title: Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease.
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 p110δ 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 p110δ 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(-/-)p110δ(+/KD) mice. Importantly, we have shown that haploinsufficiency of p110δ 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 p110δ PI3K need not achieve full blockade of the enzyme to be of great benefit in the treatment of SLE.
authors.affiliation: Leukocyte Signalling Laboratory, Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia. Mhairi.Maxwell@monash.edu
authors.forename: Mhairi J
authors.initials: MJ
authors.lastname: Maxwell
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tsantikos
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kong
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
mesh_terms: D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D005838:Genotype; D057895:Haploinsufficiency / Q000235:genetics / Q000276:immunology; D006965:Hyperplasia; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D058534:Class I Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell; D019061:src-Family Kinases; C421683:Pik3cd protein, mouse; C060902:lyn protein-tyrosine kinase