title: TNF contributes to the immunopathology of perforin/Fas ligand double deficiency.
abstract: Perforin (pfp)/Fas ligand (FasL) double-deficient mice have previously been shown to be infertile, lose weight and die prematurely due to tissue destruction caused by a significant inflammatory infiltrate of monocytes/macrophages and T cells. Herein we have compared disease progression in mice additionally deficient in the inflammatory mediator TNF. Unlike pfp/FasL double-deficient mice (TNF+/+ pfp-/- gld), mice lacking functional TNF, FasL and pfp (TNF-/- pfp-/- gld) were comparatively fertile, with the majority of mice not suffering severe pancreatitis or hysterosalphingitis in the first 5 months of life. The mean lifespan of TNF-/- pfp-/- gld mice was 217 +/- 79 days compared with 69 +/- 10 days for TNF+/+ pfp-/- gld mice and the majority of moribund TNF-/- pfp-/- gld mice appeared to die as a result of severe pancreatitis, suggesting that loss of TNF was not completely protective. At 8 weeks of age, characteristics associated with the gld phenotype, such as expansion of B220+ CD4- CD8- T cells, lymphadenopathy and hypergammaglobulinemia were comparable between TNF+/+ pfp-/- gld and TNF-/- pfp-/- gld mice, although the lymphoid organs of TNF+/+ pfp-/- gld mice contained greater numbers of B220+ CD4- CD8- T cells, macrophages and T cells. We conclude that TNF is necessary for the full manifestation of immune dysregulation caused by pfp/FasL-deficiency, in particular in the early and overwhelming tissue infiltration and destruction caused by inflammatory cells.
authors.affiliation: Cancer Immunology, Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Shayna E A
authors.initials: SE
authors.lastname: Street
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004716:Endometritis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology*; D007247:Infertility, Female / Q000209:etiology; D008136:Longevity; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D012488:Salpingitis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin