Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice.
Death receptor-mediated apoptosis is a key mechanism for the control of immune responses and dysregulation of this pathway may lead to autoimmunity. Cellular FLICE-inhibitory proteins (c-FLIPs) are known as inhibitors of death receptor-mediated apoptosis. The only short murine c-FLIP splice variant is c-FLIPRaji (c-FLIPR). To investigate the functional role of c-FLIPR in the immune system, we used the vavFLIPR mouse model constitutively expressing murine c-FLIPR in all hematopoietic compartments. Lymphocytes from these mice are protected against CD95-mediated apoptosis and activation-induced cell death. Young vavFLIPR mice display normal lymphocyte compartments, but the lymphocyte populations alter with age. We identified reduced levels of T cells and slightly higher levels of B cells in 1-year-old vavFLIPR mice compared with wild-type (WT) littermates. Moreover, both B and T cells from aged vavFLIPR animals show activated phenotypes. Sera from 1-year-old WT and transgenic animals were analysed for anti-nuclear antibodies. Notably, elevated titres of these autoantibodies were detected in vavFLIPR sera. Furthermore, tissue damage in kidneys and lungs from aged vavFLIPR animals was observed, indicating that vavFLIPR mice develop a systemic lupus erythematosus-like phenotype with age. Taken together, these data suggest that c-FLIPR is an important modulator of apoptosis and enforced expression leads to autoimmunity.
1] Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, Magdeburg, Germany [2] Research Group of Systems-Oriented Immunology and Inflammation Research, Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Ewald
1] Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, Magdeburg, Germany [2] Research Group of Systems-Oriented Immunology and Inflammation Research, Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Annemann
Mouse Pathology, Animal Experimental Unit, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Pils
1] Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, Magdeburg, Germany [2] Research Group of Systems-Oriented Immunology and Inflammation Research, Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Plaza-Sirvent
Institute of Pathology, Helmholtz Centre Munich, Ingolstaedter Landstr. 1, Neuherberg, Germany.
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Neff
Cellular Proteome Research, Department of Structure and Function of Proteins, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Erck
Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, Magdeburg, Germany.
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Reinhold
1] Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, Magdeburg, Germany [2] Research Group of Systems-Oriented Immunology and Inflammation Research, Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, Germany.
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Schmitz
D000375:Aging / Q000473:pathology*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010641:Phenotype; D013601:T-Lymphocytes / Q000473:pathology
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein