Journal article

Loss of c-REL but not NF-kappa B2 prevents autoimmune disease driven by FasL mutation

LA O'Reilly, P Hughes, A Lin, P Waring, U Siebenlist, R Jain, DHD Gray, S Gerondakis, A Strasser

CELL DEATH AND DIFFERENTIATION | NATURE PUBLISHING GROUP | Published : 2015

Abstract

FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL(Δm/Δm)), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL(Δm/Δm) mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-κB-regulated cytokine levels, indicating that NF-κB-dependent inflammation may be a key pathological driver in this multifaceted autoimmune disease. We tested this hypothesis by genetically impairing canonical or non-canonical NF-κB signaling in FasL(Δm/Δm) mice by dele..

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Grants

Awarded by NHMRC (Canberra)


Awarded by Independent Research Institutes Infrastructure Support Scheme Grant


Awarded by Leukemia and Lymphoma Society (SCOR grant)


Awarded by JDRF/NHMRC


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Funding Acknowledgements

We thank G Siciliano, K Hughes, J Coughlin, K McKenzie and F Dabrowski, for animal care; J Corbin for automated blood analysis; B Helbert and C Young for genotyping; and E Tsui, V Babo, K Weston and all histology staff for preparation of histological sections. This work was supported by fellowships and grants from the NHMRC (Canberra; programs #461221 and #1016701, fellowship; (DG) #637353 and project grants #1009145 (LOR), #637332 (DG) and an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme Grant #361646, the Victorian State Government (OIS grant), the Leukemia and Lymphoma Society (SCOR grant #7413 and #7001-13) and the JDRF/NHMRC #466658 (AS). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (US).