Literature review written for Dr. Gene Mesco, PhD's Special Topics – Neurobiology course at Dalton State College during the Spring 2014 semester.

1. Literature Review
of
Unraveling the Pathogenesis of Myasthenia Gravis
from
Nature Reviews Immunology
Jackson David Reynolds
March 27, 2014
BIOL 4900
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2. Angela Vincent’s 2002 review journal article in Nature Reviews Immunology, Volume 2,
Unraveling the pathogenesis of myasthenia gravis, seeks to linearly appraise the history of
research pertaining to the investigation of the physiological mechanism(s) underlying the
pathology of myasthenia gravis (MG), as well as to assess the current applicability of historical
and contemporary research on MG to the evolving understanding of MG as an autoimmune
disease and to the clinical approaches taken as the medical community continues to define new
antibody-mediated pathologies.
Vincent begins her overview with an examination of the infancy of MG as a somewhat
clearly defined pathophysiological disorder, briefly touching on the clinical observations of 17th-
century British physician Thomas Willis, who described a patient (pt) suffering from an activity-
induced paralysis that was notably improved by rest. The first indications that MG might perhaps
be an immune-mediated/autoimmune condition, Vincent relays, came in the form of
demographic studies conducted by J.A. Simpson (published 1960), which outlined clear
correlations between pts suffering from MG and the concurrent presence of manifest immune
disorders such as thyroiditis and thymic abnormalities. Simpson proposed that MG was due to
the presence of an antibody specific for an endplate neuromuscular junction (NMJ) protein. This
hypothesis was made decades after MG had already been established as a malady exclusively
resultant from the blocking of acetylcholine receptor proteins (AChRs) , a conclusion arrived at1
from voltage-clamp research conducted by Fatt and Katz in which the miniature endplate
potentials (MEPPs) of MG pts demonstrated a significant reduction in amplitude, indicating
either a reduced sensitivity to ACh at the NMJ or a reduction in the amount of ACh present in
each synaptic vesicle. Further support was imparted to the immune-mediated hypothesis of MG
in the 1970s, when Patrick and Lindstrom conducted further studies on animal models, which
involved rabbits that had been immunized via purified xenogeneic AChRs to raise specific
antibodies. The inoculated animals exhibited muscular weakness, which could be reversed by the
systemic introduction of acetylcholinesterase (AChE) inhibitors.
It is to be noted that at the time of the conduction of this research, the protein nature of AChR had not been1
established.
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3. The autoimmune nature of MG still remained to be fully empirically confirmed, however,
and the subsequent research that provided such validation can be broken down into four broad
categories.
1. Pts were determined to possess serum antibodies specific to AChR in a set of
trials executed by Almon,. in which serum from MG pts was shown to be potent
in the inhibition of radioactive 125I-α-bungarotoxin (125I-α-BTX) in rat AChRs.
2. Research performed by Tokya, et al., demonstrated that the local injection of
immunoglobulin G (IgG) from MG pts in mice engendered neuromuscular
weakness and a diminution in the number of AChRs at the NMJs akin to that
found in MG, thereby denoting a relationship between an exogenous immune
response and a symptomatic presentation nearly indistinguishable from that of
MG.
3. Studies conducted by Pinching, et al., showed that therapeutic plasma exchange in
MG pts produced a dramatic reduction in symptoms, the clinical benefit of which
correlated inversely with the serum level of AChR-specific antibody, even in pts
with a long history (Hx) of MG.
4. Investigations carried out by Engel, et al., revealed that both IgG and complement
are present at the NJMs of MG pts and that they co-localize with unbound
AChRs.
The conclusions reached from these studies are of use in assessing the clinical utility and
prudence of potential therapies for other autoimmune disorders etiologically analogous to MG,
such as weighing the benefits between immunotherapy and surgery in treating pts suffering from
thymus-mediated autoimmune conditions.
Vincent’s survey of the Hx of MG research as well as her analysis of the potential
relevance of such studies to clinical approaches presently applied to pathologies similar to MG is
simultaneously comprehensive and concise.
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4. Work Cited
Vincent, A. (2002). Unravelling the pathogenesis of myasthenia gravis. Nature Reviews |
Immunology, 2(10), 797-804. Retrieved January 22, 2014.
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