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Loss\u2010of\u2010function mutations in the \u2018death receptor\u2019 FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus\u2010like autoimmune disease in mice (<jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup> (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL\/nuclear factor\u2010\u03baB (NF\u2010\u03baB) 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\u2010\u03baB family members NF\u2010\u03baB1, NF\u2010\u03baB2 and c\u2010REL in the various autoimmune pathologies of <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup> 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\u2010nuclear autoantibodies and autoantibodies against tissue\u2010specific antigens. Remarkably, only c\u2010REL deficiency substantially reduced immune complex\u2010mediated glomerulonephritis and extended the lifespan of <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup> mice. Interestingly, compared with the <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup> animals, <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup><jats:italic>nfkb2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup><jats:italic>nfkb1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibited the combined pathologies caused by defects in FAS\u2010mediated apoptosis and premature ageing due to loss of NF\u2010\u03baB1. These findings demonstrate that different NF\u2010\u03baB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in <jats:italic>Fas<\/jats:italic><jats:sup><jats:italic>lpr\/lpr<\/jats:italic><\/jats:sup> mice, and suggest that pharmacological targeting of c\u2010REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.<\/jats:p>","DOI":"10.1038\/icb.2015.66","type":"journal-article","created":{"date-parts":[[2015,6,18]],"date-time":"2015-06-18T08:21:54Z","timestamp":1434615714000},"page":"66-78","source":"Crossref","is-referenced-by-count":19,"title":["Impact of loss of NF\u2010\u03baB1, NF\u2010\u03baB2 or c\u2010REL on SLE\u2010like autoimmune disease and lymphadenopathy in <i>Fas<\/i><sup><i>lpr\/lpr<\/i><\/sup> mutant mice"],"prefix":"10.1111","volume":"94","author":[{"given":"J T","family":"Low","sequence":"first","affiliation":[{"name":"Molecular Genetics of Cancer 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