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doi:10.

1093/brain/awn131 Brain (2008), 131, 1684 ^1685

SCIENTIF IC COMMENTARY
‘Seronegative’ myasthenia gravis is no longer
seronegative
High-affinity IgG autoantibodies to muscle nicotinic were seronegative using the conventional assay (Yamamoto
acetylcholine receptors (AChRs) were discovered to cause et al., 1991; Barrett-Jolley et al., 1994; Bufler et al., 1998).
myasthenia gravis (MG) and its animal model more than In this issue of Brain, Angela Vincent and coworkers
30 years ago (Patrick and Lindstrom, 1973; Lindstrom et al., report that they have, at last, devised an assay which detects
1976a, b; Vincent et al., 2006), and the antigenic structure of low-affinity IgG autoantibodies to AChRs in 66% of the
muscle AChRs is still being actively investigated (Kalamida remaining seronegative patients. The trick was to aggregate
et al., 2007; Lindstrom et al., 2008). Immune precipitation the AChRs on the surface of the transfected cells so that
of AChRs tagged in their acetylcholine-binding sites with high concentrations of AChRs could compensate for the
125
I-labelled a bungarotoxin provided a sensitive immuno- low affinity of the autoantibodies. Bound autoantibodies
diagnostic assay for MG (Lindstrom et al., 1976b). However, were detected by microscopy using fluorescently labelled
up to 20% of those who appeared to have autoimmune MG, antibodies to IgG. Cotransfection of human embryonic
because they benefited from plasmapheresis or exhibited kidney cells with human muscle AChR and rapsyn, the
antibodies bound to their neuromuscular junctions, did not protein which anchors AChRs to the cytoskeleton in
have autoantibodies detectable by the conventional assay muscle, provided the aggregate that permitted detection
(Vincent et al., 2006). of the low-affinity autoantibodies.
Angela Vincent and her co-workers discovered that Problems with the assay are that it provides subjective
about half of the putative seronegative MG patients actu- qualitative results evaluated by microscopy rather than
ally had autoantibodies to muscle-specific kinase objective quantitative assay values in moles of toxin-labelled
(MuSK) (Hoch et al., 2001; Vincent and Leite, 2005). AChRs bound per litre of serum obtained by g counting in
These MuSK-MG patients exhibited distinct clinical features the conventional assay for high-affinity autoantibodies;
and their neuromuscular transmission was impaired and the transient transfection and evaluation of binding are
indirectly through disrupted signalling by MuSK released very laborious compared to an immunoprecipitation assay.
by the nerve ending that trophically mediates localization of One possible solution to these problems would be to grow
AChRs and other post-synaptic components (Vincent and transfected cell lines in microwell cultures and measure the
Leite, 2005). amount of bound autoantibody using 125I-labelled anti-IgG.
In classical seropositive MG, autoantibodies bound to the If successful, this would eliminate microscopy, speed
AChRs impair neuromuscular transmission by three mecha- throughput and permit objective quantification of the
nisms (Lindstrom, 2000; Engel and Hohlfeld, 2004; Vincent amount of autoantibodies in moles of autoantibody per
et al., 2006): litre of serum. Further upregulation of the amount of
AChR in the cell lines by growth in nicotine (Kuryatov
 fixation of complement that causes focal lysis of the et al., 2005) might enhance the sensitivity of the assay.
post-synaptic membrane that reduces the number of Another approach to detection of these antibodies could
AChRs and disrupts their localization next to sites of involve the use of heavily loaded blots of bacterially
ACh release; expressed AChR subunit constructs, since it was observed
 cross-linking of AChRs by antibodies increases their that the autoantibodies could be adsorbed using bacterially
rate of endocytosis, which causes loss of AChRs by the expressed a subunits.
process of antigenic modulation; and These experiments have illuminated the status of
 rarely, autoantibodies directly impair AChR function ‘seronegative’ MG patients:
either competitively or non-competitively.
 autoantibodies to AChRs are present;
The discovery of autoantibodies to MuSK still left 12%  these are directed at the extracellular surface, predomi-
of MG patients as seronegative, yet clinically and by thymic nantly at a subunits, usually away from the ACh-binding
and endplate pathology appearing much like seropositive site, and are detectable despite apparently low-affinity
MG patients (Vincent and Leite, 2005). Occasional hints binding because they can cross-link tightly packed
suggested that IgM or low-affinity antagonist IgG anti- AChRs; thus they might be able to cause AChR loss
bodies to AChRs might explain why the remaining patients through antigenic modulation; however, their low

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Scientific Commentary Brain (2008), 131, 1684 ^1685 1685

affinity and dependence on aggregation by rapsyn may myasthenia gravis without acetylcholine receptor antibodies. Nat Med
prevent this; 2001; 7: 365–8.
Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G,
 these autoantibodies are complement-fixing IgG1 anti- Lazaridis K, et al. Muscle and neuronal nicotinic acetylcholine
bodies, thus they should be able to impair transmission receptors. Structure, function and pathogenicity. FEBS J. 2007; 274:
by disrupting synaptic architecture and causing AChR 3799–845.
loss through focal lysis; Kuryatov A, Luo J, Cooper J, Lindstrom J. Nicotine acts as a
 thymic pathology in these patients resembles that in pharmacological chaperone to up-regulate human a4b2 acetylcholine
receptors. Mol Pharmacol 2005; 68: 1839–51.
‘seropositive’ MG patients with lymphocytic infiltrates,
Lindstrom J. Acetylcholine receptors and myasthenia. Muscle Nerve 2000;
germinal centres and myoid cells showing deposits of 23: 453–77.
complement. Lindstrom J, Einarson B, Lennon V, Seybold M. Pathological mechanisms
in experimental autoimmune myasthenia gravis. I. Immunogenicity of
syngeneic muscle acetylcholine receptor and quantitative extraction of
Jon Lindstrom receptor and antibody-receptor complexes from muscles of rats with
Department of Neuroscience, Medical School of the University experimental automimmune myasthenia gravis. J Exp Med 1976a; 144:
of Pennsylvania, Pennsylvania, PA, USA 726–38.
Lindstrom J, Luo J, Kuryatov A. MG and the tops and bottoms of AChRs.
E-mail: jslkk@mail.med.upenn.edu
Ann NY Acad Sci. 2008; in press.
Advance Access publication June 16, 2008 Lindstrom J, Seybold M, Lennon V, Whittingham S, Duane D.
Antibody to acetylcholine receptor in myasthenia gravis. Prevalence,
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Auto-antibodies to the receptor tyrosine kinase MuSK in patients with

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