Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Specific Autoantibody Production in Primary Thymic Cell Cultures from Early-Onset Myasthenia Gravis Patients

Alejandro M. Gomez, Nick Willcox, Kathleen Vrolix, Jonas Hummel, Gisela Nogales-Gadea, Abhishek Saxena, Hans Duimel, Fons Verheyen, Peter C. Molenaar, Wim A. Buurman, Marc H. De Baets, Pilar Martinez-Martinez*, Mario Losen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)1055-1063
JournalJournal of Immunology
Volume193
Issue number3
DOIs
Publication statusPublished - 1 Aug 2014

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