Abstract
To determine if patients with myasthenia gravis (MG) have antibodies to agrin, a proteoglycan released by motor neurons and is critical for neuromuscular junction (NMJ) formation, we collected serum samples from 93 patients with MG with known status of antibodies to acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related 4 (LRP4) and samples from control subjects (healthy individuals and individuals with other diseases). Sera were assayed for antibodies to agrin. We found antibodies to agrin in 7 serum samples of MG patients. None of the 25 healthy controls and none of the 55 control neurological patients had agrin antibodies. Two of the four triple negative MG patients (i.e., no detectable AChR, MuSK or LRP4 antibodies, AChR-/MuSK-/LRP4-) had antibodies against agrin. In addition, agrin antibodies were detected in 5 out of 83 AChR+/MuSK-/LRP4- patients but were not found in the 6 patients with MuSK antibodies (AChR-/MuSK+/LRP4-). Sera from MG patients with agrin antibodies were able to recognize recombinant agrin in conditioned media and in transfected HEK293 cells. These sera also inhibited the agrin-induced MuSK phosphorylation and AChR clustering in muscle cells. Together, these observations indicate that agrin is another autoantigen in patients with MG and agrin autoantibodies may be pathogenic through inhibition of agrin/LRP4/MuSK signaling at the NMJ.
Highlights
Autoimmune myasthenia gravis (MG) is the most common disorder of neuromuscular junction (NMJ), affecting nearly 20 per 100,000 people in various populations [1,2,3,4,5]
There were sera from 6 patients with MG who were known to be negative for LRP4 antibodies but had not been tested for acetylcholine receptor (AChR) and muscle specific kinase (MuSK) antibodies and they were all negative for agrin antibodies
About 80–90% of MG patients have detectable serum antibodies against AChRs with 40–70% of the remaining patients being positive for anti-MuSK antibodies and 2–50% for antiLRP4 antibodies [12,16,17,18,46]
Summary
Autoimmune MG is the most common disorder of NMJ, affecting nearly 20 per 100,000 people in various populations [1,2,3,4,5]. The symptoms and pathology of MG are known to be due to an antibody-mediated, autoimmune attack directed against molecules at the NMJ. Autoantibodies against AChR can be detected in the circulation of ,80–90% of MG patients [6,7]. Evidence from classic experiments indicates the anti-AChR antibodies are pathogenic [8,9,10,11]. AChR antibodies cannot be detected in ,10–20% of generalized MG patients. 40–70% of the seronegative patients have antibodies against MuSK [4,5,12,13,14,15]. Our group and others reported that 2–50% of AChR and MuSK double seronegative patients have anti-LRP4 antibodies [16,17,18,19]
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