Long-lived antibody-secreting plasma cells (PCs) are key to host defense, but PCs secreting self-reactive antibodies can cause a spectrum of autoimmune diseases. Likewise, PCs secreting allograft-specific antibodies are major mediators of chronic graft rejection. Current B cell ablation therapies target naive and memory B cells, but spare long-lived pathogenic PCs. We propose to define the role of the unfolded protein response (UPR) in the survival and function of long-lived PCs. Although the UPR is known to control the function of professional secretory cells such as PCs, how the UPR is regulated in PCs, and its role in long-term PC survival, has not been addressed. These studies will focus on the regulation of PC survival by the UPR component and endoplasmic reticulum sensor IRE1 and a novel IRE1 regulator - PDIA6. The main hypothesis to be tested is that sustained but limited IRE1 activity is required for the survival of long-lived PCs. To test this hypothesis we wil: 1) Define the role of IRE1 activity in short- and long-lived PCs, and 2) Define the role of PDIA6 activity in short- and long-lived PCs. These studies will enhance knowledge of the processes underlying the generation of long-lived PCs, and perhaps provide insights into novel strategies to constrain the survival or activity of pathogenic PCs.
The regulation of long-term survival of antibody-secreting plasma cells by components of the unfolded protein response (UPR) has not been addressed. Our studies will define the role of the UPR component IRE1 and its regulator PDIA6 in plasma cell survival. These studies will enhance knowledge of the biochemical pathways regulating plasma cell survival, and thus reveal novel strategies to enhance or constrain antibody responses to foreign and self-antigens.
| Wilmore, Joel R; Jones, Derek D; Allman, David (2017) Protocol for improved resolution of plasma cell subpopulations by flow cytometry. Eur J Immunol 47:1386-1388 |
