The Early Marginal Zone B Cell-Initiated T-Independent Type 2 Response Resists the Proteasome Inhibitor Bortezomib

Abstract

The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma. We recently demonstrated that bortezomib eliminates autoreactive plasma cells in systemic lupus erythematosus mouse models, thereby representing a promising novel treatment for Ab-mediated diseases. In this study, we investigated the effects of bortezomib on the just developing and pre-existing T-dependent Ab response toward dinitrophenyl-keyhole limpet hemocyanin and the T-independent type 2 response toward (4-hydroxy-3-iodo-5-nitrophenyl)acetyl (NIP)-Ficoll in BALB/c mice. Bortezomib treatment strongly reduced T-dependent Ab titers mainly due to depletion of plasma cells. In contrast, the early T-independent type 2 response against i.v. administered NIP-Ficoll, which is predominantly dependent on marginal zone (MZ) B cells, resisted bortezomib. Upon bortezomib treatment, immunoproteasome subunits and the antiapoptotic unfolded protein response including NF-κB were induced in NIP-Ficoll–stimulated MZ B cells, but not in plasma cells and follicular B cells. In summary, bortezomib treatment decreases Ab titers arising from T-dependent immune responses predominantly by eliminating plasma cells. In contrast, the early T-independent type 2 response protecting the organism against blood-borne pathogens remains largely intact due to a remarkable resistance of MZ B cells against proteasome inhibition.

Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors

“…Activated B cells are able to produce cytokines and consequently contribute to inflammation [43] or protective cytokine environments [44]. To this end, we examined the secretion profile of the prototypical pro-inflammatory cytokine TNF-α by activated JY cells and explored whether or not this profile is altered in JY/BTZ cells.…”

Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors

“…Clearly, in vitro systems of terminal B cell differentiation into antibody secretors prescind from the physiological environmental cues that regulate plasma cell homeostasis and survival in vivo. However, these models proved crucial to study cell-autonomous aspects of plasma cell differentiation, including challenged protein homeostasis, shown to underlie PI sensitivity also in vivo [24,25,36,42].…”

Evolution of B Cell Immunity

“…Furthermore, B-2 B cells have extensive N regions in contrast to B-1 cells, in which there are few. Owing to their capacity to secrete natural antibodies, which participate in immune exclusion in the gut as well as in protection in several infections, and to respond to T-independent antigens (129, 130), MZ and B-1 B cells are considered innate-like B cells. Recent findings reinforced this role in innate immunity, describing for the first time the capacity of mouse peritoneal cavity (PerC) B-1 B cells to perform phagocytosis and kill internalized bacteria (131, 132).…”