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JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation.

ABSTRACT: We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naïve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE.

ORGANISM(S): Mus musculus

PROVIDER: GSE78825 | GEO | 2016/03/03

SECONDARY ACCESSION(S): PRJNA314071

REPOSITORIES: GEO

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JAK inhibitor ameliorate autoimmunity and nephritis in lupus prone mice

Project description:We previously reported that JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from SLE patients. Recently pan-JAK inhibitor (JAKi) tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE. Anti-dsDNA antibody and proteinuria were decreased and glomerulo/interstitial nephritis were ameliorated in any TOFA administered SLE mice. In splenic CD4+ T cell analysis, naÃ¯ve cells significantly increased and effector/memory cells decreased. TOFA with dexamethasone (DEXA) therapy showed tendency to indicate stronger inhibitory effect comparing with TOFA or DEXA monotherapy. The gene expression of Ifit3/IFIT3 that related with anti-viral IFN signaling pathway was significantly suppressed in both CD4+ from SLE mice and CD3+ T cells from SLE patients after treatment. Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE. The gene expression analysis was compared among tofacitinib, tofacitinib+dexamethsone, dexamethsone and non-treated control groups and extracted TOFA specific decreased genes in NZBWF1 mice.

2016-03-03 | E-GEOD-78825 | biostudies-arrayexpress

Global gene expression profiles in whole blood total RNA from patients with lupus nephritis, before and after initiation of therapy

Project description:Patients with systemic lupus erythematosus are characterized by the spontaneous over-expression of interferon(IFN)-induced genes in peripheral blood RNA samples. In the present study, we wanted to study the evolution of the IFN gene signature in the peripheral blood of patients with lupus nephritis, before and after initiation of immunosuppressive therapy. Strikingly, we found that immunosuppressive therapy did not strongly reduce the expression of IFN-induced genes in patients who responded to therapy, as indicated by decreased general and renal indices of disease activity. By contrast, the IFN gene signature decreased in patients developing renal failure. Global gene expression studies were performed in serial whole blood samples from SLE patients with a renal BILAG A prior to, 3 months, and 6 months after initiation of conventional immunosuppressive therapy (induction with high-dose corticosteroids, IV cyclophosphamide or oral mycophenolate during the first 3 months, followed by maintenance with moderate- to low-dose corticosteroids, azathioprine or mycophenolate). The expression of IFN-induced genes was analyzed, in comparison to global and renal indices of disease activity.

2016-02-29 | E-GEOD-72747 | biostudies-arrayexpress

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Project description:To screen the differentially expressed lncRNAs, we performed lncRNA profiling using ArrayStar Human LncRNA Microarray in 24 new-onset systemic lupus erythematosus (SLE) patients and 12 age- and sex-matched healthy controls (HCs). For the lncRNA microarray screening, total RNA from plasma was isolated from 12 SLE without nephritis, 12 lupus nephritis (LN) and 12 HCs. Four RNA samples were mixed togther as a pool of sample for microarray analysis. Accordingly, there were each three pooled RNA samples from 12 SLE without nephritis, 12 LN and 12 HCs for microarray analysis. Hierarchical clustering showed the plasma levels of lncRNAs and mRNAs differed significantly between 24 new-onset SLE patients and 12 control subjects. With a fold change ≥ 2 and P ≤ 0.05, we identified 1315 significantly differentially expressed lncRNAs (743 lncRNAs up-regulated and 572 lncRNAs down-regulated) and 1363 differentially expressed mRNAs (745 mRNAs up-regulated and 618 mRNAs down-regulated) in plasma of SLE patients compared with control samples.

2017-08-12 | GSE102547 | GEO

RNA-seq of murine mesenchymal stem cells during differentiation to osteoblasts, treated with tofacitinib or baricitinib against vehicle control

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2020-02-12 | E-MTAB-8536 | biostudies-arrayexpress

Interactions of cytokines in peripheral blood cells from Systemic Lupus Erythematosus

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2009-05-31 | E-GEOD-12374 | biostudies-arrayexpress

Expression data from lupus NZB/W and NZW/BXSB mouse prenephritic kidneys

Project description:We defined the shared and unique features of systemic lupus erythematosus (SLE) nephritis in 2 mouse models of proliferative renal disease. We identified shared inflammatory mechanisms of SLE nephritis that can be therapeutically targeted. Some common mechanisms are shared with non-immune-mediated renal diseases, suggesting that new strategies to prevent tissue hypoxia and remodeling may be useful in SLE nephritis.

2014-12-31 | GSE44691 | GEO

Janus kinase-Inhibition modulates hepatitis E virus infection

Project description:Background: Human hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication in vivo and in authentic cell culture models ex vivo. Methods: We evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E and HEV infections in a cohort of AIRD patients. Experiments with HEV were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Results: Acute hepatitis was observed in a patient with AIRD and concomitant HEV infection. No acute infection could be detected in the AIRD cohort. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. This induction was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. Conclusion: Therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, clinical monitoring of HEV infection during JAKi treatment and in case of elevated liver enzymes should be considered.

2023-02-09 | GSE224795 | GEO

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Project description:The establishment of an interferon (IFN) signature to subset SLE patients on disease severity has led to therapeutics targeting IFNa. Here, we investigate IFN signaling in SLE by first determining the IFN signature for SLE patients (n=81) from the Stanford Lupus Registry using fluidigm qPCR. We measured 44 previously determined IFN-inducible transcripts to subset patients as IFN-high (IFN-H) or IFN-low (IFN-L).

2022-02-23 | GSE193174 | GEO

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

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2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress

Activation of the Interferon Pathway is Dependent upon Autoantibodies in African-American SLE Patients, but not in European-American SLE Patients

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2013-11-15 | E-GEOD-50635 | biostudies-arrayexpress

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