title: Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice.
abstract: To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3(+)CD4(-)CD8(-)B220(+) T cells, CD4(+) and CD8(+) T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4(+) and CD8(+) T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-gamma once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease.
authors.affiliation: Institute for Biotechnology of Infectious Disease, and Department of Medical and Molecular Biosciences, University of Technology, Sydney. Lisa.Sedger@uts.edu.au
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sedger
authors.forename: Arna
authors.initials: A
authors.lastname: Katewa
authors.forename: Ann K
authors.initials: AK
authors.lastname: Pettersen
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Osvath
authors.forename: Geoff C
authors.initials: GC
authors.lastname: Farrell
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000172:deficiency* / Q000235:genetics; D005434:Flow Cytometry; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency* / Q000235:genetics
chemical_list: D001323:Autoantibodies; D053222:Fas Ligand Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse