Dampening Ab responses using proteasome inhibitors following in vivo B cell activation.
Upon encounter with Ag, B lymphocytes undergo terminal differentiation into plasma cells, highly specialized Ab secretors that mediate humoral immune responses. Profound changes adapt cellular morphology and proteome to the new secretory functions. Although a massive secretory activity is expected to require an efficient ubiquitin-proteasome degradation system, recent in vitro studies have surprisingly revealed that the proteasome function sharply decreases during plasma cell development, thereby limiting the proteolytic capacity. We challenged this paradigm in mouse models of B cell activation, and observed that following polyclonal activation, proteasome activity decreases more than previously reported in vitro. This decrease is linked to enhanced apoptosis after treatment with the potent anti-myeloma proteasome inhibitor PS-341. Accordingly, in vivo treatment with PS-341 decreases Ab titres in T-dependent and -independent mouse immunization models. This study provides the rationale for limiting the activity of Ab-secreting cells in vivo by impacting proteasome function.
Cascio
Paolo
P
Department of Veterinary Morphophysiology, University of Turin, Italy.
Oliva
Laura
L
Cerruti
Fulvia
F
Mariani
Elisabetta
E
Pasqualetto
Elena
E
Cenci
Simone
S
Sitia
Roberto
R
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007148:Immunoglobulin mu-Chains / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D001897:Boronic Acids; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D010047:Ovalbumin; D046988:Proteasome Endopeptidase Complex