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Stabilized ?-Catenin Ameliorates ALPS-Like Symptoms of B6/lpr Mice.

ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease mainly caused by the defect of Fas-mediated apoptosis and characterized by nonmalignant autoimmune lymphoproliferation. Stabilized ?-catenin could not only potentiate Fas-mediated T cell apoptosis via upregulating the expression of Fas on activated T cells, but also potentiate T cell apoptosis via intrinsic apoptotic pathway. In the present study, we introduced ?-catTg into lpr/lpr mice and aimed to explore the potential role of stabilized ?-catenin (?-catTg) in the development of ALPS-like phenotypes of lpr/lpr mice. We found that the total splenocyte cells and some compositions were slightly downregulated in ?-catTglpr/lpr mice, especially the CD4 and CD8 TEM cells were significantly reduced. Meanwhile, stabilized ?-catenin obviously decreased the numbers of spleen TCR?+CD4-CD8- T (DNT) cells, and the levels of some serum proinflammatory factors also were lowered in ?-catTglpr/lpr mice. Beyond that, stabilized ?-catenin slightly lowered the levels of the serum autoantibodies and the scores of kidney histopathology of ?-catTglpr/lpr mice compared with lpr/lpr mice. Our study suggested that stabilized ?-catenin ameliorated some ALPS-like symptoms of lpr/lpr mice by potentiating Fas-independent signal-mediated T cell apoptosis, which might uncover a potential novel therapeutic direction for ALPS.

SUBMITTER: Xu X

PROVIDER: S-EPMC5700472 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Stabilized β-Catenin Ameliorates ALPS-Like Symptoms of B6/lpr Mice.

Xu Xiaoxie X Huang Jun J Zhao Mei M Chen Huanpeng H Mo Jinhua J Zhou Xiaoqing X Su Qiao Q Yu Bolan B Huang Zhaofeng Z

Journal of immunology research 20171109

Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease mainly caused by the defect of Fas-mediated apoptosis and characterized by nonmalignant autoimmune lymphoproliferation. Stabilized β-catenin could not only potentiate Fas-mediated T cell apoptosis via upregulating the expression of Fas on activated T cells, but also potentiate T cell apoptosis via intrinsic apoptotic pathway. In the present study, we introduced β-catTg into lpr/lpr mice ...[more]

PMID: 29250557

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Project description:Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lpr and EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+ regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+ Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 in in vitro activated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+ double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.

Dataset Information

Stabilized ?-Catenin Ameliorates ALPS-Like Symptoms of B6/lpr Mice.

Publications

Stabilized <i>β</i>-Catenin Ameliorates ALPS-Like Symptoms of B6/<i>lpr</i> Mice.

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