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Ewald, F.* ; Annemann, M.* ; Pils, M.C.* ; Plaza-Sirvent, C.* ; Neff, F. ; Erck, C.* ; Reinhold, D.* ; Schmitz, I.*

Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice.

Cell Death Dis. 5:e1168 (2014)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords C-flip ; Apoptosis ; Cd95 ; Autoimmunity; Regulatory T-cells; Flice-inhibitory Protein; Caspase-8 Activation; Multiple-sclerosis; Signaling Complex; Cellular-flip; Systemic Autoimmunity; Mediated Apoptosis; Up-regulation; Death
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Quellenangaben Volume: 5, Issue: 4, Pages: , Article Number: e1168 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed