The first identified neurological autoimmune disease: myasthenia gravis

Myasthenia gravis (MG) is a rare autoimmune mediated neurological disease.  The name stems from Greek mya, “muscle” and sthenia “weakness, ” and the Latin gravis “serious” which describe the hallmark symptoms of severe muscle fatigue.  This fatigue can be life threatening if the muscles affected include respiratory and/or bulbar, those of the mouth and throat. 

Thomas Willis, a physician in London, first documented the disease in 1667.  In 1960, Simpson was the first to propose that the pathogenesis of MG was an autoimmune reaction that involved an antibody specific for a neuromuscular junction protein.  Which turned out to be correct, the most common form of MG is characterized by the presence of autoantibodies for the nicotinic acetylcholine receptor (nAChR).  This receptor is found in the neuromuscular junction and when bound to the neurotransmitter acetylcholine (Ach) muscle contractions are stimulated.  There are a few ways that the autoantibody for nAChR can interfere with proper muscle contractions.  First by binding to the receptor it is competitively inhibiting muscle stimulation via ACh.  Also the valence of the antibody can play a role in AChR degradation.  In class we discussed that IgG is divalent, and the autoantibody is classified as IgG.  When the divalent IgG is bound to the AChR it can cross-link two AChR thus prompting the degradation of both receptors.  Yet interestingly, if FAb is bound (only one) then degradation of the receptor is not promoted (Fig 1).  If there is less AChR then muscle contraction would be reduced.  Another interesting way autoantibody binding can interfere with normal muscle contraction is by inducing the complement system and subsequent lysis of the muscle tissue.   

The rate of acetylcholine receptor (AChR) degradation was measured in terms of loss of AChRs by Drachman and colleagues. Accelerated degradation was observed when divalent anti-AChR antibodies were used (a), but not when monovalent anti-AChR Fab' was applied (b). To prove that it was crosslinking per se, rather than antibody binding to the AChR, that caused the degradation, they showed that increased degradation could also be seen when AChR-specific Fab's were crosslinked by anti-Fab' antibody. (Figure adapted from Vincent 2002)

While much is understood about the mechanism of MG, the cause is unknown.  We discussed that some autoimmunity can stem from cross reactivity of antibody for an antigen, i.e. streptococci, that has a low affinity for a protein found in the body, i.e. the heart valve, but this does not appear to be the case for MG as the high-affinity for AChR implies that AChR is the primary antigen not something else (Tzartos 1998).  Even though a clear target for MG treatment remains elusive, common treatment include thymectomy, removal of the thymus.  The thymus contains germinal centers, where B cell and T cells mature, and when removed a reduction in the autoimmune reaction is seen.  Another treatment option involves acetlycholinesterase inhibitors, which reduce the degradation of ACh in the neuromuscular junction in combination with immunosuppressive drugs.  Yet, neither of these options are long-term treatment plans as they make the patient susceptible to infections, among other complications.

One intriguing fact about MG patients is that they often have some other associated condition that is typically autoimmune.  Some of these conditions include Graves disease, Multiple Sclerosis and other demyelinating CNS disorders, and Rheumatoid Arthritis.  This occurrence is not understood, and considering there is no current evidence for a genetic source of MG, what types of mechanisms might be driving the presentation of both MG and another condition?  Or do you think that the presentation of one autoimmune disease causes the other (e.g. is MG caused by another autoimmune disease or vice versa)?

Drachman, D. B., Angus, C. W., Adams, R. N., Michelson, J. D. & Hoffman, G. J.Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation.N. Engl. J. Med. 298, 1116–1122 (1978).

Tzartos, S. J. et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol. Rev. 163, 89–120 (1998).

Vincent, A. Unravelling the pathogenesis of myasthenia gravis. Nature Reviews Immunology 2, 797-804 (October 2002)