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P55 and p75 tumor necrosis factor receptor double KO and systemic lupus erythematosis

ABSTRACT: Gene expresion comperison of p55/p75 double knock and it control B57B6 identified a number of inflammatory genes and cytokines genes play important roles in this study. TNFa has both pro-inflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in SLE-prone (NZB x NZW)F1 mice has been established, it remains uncertain whether this effect segregates at the individual TNF receptors (TNFR). We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNF receptor 1, in TNF receptor 2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4+ T lymphocytes, especially activated memory (CD44highCD62Llow) CD4+ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNF receptor alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNFa-mediated signaling was highly deleterious to the host in the NZM 2328 SLE model. These observations may have profound ramifications for the use of TNF- and TNF receptor-antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.

ORGANISM(S): Mus musculus

PROVIDER: GSE13855 | GEO | 2009/12/06

SECONDARY ACCESSION(S): PRJNA110537

REPOSITORIES: GEO

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CIP2A negatively regulates Th17 differentiation

Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.

2020-05-26 | PXD010612 | Pride

Tsirvouli2021 - Cytokine and eicosanoid signaling in psoriatic keratinocytes

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Expression data from murine Fancc-deficient hematopoietic stem and progenitor cells

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2012-05-22 | E-GEOD-30318 | biostudies-arrayexpress

Expression data from murine Fancc-deficient hematopoietic stem and progenitor cells

2012-05-23 | GSE30318 | GEO

B cell signature during inactive systemic lupus

Project description:Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomes of quiescent lupus patients to normal B cell transcriptomes. 17 patients with quiescent lupus (patient1-17) versus 9 controls (Control1-6,Control8-10).

2011-06-23 | E-GEOD-30153 | biostudies-arrayexpress

The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription

Project description:Aberrant expression of IL-17A together with abated IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while it promotes their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K and the activation of the mTORC1/HIF-1α/RORγt pathway and the generation of Th17 cells differentiation. Additionally, SIRT2 is responsible for the deacetylation of c-Jun and histones on the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, binds directly to the Sirt2 promoter and promotes its transcription. AK-7, a SIRT2 inhibitor limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis and disease in the lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated their ability to differentiate into Th17 cells and promoted IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential for the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new therapies for SLE.

2022-03-30 | GSE199496 | GEO

Cell intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses

Project description:Endosomal Toll-like receptors (TLRs) play an important role in the etiology of systemic autoimmune diseases such as SLE, where DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways, respectively. Nevertheless, TLR9-deficient autoimmune prone mice develop more severe clinical disease, while TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we have now directly compared the functional properties of autoantigen activated WT, TLR9-deficient and TLR7-deficient B cells, in an experimental system where proliferation depends on BCR/TLR co-engagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than either WT or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, and TLR7 to promote, the clinical features of SLE. AM14 WT, Tlr7-/-, Tlr9-/- and Tlr7/9-/- B cells were stimulated with PL2-3 for 0, 6, 24, and 42 hours, for a total of 16 samples.

2015-03-04 | E-GEOD-58756 | biostudies-arrayexpress

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| 2663054 | ecrin-mdr-crc

Cell intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses

2015-03-04 | GSE58756 | GEO

Gene Microarray analysis of Th17 cells

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2007-10-17 | GSE9316 | GEO

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