title: Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients.
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.
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Alejandro M
authors: AM
authors: Gomez
authors: Department of Clinical Neurology, University of Oxford, UK.
authors: Nick
authors: N
authors: Willcox
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Kathleen
authors: K
authors: Vrolix
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Jonas
authors: J
authors: Hummel
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.|Neuromuscular Diseases Unit, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain.
authors: Gisela
authors: G
authors: Nogales-Gadea
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Abhishek
authors: A
authors: Saxena
authors: ELMI Unit-CRISP, Department of Molecular Cell Biology, Maastricht University, Maastricht, the Netherlands.
authors: Hans
authors: H
authors: Duimel
authors: ELMI Unit-CRISP, Department of Molecular Cell Biology, Maastricht University, Maastricht, the Netherlands.
authors: Fons
authors: F
authors: Verheyen
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Peter C
authors: PC
authors: Molenaar
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Wim A
authors: WA
authors: Buurman
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Marc H
authors: MH
authors: De Baets
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Pilar
authors: P
authors: Martinez-Martinez
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors: Mario
authors: M
authors: Losen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000970:Antineoplastic Agents / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001323:Autoantibodies; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex