Attenuation of phosphoinositide 3-kinase delta signaling restrains autoimmune disease
- Author(s)
- Maxwell, MJ; Tsantikos, E; Kong, AM; Vanhaesebroeck, B; Tarlinton, DM; Hibbs, ML;
- Details
- Publication Year 2012-06,Volume 38,Issue #4,Page 381-391
- Journal Title
- JOURNAL OF AUTOIMMUNITY
- Publication Type
- Journal Article
- Abstract
- Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by the production of autoantibodies against nuclear components. Lyn-deficient mice are an excellent animal model of SLE manifesting clinical, pathological and biochemical features seen in the human disease. They develop autoreactive antibodies, glomerulonephritis and show generalized inflammation, and their B cells have a hyperactive phenotype. Since loss of Lyn confers hyper-activation of phosphoinositide 3-kinase (PI3K) signaling, we studied the effect of down-modulating PI3K in Lyn-deficient mice. We found that heterozygous inactivation of the p110 delta isoform of PI3K was sufficient to restrain disease in Lyn-deficient mice, leading to significantly decreased autoantibody development and autoimmune-mediated kidney pathology, and improved survival. Intriguingly, haploinsufficiency of p110 delta did not dampen signaling in Lyn-deficient B cells. However, plasma cell numbers, serum immunoglobulin titers, inflammation and T cell signaling and activation were significantly moderated in Lyn(-/-)p110 delta(+/KD) mice. Importantly, we have shown that haploinsufficiency of p110 delta has minor effects on the B cell compartment per se but leads to significant defects in T cell activation and B cell class-switching. These studies suggest that agents targeting p110 delta PI3K need not achieve full blockade of the enzyme to be of great benefit in the treatment of SLE. (C) 2012 Elsevier Ltd. All rights reserved.
- Publisher
- ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
- Keywords
- Systemic lupus erythematosus; Autoimmune disease; Lyn tyrosine kinase; Phosphoinositide 3-kinase p110δ; Autoimmune disease therapy
- Research Division(s)
- Immunology
- Publisher's Version
- https://doi.org/10.1016/j.jaut.2012.04.001
- Terms of Use/Rights Notice
- Copyright © 2012 Elsevier Ltd. All rights reserved.
Creation Date: 2012-06-01 12:00:00