1. Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients.
- Author
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Gomez AM, Willcox N, Vrolix K, Hummel J, Nogales-Gadea G, Saxena A, Duimel H, Verheyen F, Molenaar PC, Buurman WA, De Baets MH, Martinez-Martinez P, and Losen M
- Subjects
- Adolescent, Adult, Age of Onset, Antineoplastic Agents pharmacology, Autoantibodies biosynthesis, Autoantibodies drug effects, Bortezomib, Cells, Cultured, Endoplasmic Reticulum Stress drug effects, Endoplasmic Reticulum Stress immunology, Female, Humans, Male, Plasma Cells drug effects, Plasma Cells ultrastructure, Primary Cell Culture, Proteasome Endopeptidase Complex drug effects, Thymus Gland drug effects, Thymus Gland ultrastructure, Young Adult, Autoantibodies metabolism, Boronic Acids pharmacology, Plasma Cells immunology, Proteasome Endopeptidase Complex immunology, Proteasome Endopeptidase Complex metabolism, Pyrazines pharmacology, Thymus Gland immunology
- Abstract
Bortezomib is a potent inhibitor of proteasomes currently used to eliminate malignant plasma cells in multiple myeloma patients. It is also effective in depleting both alloreactive plasma cells in acute Ab-mediated transplant rejection and their autoreactive counterparts in animal models of lupus and myasthenia gravis (MG). In this study, we demonstrate that bortezomib at 10 nM or higher concentrations killed long-lived plasma cells in cultured thymus cells from nine early-onset MG patients and consistently halted their spontaneous production not only of autoantibodies against the acetylcholine receptor but also of total IgG. Surprisingly, lenalidomide and dexamethasone had little effect on plasma cells. After bortezomib treatment, they showed ultrastructural changes characteristic of endoplasmic reticulum stress after 8 h and were no longer detectable at 24 h. Bortezomib therefore appears promising for treating MG and possibly other Ab-mediated autoimmune or allergic disorders, especially when given in short courses at modest doses before the standard immunosuppressive drugs have taken effect., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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