RT Journal Article
SR Electronic
T1 1703 Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing endoplasmic reticulum stress
JF Lupus Science & Medicine
JO Lupus Sci Med
FD Lupus Foundation of America
SP A70
OP A70
DO 10.1136/lupus-2021-lupus21century.98
VO 8
IS Suppl 2
A1 Rawlings, David J
A1 Qureshah, Fahd Al
A1 Sagadiev, Sara
A1 Thouvenel, Christopher D
A1 Liu, Shuozhi
A1 Hua, Zhaolin
A1 Hou, Baidong
A1 Acharya, Mridu
A1 James, Richard G
YR 2021
UL http://lupus.bmj.com/content/8/Suppl_2/A70.1.abstract
AB Background Understanding key signals that control the differentiation, function, and survival of plasma cells (PCs) is critical for development of improved therapeutic approaches to attenuate pathogenic antibody responses in SLE. While phosphatidylinositide 3-kinase delta (PI3Kδ) plays an essential role in humoral immune responses, its role(s) in PC function remains poorly understood.Methods We utilized a conditional mouse model of Activated PI3Kδ Syndrome (APDS), to interrogate the role of this key signaling program.Results Mice expressing a gain-of-function mutation in PIK3CD in B cells, referred to as activated (a) PIK3CD, generated increased numbers of memory B cells, mounted enhanced secondary response, yet exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation. Remarkably, PC specific aPIK3CD expression was sufficient to diminish humoral responses in vivo. Mechanistically, aPIK3CD disrupted endoplasmic reticulum proteostasis and autophagy, leading to increased PC death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3Kδ-specific inhibitors.Conclusions Taken together, these data demonstrate an unexpected requirement to down-regulate PI3Kδ activity to balance autophagy and the unfolded protein response, events essential to modulate ER stress and ensure PC survival. Thus, enhancing PI3Kδ activity may provide a novel means to trigger early PC death and dampen autoantibody responses.