The Molecular Nature of Myasthenia Gravis

Ribbon model depicting the structure of an antibody

Myasthenia Gravis is an automimmune syndrome caused when the adaptive immune system generates auto-antibodies against components of the neuromuscular junction (NMJ), resulting in the failure of neuromuscular transmission.

It remains unclear why auto-antibodies are produced; aetiological studies suggest causation to be combination of:


  • Genetic predispostion
  • Exposure to an environmental trigger


Auto-antibodies are found to be raised against the nicotinic acetylcholine receptor (nACHR), or less commonly muscle specific tyrosine kinase (MuSK) which plays a role in nAChR clustering at the NMJ.  Typical incidences are:


  • 90% cases nAchR-MG
  • 5% cases MuSK-MG 
  • 5%  cases seronegative (no detectable antibodies to nAchR or MuSK)


In all instances, a reduction in the function or number of nAchR is the post-synaptic membrane is found.

Nicotinic Acetylcholine receptor

Normal functioning of the Neuromuscular Junction:

  • α-motor neurons (αMN) from the ventral horn of the spinal cord contribute the presynaptic terminal of the NJM.
  • Near termination, axons of an αMN become subdivided, and innervate many individual muscle fibres.
  • The collection of muscle fibres innervated by the axons a single aMN is termed its motor group.
  • The presynaptic terminal is seperated from the motor end plate by the synaptic cleft. The motor end plate contains involutions to increase its surface area and thus the number of receptors in the meElectron Micrograph of a Neuromuscular junction- note the highly folded muscle membranembrane.
  • Presynaptic terminal contains vesicles of ACh, and when an action potential travels down αMN it results in depolarisation. This causes voltage gated (V.G) Ca2+ channels in the pre-synaptic membrane to open.
  • Ca2+ influx into the pre-synaptic terminals culminates in the fusion of the vesicles with the presyptic membrane, followed by quantal release of ACh.
  • ACh diffuses across the synaptic cleft and binds nACHR on the post synaptic membrane.
  • Binding of 2 ACh molecules to sites located on the alpha subunits of the nACHR results in a conformational change in the transmembrane helices and influx of Na+ into the muscle fibre.
  • Induction of an end-plate potential (EPP), triggering activation of V.G Na+ channels in the post-synaptic membrane generating an action potential which spread across the membrane surface (Boron and Boelpaep, 2009).


 Normal interactions of the motor neurone and muscle at NMJ in the induction of an EPSP


So, what goes wrong in Myasthenia Gravis?

Auto-antibodies raised against nAChR or MuSK can exert their effect via 3 main mechanisms (Vrollix et al 2010, Gomez et al 2010):

  • Antibodies bind and active the complement cascade, recruiting the constituents of the membrane attack complex (MAC) which makes membrane lose its specialised folded structure 
  • Antigenic Modulation: antibody mediated cross linking of nAChR, causing endocytosis and degredation.
  • Antibodies bind the Ach receptor sites, antagonising Ach binding.

Simplified schematic of the complement cascade


By reducing the number or impairing the function/localisation of nAChR and damaging the end plate, the SAFETY FACTOR is reduced (Conti-Fine et al, 2006).

What is the 'safety factor'? The ratio between EPP and threshold for muscle AP generation.

If a reduced number of nAchr are being activated, the EPP is reduced, consequently reducing the AP generated.

It is the failure of this electophysiological phenomenon which induces the symptoms seen in Myasthenia Gravis. 


Antibody Image courtesy of Wikicommons via the Creative Commons Licence

Nicotinic acetylcholine receptor courtesy of wikicommons via the Creative Commons Licence

EM of NMJ courtesy of Wikicommons via Creative Commons Licence

Schematic of complement cascade courtesy of Wikicommons via Creative Commons Licence