AChR phosphorylation and indirect inhibition of AChR function in seronegative MG
CP Plested, T Tang, I Spreadbury, ET Littleton… - Neurology, 2002 - AAN Enterprises
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 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 …
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.
American Academy of Neurology