AChR phosphorylation and indirect inhibition of AChR function in seronegative MG.
BACKGROUND
Approximately 10% to 20% of patients with autoimmune MG do not have antibodies to the acetylcholine receptor (AChR), so-called seronegative MG (SNMG). IgG antibodies from up to 70% of SNMG patients bind to the muscle-specific receptor tyrosine kinase, MuSK. The plasmas and non-IgG fractions from SNMG patients (and some with AChR antibodies) also contain a factor, perhaps an IgM antibody, that inhibits AChR function, but it is not clear how this factor acts and whether it is related to the MuSK IgG antibodies.


METHODS
The authors studied 12 unselected SNMG plasmas and their non-IgG fractions; seven were positive for MuSK IgG antibodies. Ion flux assays, electrophysiology, phosphorylation, and kinase assays were used to look at mechanisms of action.


RESULTS
Eight of the 12 plasmas and their non-IgG fractions inhibited AChR function, but the inhibitory activity was transient and did not correlate with the presence of MuSK IgG antibodies. Two of three plasmas added outside of a cell-attached patch pipette inhibited AChR function within the patch, and these two plasmas also increased AChR phosphorylation.


CONCLUSIONS
The authors propose that a plasma factor(s) in SNMG patients, distinct from MuSK IgG antibodies, binds to a muscle membrane receptor and activates a second messenger pathway leading to AChR phosphorylation and reduced AChR function. Identifying the target for this factor should lead to improved diagnosis of MG in MuSK antibody-negative patients and may provide new insights into the function of the neuromuscular junction and pathophysiological mechanisms in MG.
Plested
C P
CP
Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
Tang
T
T
Spreadbury
I
I
Littleton
E T
ET
Kishore
U
U
Vincent
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007223:Infant; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000097:blood*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011494:Protein Kinases / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000097:blood* / Q000276:immunology; D011950:Receptors, Cholinergic / Q000097:blood* / Q000276:immunology / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
D001323:Autoantibodies; D018680:Cholinergic Antagonists; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; D000255:Adenosine Triphosphate; D012964:Sodium; D011494:Protein Kinases; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases