Scroll to learn about the neonatal Fc receptor (FcRn) and its role in prolonging the half-life of immunoglobulin G (IgG), including pathogenic IgG autoantibodies, that drive generalized myasthenia gravis (gMG).1-7
IgG: A key driver
of gMG2-4
gMG is a chronic neuromuscular autoimmune disease driven by pathogenic IgG autoantibodies against key components of the neuromuscular junction (NMJ).²⁻⁴
IMMUNOGLOBULIN G (IgG)
ACETYLCHOLINE RECEPTOR (AChR)
~85% of patients have
autoantibodies against AChR⁴
IgG autoantibodies target multiple components of the NMJ2-4
Pathogenic IgG autoantibodies targeting acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) have been described in patients with gMG.3,4
IgG autoantibodies target multiple components of the NMJ2-4
Pathogenic IgG autoantibodies targeting acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) have been described in patients with gMG.3,4
MUSCLE-SPECIFIC TYROSINE
KINASE (MuSK)
~5% of patients have
autoantibodies against MuSK3,4
IgG autoantibodies target multiple components of the NMJ2-4
Pathogenic IgG autoantibodies targeting acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) have been described in patients with gMG.3,4
LIPOPROTEIN RECEPTOR-
RELATED PROTEIN 4 (LRP4)
~1-3% of patients have
autoantibodies against LRP43
IgG autoantibodies target multiple components of the NMJ2-4
Pathogenic IgG autoantibodies targeting acetylcholine receptors (AChR), muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) have been described in patients with gMG.3,4
SERONEGATIVE
~10% of patients are seronegative,
with no identifiable autoantibodies³
FcRn: A central role in IgG regulation1,5
FcRn is present in several cell types, including vascular endothelial cells, and is responsible for recycling all kinds of IgG antibodies, reducing their clearance, and prolonging their half-life.¹
NEONATAL FC RECEPTOR
(FcRn)
ENDOTHELIAL CELL
FcRn-mediated IgG recycling1,8,9
FcRn is known to bind IgG antibodies, including autoantibodies, and rescue them from lysosomal degradation thereby extending their half-life to approximately 4 times that of IgA or IgM antibodies.1,8,9
LYSOSOME
Exploring the FcRn pathway in gMG10-13
In prolonging IgG half-life, FcRn has been shown to help maintain high concentrations of pathogenic autoantibodies in the neuromuscular junction, thereby contributing to the disruption in neurotransmission and destruction that drives the chronic muscle weakness seen in gMG.¹⁰⁻¹³
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FcRn-mediated IgG recycling in gMG?
Patients and physicians have concerns about current gMG management14
84% of patients with gMG and all of the physicians sampled in a recently published survey raised concerns about long-term side effects of immunosuppressive therapy.14*
The majority of both groups also expressed concerns about the potential implications of a dose reduction, such as symptomatic relapse, possible hospitalization, and uncertainty about their future health.14
Results were based on a peer-reviewed study of 283 patients with gMG and 45 physicians. The goal of the surveys was to better define patient and physician opinions about gMG long-term immunosuppressant exposure and dose reduction to inform the potential design of a randomized clinical trial.
84%
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References: 1. Roopenian DC, Akilesh S. Nat Rev Immunol. 2007;7(9):715-725. doi:10.1038/nri2155 2. Rødgaard A et al. Clin Exp Immunol. 1987;67(1):82-88. 3. Gilhus NE. N Engl J Med. 2016;375(26):2570-2581. doi:10.1056/NEJMra1602678 4. Behin A, Le Panse R. J Neuromuscul Dis. 2018;5(3):265-277. doi:10.3233/JND-170294 5. Ward ES, Ober RJ. Trends Pharmacol Sci. 2018;39(10):892-904. doi:10.1016/j.tips.2018.07.007 6. Ghetie V et al. Eur J Immunol. 1996;26(3):690-696. doi:10.1002/eji.1830260327 7. Ulrichts P et al. J Clin Invest. 2018;128(10):4372-4386. doi:10.1172/JCI97911 8. Pyzik M, Sand KMK, Hubbard JJ, Andersen JT, Sandlie I, Blumberg RS. Front Immunol. 2019;10:1540. doi: 10.3389/fimmu.2019.01540 9. Gable KL, Guptill JT. Front Immunol. 2020;10:3052. doi: 10.3389/fimmu.2019.03052 10. Gilhus NE et al. Nat Rev Neurol. 2016;12(5):259-268. doi:10.1038/nrneurol.2016.44 11. Gotterer L, Li Y. J Neurol Sci. 2016;369:294-302. doi: 10.1016/j.jns.2016.08.057 12. Huijbers MG et al. J Intern Med. 2014;275(1):12-26. doi:10.1111/joim.12163 13. Mantegazza R et al. Neuropsychiatr Dis Treat. 2011;7:151-160. doi:10.2147/NDT.S8915 14. Hehir MK et al. Muscle Nerve. 2020;61(6):767-772. doi:10.1002/mus.26850
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