Article: article from journal or magazin.
Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.
Cell Death and Differentiation
The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.
Animals, Apoptosis/physiology, Autoantibodies/metabolism, B-Lymphocytes/immunology, CASP8 and FADD-Like Apoptosis Regulating Protein/genetics, CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism, Cell Proliferation, Cytokines/metabolism, Dendritic Cells/immunology, Humans, Lupus Erythematosus, Systemic/immunology, Lupus Erythematosus, Systemic/pathology, Lymphocyte Activation, Mice, Mice, Inbred BALB C/immunology, Mice, Inbred C57BL/immunology, Mice, Transgenic, Phenotype, T-Lymphocyte Subsets/cytology, T-Lymphocyte Subsets/immunology, T-Lymphocytes/cytology, T-Lymphocytes/immunology, Thymus Gland/cytology, Thymus Gland/immunology, Transgenes, ZAP-70 Protein-Tyrosine Kinase/metabolism
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