin G; NMJ=neuromuscular junction.
This recycling process prolongs the half-life of IgG antibodies and maintains high concentrations of IgG autoantibodies that attack vital components of the NMJ.
Explore resources to help explain gMG to your patients
References: 1. Gilhus NE. N Engl J Med. 2016;375(26):2570-2581. doi:10.1056/NEJMra1602678 2. Rødgaard A et al. Clin Exp Immunol. 1987;67(1):82-88. 3. Behin A, Le Panse R. J Neuromuscul Dis. 2018;5(3):265-277. doi:10.3233/JND-170294 4. Twork S et al. Health Qual Life Outcomes. 2010;8:129. doi:10.1186/1477-7525-8-129 5. Gilhus NE et al. Nat Rev Neurol. 2016;12(5):259-268. doi:10.1038/nrneurol.2016.44 6. Roopenian DC, Akilesh S. Nat Rev Immunol. 2007;7(9):715-725. doi:10.1038/nri2155 7. Ward ES, Ober RJ. Trends Pharmacol Sci. 2018;39(10):892-904. doi:10.1016/j.tips.2018.07.007 8. Huijbers MG et al. J Intern Med. 2014;275(1):12-26. doi:10.1111/joim.12163 9. Mantegazza R et al. Neuropsychiatr Dis Treat. 2011;7:151-160. doi:10.2147/NDT.S8915 10. Conti-Fine BM et al. J Clin Invest. 2006;116(11):2843-2854. doi:10.1172/JCI29894 11. Zhu LN et al. Neural Regen Res. 2023;18(8):1637-1644. doi:10.4103/1673-5374.363824 12. Ulrichts P et al. J Clin Invest. 2018;128(10):4372-4386. doi:10.1172/JCI97911
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gMG=generalized myasthenia gravis.