Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis

Alejandro M. Gomez, Kathleen Vrolix, Pilar Martínez-Martínez, Peter C. Molenaar, Marko Phernambucq, Eline Van Der Esch, Hans Duimel, Fons Verheyen, Reinhard E. Voll, Rudolf A. Manz, Marc H. De Baets, Mario Losen*

*Corresponding author for this work
96 Citations (Scopus)

Abstract

Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

Original languageEnglish
JournalJournal of Immunology
Volume186
Issue number4
Pages (from-to)2503-2513
Number of pages11
ISSN0022-1767
DOIs
Publication statusPublished - 15.02.2011

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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