Myasthenia Gravis

Myasthenia gravis (MG) is a rare autoimmune-mediated disorder, but it is the disorder most commonly affecting the neuromuscular junction (NMJ) in skeletal muscle. The condition causes fluctuating fatigue and weakness in voluntary skeletal muscles, particularly those of the eyes, throat, and limbs. MG may also affect the respiratory muscles to cause a myasthenic crisis, which can be life-threatening if respiratory failure develops.¹ 

Normal Physiology

Normally, the neurotransmitter acetylcholine (ACh) is released from the motor nerve terminal of the NMJ in small vesicles, or quanta. The ACh-containing quanta diffuse across the synaptic cleft and adhere to ACh receptors (AChRs) on the folded muscle endplate membrane. When a stimulated motor nerve releases a specific amount of ACh quanta and enough ACh quanta bind to the muscle endplate region, the motor unit endplate depolarizes and the muscle contracts.²

Pathophysiology

In MG, immune system autoantibodies attack components of the post-synaptic motor unit endplate membrane, causing abnormal endplate membrane folding that interferes with proper transmission of the nerve signal to the muscle fibers.^2,3 

In most cases of MG, the attachment of immunoglobulin G1 (IgG1) and IgG3 antibodies to motor unit AChRs results in complement-mediated AChR damage via formation of the membrane attack complex (MAC), and the rate of AChR turnover is increased. Autoantibodies may also block ACh binding to the AChRs. These processes decrease the number of available AChRs in the post-synaptic membrane, so that the number of ACh quanta that can successfully bind to the endplate membrane to achieve depolarization and muscle contraction is reduced. The result is muscle weakness, which gradually becomes more pronounced after repeated muscle contractions. AChR depletion within the NMJ manifests as the clinically observed symptom of rapid muscle fatigue.^1,3 

MG especially affects the extraocular muscles, in which tension develops relatively rapidly because synaptic firing occurs at a higher frequency than in peripheral muscles. The fast-twitch muscle fibers of the eye muscles make them more susceptible to fatigue. As well, the number of AChRs in the tonic eye muscle fibers required for sustained gaze are less, so these motor units are more susceptible to AChR loss or damage.⁴ 

Many patients who have MG with AChR autoantibodies demonstrate epithelial hyperplasia of the thymus and T-cell infiltrates, which indicate a potential contribution of the thymus to the production of autoantibodies to muscle proteins.¹ This observation explains the successful postoperative recovery and stabilization of many patients with severe MG following thymectomy.⁵   

Myasthenia Subtype Pathophysiology

MG is classified into subtypes according to the antigen specifically targeted by the immune system. The most common subtype (approximately 85% of cases) is caused by IgG1, IgG2, and IgG3 autoantibodies targeting nicotinic AChRs (n-AChRs). Scientists believe that the autoantibodies targeting n-AChRs develop from long-lived plasma cells. Autoantibodies targeting muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4) account for the remaining 15% of cases of MG. A very small percentage of patients with MG lack detectable autoantibodies with known antigens.⁶

In the MuSK subtype of MG, predominantly IgG4 antibodies dissociate into halves with the aid of short-lived plasmablasts during the Fab-arm exchange (FAE) process. The IgG4 halves recombine with other IgG4 halves, producing bispecific autoantibodies. The bispecific autoantibodies directly interrupt AChR signal transmission to the muscle by disrupting NMJ protein-protein interactions.⁶ MuSK autoantibodies likely interfere with the interaction between MuSK, LRP4, and collagen Q.⁷ MuSK plays a critical role in NMJ maintenance and adaptation, contributing to post-synaptic differentiation and NMJ formation. ^3,6,7  

In a small subset of patients with MG who lack AChR autoantibodies or who are doubly seronegative for AChR and MuSK autoantibodies, predominantly IgG1 autoantibodies target LRP4.⁸ The IgG1 autoantibodies to LRP4 inhibit attachment of the protein to its ligand, agrin.^8,9 LRP4 and agrin form a complex by binding to a MuSK receptor tyrosine kinase and an amyloid precursor protein (APP).^1,10,11 LRP4 is the catalyst of MuSK phosphorylation by agrin. The entire LRP4-agrin-MuSK-APP complex synergistically induces n-AChR clustering and post-synaptic NMJ formation.^1,9,10,12 

References 

1. Beloor Suresh A, Asuncion RMD. Myasthenia gravis. StatPearls [Internet]. Updated August 11, 2021. Accessed February 1, 2022.
2. Myasthenia gravis clinical overview. Myasthenia Gravis Foundation of America. Accessed February 1, 2022.
3. Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5. doi:10.12688/f1000research.8206.1
4. Nair AG, Patil-Chhablani P, Venkatramani DV, Gandhi RA. Ocular myasthenia gravis: a review. Indian J Ophthalmol. 2014;62(10):985. doi:10.4103/0301-4738.145987
5. Kirschner PA. Alfred Blalock and thymectomy for myasthenia gravis. Ann Thorac Surg. 1987;43(3):348-349. doi:10.1016/s0003-4975(10)60635-2
6. Fichtner ML, Jiang R, Bourke A, Nowak RJ, O’Connor KC. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020. doi:10.3389/fimmu.2020.00776
7. Jowkar AA. Myasthenia gravis: pathophysiology. Medscape. Updated August 27, 2018. Accessed February 1, 2022.
8. Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor–related protein 4 in myasthenia gravis. Ann Neurol. 2011;69(2):418-422. doi:10.1002/ana.22312
9. Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69(4):445-451. doi:10.1001/archneurol.2011.2393
10. Choi HY, Liu Y, Tennert C, et al. APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. eLife. 2013;2:e00220. doi:10.7554/eLife.00220
11. Kim N, Stiegler AL, Cameron TO, et al. Lrp4 is a receptor for agrin and forms a complex with MuSK. Cell. 2008;135(2):334-342. doi:10.1016/j.cell.2008.10.002
12. Weatherbee SD, Anderson KV, Niswander LA. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development. 2006;133(24):4993-5000. doi:10.1242/dev.02696

Reviewed by Harshi Dhingra, MD, on 2/4/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.