Overexpression of rapsyn in rat muscle increases acetylcholine receptor levels in chronic experimental autoimmune myasthenia gravis.
The primary autoantigen in myasthenia gravis, the acetylcholine receptor (AChR), is clustered and anchored in the postsynaptic membrane of the neuromuscular junction by rapsyn. Previously, we found that overexpression of rapsyn by cDNA transfection protects AChRs in rat muscles from antibody-mediated loss in passive transfer experimental autoimmune myasthenia gravis (EAMG). Here, we determined whether rapsyn overexpression can reduce or even reverse AChR loss in muscles that are already damaged by chronic EAMG, which mimics the human disease. Active immunization against purified AChR was performed in female Lewis rats. Rapsyn overexpression resulted in an increase in total muscle membrane AChR levels, with some AChR at neuromuscular junctions but much of it in extrasynaptic membrane regions. At the ultrastructural level, most endplates in rapsyn-treated chronic EAMG muscles showed increased damage to the postsynaptic membrane. Although rapsyn overexpression stabilized AChRs in intact or mildly damaged endplates, the rapsyn-induced increase of membrane AChR enhanced autoantibody binding and membrane damage in severe ongoing disease. Thus, these results show the complexity of synaptic stabilization of AChR during the autoantibody attack. They also indicate that the expression of receptor-associated proteins may determine the severity of autoimmune diseases caused by anti-receptor antibodies.
Martínez-Martínez
Pilar
P
Department of Neurology, Research Institute Brain and Behaviour, University of Maastricht, Maastricht University Hospital, The Netherlands. p.martinez@np.unimaas.nl
Losen
Mario
M
Duimel
Hans
H
Frederik
Peter
P
Spaans
Frank
F
Molenaar
Peter
P
Vincent
Angela
A
De Baets
Marc H
MH
D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D015870:Gene Expression; D006801:Humans; D009045:Motor Endplate / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology / Q000378:metabolism*; D013570:Synaptic Membranes / Q000276:immunology / Q000378:metabolism*
D001323:Autoantibodies; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K