Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death

Abstract

Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class IA PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

“…Inhibition or deletion of p110g in lupusprone mice alleviates disease symptoms (34,35), suggesting that this isoform might be useful for SLE treatment. Study of the PI3K pathway in SLE patient peripheral blood cells nonetheless showed that p110d is the isoform most frequently activated in human patients (36). The consequences of p110d inhibition for lupus development in vivo are incompletely understood.…”

“…These analyses showed that p110d inhibition in MRL/lpr mice tends to reduce total B and T cell numbers as well as the percentages of CD4 + effector memory, and Tregs. More than 50% of human SLE patients show enhanced p110d activation in T cells and defective activation-induced cell death (AICD) (36). p110d inhibition corrected the AICD defect of SLE patient T cells in vitro (36), suggesting that p110d enhances activated and/or memory T cell survival and promotes T and B cell accumulation in SLE.…”

“…More than 50% of human SLE patients show enhanced p110d activation in T cells and defective activation-induced cell death (AICD) (36). p110d inhibition corrected the AICD defect of SLE patient T cells in vitro (36), suggesting that p110d enhances activated and/or memory T cell survival and promotes T and B cell accumulation in SLE. AICD cannot be studied in MRL/lpr mice because Fas is mutated in this mouse strain (lpr mutation) (37).…”

A 50‐Year‐Old Woman With Cowden Syndrome and Joint Pains

“…Several studies support the role of PTEN-and PI3K-signaling pathways in the pathogenesis of SLE and RA (17,18). Decreased PTEN mRNA expression has been described in synovial fibroblasts from RA patients and activation of Akt-1 suppresses apoptosis in synoviocytes, and promotes cell survival and disease progression.…”

B cells biology in systemic lupus erythematosus—from bench to bedside

“…Our group together with other groups has demonstrated that increased PI3K/Akt activation in SLE patients, both in T cells and B cells [95,96]. And PI3K (p110 containing PI3K complex) plays an important role in B cell differentiation and function, regulating class switch recombination and AID [97,98].…”