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Bcl-3 inhibits lupus-like phenotypes in BL6/lpr mice.
- Source :
-
European journal of immunology [Eur J Immunol] 2021 Jan; Vol. 51 (1), pp. 197-205. Date of Electronic Publication: 2020 Jul 29. - Publication Year :
- 2021
-
Abstract
- Bcl-3 is an atypical member of the IκB family that modulates NF-κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl-3 in this disease model, we generated BL6/lpr mice lacking Bcl-3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus- or ALPS-like phenotypes. Bcl-3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells - a hallmark of human lupus, ALPS, and MRL/lpr mice - and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl-3 specifically in T cells exacerbated select lupus-like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl-3 KO BL6/lpr mice may promote lupus-like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl-3. Contrary to the inhibitory functions of Bcl-3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context-dependent roles of Bcl-3 in the development of inflammation-associated pathology.<br /> (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)
- Subjects :
- Animals
Autoimmune Diseases genetics
Autoimmune Diseases immunology
Autoimmune Diseases prevention & control
B-Cell Lymphoma 3 Protein deficiency
B-Cell Lymphoma 3 Protein genetics
Disease Models, Animal
Female
Kidney immunology
Kidney pathology
Liver immunology
Liver pathology
Lung immunology
Lung pathology
Lupus Erythematosus, Systemic genetics
Lupus Erythematosus, Systemic immunology
Lymphocyte Subsets immunology
Lymphocyte Subsets pathology
Male
Mice
Mice, Inbred MRL lpr
Mice, Knockout
Phenotype
Splenomegaly genetics
Splenomegaly immunology
Splenomegaly prevention & control
Tumor Necrosis Factor-alpha immunology
B-Cell Lymphoma 3 Protein immunology
Lupus Erythematosus, Systemic prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 51
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 32652549
- Full Text :
- https://doi.org/10.1002/eji.202048584