The spectacular differentiation of a B cell into a plasma cell, the antibody factory, entails massive development of the endoplasmic reticulum (ER) and requires a powerful response against ER stress, the unfolded protein response (UPR). Immune homeostasis requires that the vast majority of mature plasma cells be eliminated, but the molecular events that drive death decisions are still obscure1. To shed light on this issue, we adopted different models of plasma cell differentiation in vitro and in vivo. We found that proteasomal inhibition selectively induces apoptosis in mature plasma cells, with efficacy positively correlating with the Ig-synthetic load, indicating that sensitivity to proteasome inhibitors (PI) is a feature of normal plasma cells. In striking correlation with the apoptotic behaviour, the relative amount and proteolytic activity of proteasomes decrease during the late phases of plasma cell differentiation. Thus, the demand for a higher degradative capacity is denied when antibody production becomes maximal. The excessive load for the reduced proteolytic capacity causes accumulation of poly-ubiquitinated proteins and stabilization of endogenous proteasomal substrates such as the UPR mediator Xbp1, the NF-kB inhibitor Ik-B, and the pro-apoptotic Bcl-2 relatives Bim and Bax, two proteins critical in limiting B lymphocytes lifespan and activity. Accumulation of such proteins leads to exaggerated endoplasmic reticulum stress and predisposes plasma cells to apoptosis by proteasome inhibitors. Our results suggest that a developmental program allows plasma cells to count the integral of produced Ig, linking death to protein production, thus ending the humoral immune response upon accomplishment of its goal. Based on our data, we propose that the high efficacy of PI against certain tumours as Multiple myeloma (MM) is due, to a significant extent, to overloading the cell’s degradative capacity, a key component of the stress response, already challenged by misfolded chains generated as a side product of intense Ig synthesis. This model provides a framework for attempting to achieve tumour cell destruction through modulation of stress. 1) Manz, R.A., Arce, S., Cassese, G., Hauser, A.E., Hiepe, F. and Radbruch, A. Curr Opin Immunol, 2002, 14, 517-521
Progressively impaired proteosomal capacity limits plasma cell lifespan
CASCIO, Paolo;CERRUTI, Fulvia;BRUNO, Renato;
2006-01-01
Abstract
The spectacular differentiation of a B cell into a plasma cell, the antibody factory, entails massive development of the endoplasmic reticulum (ER) and requires a powerful response against ER stress, the unfolded protein response (UPR). Immune homeostasis requires that the vast majority of mature plasma cells be eliminated, but the molecular events that drive death decisions are still obscure1. To shed light on this issue, we adopted different models of plasma cell differentiation in vitro and in vivo. We found that proteasomal inhibition selectively induces apoptosis in mature plasma cells, with efficacy positively correlating with the Ig-synthetic load, indicating that sensitivity to proteasome inhibitors (PI) is a feature of normal plasma cells. In striking correlation with the apoptotic behaviour, the relative amount and proteolytic activity of proteasomes decrease during the late phases of plasma cell differentiation. Thus, the demand for a higher degradative capacity is denied when antibody production becomes maximal. The excessive load for the reduced proteolytic capacity causes accumulation of poly-ubiquitinated proteins and stabilization of endogenous proteasomal substrates such as the UPR mediator Xbp1, the NF-kB inhibitor Ik-B, and the pro-apoptotic Bcl-2 relatives Bim and Bax, two proteins critical in limiting B lymphocytes lifespan and activity. Accumulation of such proteins leads to exaggerated endoplasmic reticulum stress and predisposes plasma cells to apoptosis by proteasome inhibitors. Our results suggest that a developmental program allows plasma cells to count the integral of produced Ig, linking death to protein production, thus ending the humoral immune response upon accomplishment of its goal. Based on our data, we propose that the high efficacy of PI against certain tumours as Multiple myeloma (MM) is due, to a significant extent, to overloading the cell’s degradative capacity, a key component of the stress response, already challenged by misfolded chains generated as a side product of intense Ig synthesis. This model provides a framework for attempting to achieve tumour cell destruction through modulation of stress. 1) Manz, R.A., Arce, S., Cassese, G., Hauser, A.E., Hiepe, F. and Radbruch, A. Curr Opin Immunol, 2002, 14, 517-521
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
