The effects of prednisone and steroid-sparing agents on decay accelerating factor (CD55) expression: implications in myasthenia gravis.
Decay accelerating factor (DAF) expression at the muscle endplate is an important defence against complement-mediated damage in myasthenia gravis. Previously we implicated the c.-198C>G DAF polymorphism with the development of treatment-resistant myasthenia-associated ophthalmoplegia by showing that the C>G DAF polymorphism prevented lipopolysaccharide-induced upregulation of lymphoblast DAF. We postulated that drugs used in myasthenia gravis may increase the susceptibility of extraocular muscles to complement-mediated damage and studied their effects on endogenous DAF using patient-derived lymphoblasts as well as mouse myotubes. We show that prednisone repressed C>G DAF expression in lymphoblasts and increased their susceptibility to cytotoxicity. Methotrexate, but not azathioprine or cyclosporine, increased DAF in C>G lymphoblasts. In mouse myotubes expressing wild-type Daf, prednisone also repressed Daf expression. Although cyclosporine, azathioprine, and methotrexate increased muscle Daf levels when used alone, upon co-treatment with prednisone only azathioprine maintained myotube Daf levels close to basal. Therefore, prednisone negatively influences DAF expression in C>G lymphoblasts and in myotubes expressing wild-type Daf. We speculate that myasthenic individuals at risk of developing the ophthalmoplegic complication, such as those with C>G DAF, may have inadequate endogenous levels of complement regulatory protein protection in their extraocular muscle in response to prednisone, increasing their susceptibility to complement-mediated damage.
Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa; Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
Jennifer
J
Auret
Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa; Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
Amaal
A
Abrahams
Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
Sharon
S
Prince
Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: Jeanine.heckmann@uct.ac.za.
Jeannine M
JM
Heckmann
D000818:Animals; D001379:Azathioprine / Q000494:pharmacology; D018958:CD55 Antigens / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D016572:Cyclosporine / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009157:Myasthenia Gravis / Q000378:metabolism*; D011241:Prednisone / Q000494:pharmacology*
D018958:CD55 Antigens; D005938:Glucocorticoids; D016572:Cyclosporine; D001379:Azathioprine; D011241:Prednisone; D008727:Methotrexate
Azathioprine; Complement; Cyclosporine; Decay accelerating factor (DAF); Methotrexate; Muscle; Myasthenia gravis; Post-transcriptional regulation; Prednisone; Regulatory polymorphism