Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis
- 15 February 2011
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 186 (4), 2503-2513
- https://doi.org/10.4049/jimmunol.1002539
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.Keywords
This publication has 47 references indexed in Scilit:
- Development of novel therapies for MG: Studies in animal modelsAutoimmunity, 2010
- Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in miceExperimental Neurology, 2010
- Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myelomaHaematologica, 2008
- Proteasome inhibition drastically but reversibly impairs murine lymphocyte developmentCell Death & Differentiation, 2008
- Overexpression of Rapsyn in Rat Muscle Increases Acetylcholine Receptor Levels in Chronic Experimental Autoimmune Myasthenia GravisThe American Journal of Pathology, 2007
- Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cellsBlood, 2006
- The Role of Long-Lived Plasma Cells in AutoimmunityImmunobiology, 2002
- EFFECT OF PLASMAPHERESIS IN MYASTHENIA GRAVIS 1978-1980Annals of the New York Academy of Sciences, 1981
- Plasma exchange and immunosuppressive drug treatment in myasthenia gravis: no evidence for synergy.Journal of Neurology, Neurosurgery & Psychiatry, 1981
- Experimental autoimmune myasthenia gravis.Journal of Neurology, Neurosurgery & Psychiatry, 1980