title: Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation.
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 deleting the c-Rel or NF-κB2 genes, respectively. Although the loss of NF-κB2 reduced the levels of inflammatory cytokines and autoantibodies, the impact on animal survival was minor due to substantially accelerated and exacerbated lymphoproliferative disease. In contrast, a marked increase in lifespan resulting from the loss of c-REL coincided with a striking reduction in classical parameters of autoimmune pathology, including the levels of cytokines and antinuclear autoantibodies. Notably, the decrease in regulatory T-cell numbers associated with loss of c-REL did not exacerbate autoimmunity in FasL(Δm/Δm)c-rel(-/-) mice. These findings indicate that selective inhibition of c-REL may be an attractive strategy for the treatment of autoimmune pathologies driven by defects in FASL/FAS signaling that would be expected to circumvent many of the complications caused by pan-NF-κB inhibition.
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia [2] Department of Nephrology, The Royal Melbourne Hospital, Parkville 3052, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Hughes
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville 3010 Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Waring
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
authors.forename: U
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Jain
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: D H D
authors.initials: DH
authors.lastname: Gray
authors.affiliation: Australian Centre for Blood Diseases and Department of Clinical Hematology, Monash University Central Clinical School, Melbourne 3004, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Gerondakis
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D019014:fas Receptor