title: Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice.
abstract: Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr/lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-κB (NF-κB) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-κB family members NF-κB1, NF-κB2 and c-REL in the various autoimmune pathologies of Fas(lpr/lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr/lpr) mice. Interestingly, compared with the Fas(lpr/lpr) animals, Fas(lpr/lpr)nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr/lpr)nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-κB1. These findings demonstrate that different NF-κB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr/lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: J T
authors.initials: JT
authors.lastname: Low
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Parkville, 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, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.affiliation: Immune Activation Section, 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: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Jain
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Yaprianto
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: D H D
authors.initials: DH
authors.lastname: Gray
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Gerondakis
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D003872:Dermatitis / Q000097:blood / Q000150:complications / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005838:Genotype; D006942:Hypergammaglobulinemia / Q000097:blood / Q000150:complications; D007108:Immune Tolerance / Q000276:immunology; D007962:Leukocytes / Q000473:pathology; D008136:Longevity; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000150:complications*; D008206:Lymphatic Diseases / Q000097:blood / Q000150:complications*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000172:deficiency* / Q000378:metabolism; D009928:Organ Specificity; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D013163:Splenomegaly / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D001323:Autoantibodies; D018925:Chemokines; D051858:Forkhead Transcription Factors; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel; D014157:Transcription Factors; D019014:fas Receptor; D000096927:AIRE Protein; C491899:Fas protein, mouse; C498833:Foxp3 protein, mouse; C498207:Nfkb2 protein, mouse; C073701:Nfkb1 protein, mouse