Estudio sobre el papel de pi3k en la enfermedad del lupus eritematoso sistémico humano y su posible aplicación terapeútica

Resumen

Insufficient cell death of activated T cell results in autoimmune disease. Two pathways control homeostasis of activated T cells; the main mechanism, ACAD (activated T cell autonomous death), controls the size of the T cell compartment by deleting T cells when the inflammatory cytokine environment disappears. Autoreactive T lymphocytes are eliminated by restimulation via the T cell receptor and undergo AICD (activation-induced cell death). Whereas failure of ACAD leads to lymphoma, AICD alterations lead to autoimmune disorders. Class I PI3K (phosphoinositide-3-kinases) trigger formation of 3-poly-phosphoinositide, which act as second messengers. PKB/AKT, the principal PI3K effectors, controls several T cell responses including growth, proliferation, protein synthesis, migration and survival. Genetically-induced alterations in at different points of the PI3K/PKB pathway lead to development of a lupus-like disease in mice, which develop autoimmune renal failure with increased numbers of memory T lymphocytes and reduced apoptosis. We studied the PI3K pathway in human systemic lupus erythematosus (SLE), an autoimmune disease caused by autoreactive T and B cells. We show that this pathway is frequently activated in human SLE patient peripheral blood mononuclear cells and T cells, more markedly in active disease phases. Enhanced activation of the PI3Kd isoform in SLE peripheral blood T cells paralleled accumulation of activated/memory Tcells, which showed reduced AICD. This AICD defect in SLE T cells was corrected by reduction of PI3Kd activity. In conclusion, PI3Kd contributes to induction of enhanced SLE memory T cell survival, supporting its potential as a novel therapeutic approach for SLE treatment.