Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice

• Published in: Immunology and cell biology 2016-01, Vol.94 (1), p.66-78
• Main Authors: Low, J T, Hughes, P, Lin, A, Siebenlist, U, Jain, R, Yaprianto, K, Gray, D H D, Gerondakis, S, Strasser, A, O'Reilly, L A
• Format: Article
• Language: English
• Subjects: AIRE Protein; Animals; Autoantibodies - blood; Chemokines - blood; Chemokines - metabolism; Dermatitis - blood; Dermatitis - complications; Dermatitis - immunology; fas Receptor - metabolism; Forkhead Transcription Factors - metabolism; Genotype; Hypergammaglobulinemia - blood; Hypergammaglobulinemia - complications; Immune Tolerance - immunology; Leukocytes - pathology; Longevity; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - complications; Lymphatic Diseases - blood; Lymphatic Diseases - complications; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; NF-kappa B p50 Subunit - deficiency; NF-kappa B p50 Subunit - metabolism; NF-kappa B p52 Subunit - deficiency; NF-kappa B p52 Subunit - metabolism; Organ Specificity; Proto-Oncogene Proteins c-rel - metabolism; Splenomegaly - blood; Transcription Factors - metabolism
• ISSN: 1440-1711
• DOI: 10.1038/icb.2015.66

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.