Impact of loss of NF-kappaB1, NF-kappaB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas mutant mice
- Author(s)
- Low, JT; Hughes, P; Lin, A; Siebenlist, U; Jain, R; Yaprianto, K; Gray, DH; Gerondakis, S; Strasser, A; O'Reilly, LA;
- Details
- Publication Year 2016-01,Volume 94,Issue #1,Page 66-78
- Journal Title
- Immunol Cell Biol
- Publication Type
- Journal Article
- 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 (Faslpr/lpr (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-kappaB (NF-kappaB) 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-kappaB family members NF-kappaB1, NF-kappaB2 and c-REL in the various autoimmune pathologies of Faslpr/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 Faslpr/lpr mice. Interestingly, compared with the Faslpr/lpr animals, Faslpr/lprnfkb2-/- mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Faslpr/lprnfkb1-/- mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-kappaB1. These findings demonstrate that different NF-kappaB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Faslpr/lpr mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.Immunology and Cell Biology advance online publication, 14 July 2015; doi:10.1038/icb.2015.66.
- Publisher
- NPG
- Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- 26084385
- Publisher's Version
- https://doi.org/10.1038/icb.2015.66
- NHMRC Grants
- NHMRC/637353, NHMRC/1090236, NHMRC/1020363, NHMRC/1046010, NHMRC/1009145, NHMRC/1049724,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-11-11 12:04:04
Last Modified: 2016-01-13 09:52:38