Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice.
Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of multiple immune system intracellular signalling pathways. The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P(2)) and phosphatidylinositol (3,4,5) trisphosphate (PIP(3)), are regulated by inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for Pten, a 3'-inositol phosphatase, develop a progressive lymphoproliferative syndrome with autoimmune features. Given the importance of PIP(3) species in regulating immune responses, we hypothesized that heterozygosity for the 5'-inositol phosphatase SHIP might exacerbate the autoimmune phenotype of Pten(+/-) mice. In keeping with this, mice heterozygous for both Pten and SHIP developed lymphoproliferation, hypergammaglobulinaemia, autoantibody titres and renal pathology that were more severe than that of Pten(+/-) mice. These results suggest that the relative levels of phosphatidylinositol phosphatases are likely critical to immune system homeostasis and they also highlight the potential for gene dosage effects in regulating susceptibility and/or severity of autoimmunity.
Moody
J L
JL
Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Pereira
C G
CG
Magil
A
A
Fritzler
M J
MJ
Jirik
F R
FR
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006580:Genetic Carrier Screening; D007668:Kidney / Q000276:immunology / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics* / Q000276:immunology; D008206:Lymphatic Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases