Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration
ABSTRACT Exposure of T cells to inflammatory cytokines leads to phosphorylation-dependent activation of signal transducer and activator of transcription (STAT) 3. T cells from patients with systemic lupus erythematosus (SLE) display increased levels of total and phosphorylated STAT3 which resides primarily in the nucleus. Increased STAT3 is associated with increased expression of target genes. Silencing of STAT3 expression using a small interfering RNA approach resulted in decreased chemokine-provoked SLE T cell migration. Our data suggest that inhibition of STAT3 expression may reverse the signaling aberrations involved in SLE T cell migration.
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ABSTRACT: Autologous hematopoietic stem cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to "reboot" the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify through a robust and unbiased transcriptomic analysis any changes of gene expression in T cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T cells of MS patients at 2 years post-transplantation aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T cell subsets at all time-points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data a number of significant changes in both the CD4+ and CD8+ T cells subsets from MS post-transplant. Notably, CD8+ T cells revealed more extensive changes in the expression of genes involved in effector immune responses.
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ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a multifaceted range of symptoms affecting almost every organ system. The prototypical pathology of SLE involves the production of antinuclear antibodies and the deposition of immune complexes in basement membranes throughout the body where they induce inflammatory responses. The genetic and environmental etiologies of this process are being intensively sought, and recently, T H 17 cells have been implicated in the pathogenesis of SLE. T H 17 cells are CD4+ memory T cells that behave as both helper and effector cell populations functioning through their signature IL-17 cytokines. Their differentiation is distinct to either the T H 1 or T H 2 cell lineage, but strongly influences development of adaptive responses, including autoimmunity. This paper details the biological functions and regulation of T H 17 cells, followed by an update of their expanding role in SLE.03/2011; 2011(2090-1984):810649. DOI:10.1155/2011/810649
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ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from a loss of tolerance to multiple self antigens, and characterized by autoantibody production and inflammatory cell infiltration in target organs, such as the kidneys and brain. T cells are critical players in SLE pathophysiology as they regulate B cell responses and also infiltrate target tissues, leading to tissue damage. Abnormal signaling events link to defective gene transcription and altered cytokine production, contributing to the aberrant phenotype of T cells in SLE. Study of signaling and gene transcription abnormalities in SLE T cells has led to the identification of novel targets for therapy.Arthritis research & therapy 03/2011; 13(2):207. DOI:10.1186/ar3251 · 4.12 Impact Factor