Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis.
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.
Neuroimmunology Group, Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
Alejandro M
AM
Gomez
Kathleen
K
Vrolix
Pilar
P
Martínez-Martínez
Peter C
PC
Molenaar
Marko
M
Phernambucq
Eline
E
van der Esch
Hans
H
Duimel
Fons
F
Verheyen
Reinhard E
RE
Voll
Rudolf A
RA
Manz
Marc H
MH
De Baets
Mario
M
Losen
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D005260:Female; D008212:Lymphocyte Depletion / Q000379:methods; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology*; D010950:Plasma Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew
D001323:Autoantibodies; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib