Enhanced Phosphoinositide 3-Kinase δ Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death
| Autor: | Antonio C. Zea-Mendoza, Abel Suárez-Fueyo, Ana C. Carrera, Domingo F. Barber, Jorge Martínez-Ara |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Programmed cell death Cell Survival T-Lymphocytes T cell Blotting Western Immunology Apoptosis Cell Separation Protein Serine-Threonine Kinases Lymphocyte Activation 3-Phosphoinositide-Dependent Protein Kinases Phosphatidylinositol 3-Kinases Young Adult immune system diseases Genetic model medicine Humans Lupus Erythematosus Systemic Immunology and Allergy Fluorescent Antibody Technique Indirect skin and connective tissue diseases PI3K/AKT/mTOR pathway Phosphoinositide 3-kinase Lupus erythematosus biology business.industry ZAP70 Middle Aged Flow Cytometry medicine.disease Enzyme Activation medicine.anatomical_structure biology.protein Female business Immunologic Memory Memory T cell |
| Zdroj: | The Journal of Immunology. 187:2376-2385 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1101602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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