Double negative (DN) T cells are expanded in patients with systemic lupus erythematosus (SLE) and stimulate autoantibody production as efficiently as CD4+ T cells. In this study, we demonstrate that DN T cells from patients with SLE produce significant amounts of IL-17 and IFN-γ, and expand when stimulated in vitro with an anti-CD3 Ab in the presence of accessory cells. Furthermore, IL-17+ and DN T cells are found in kidney biopsies of patients with lupus nephritis. Our findings establish that DN T cells produce the inflammatory cytokines IL-17 and IFN-γ, and suggest that they contribute to the pathogenesis of kidney damage in patients with SLE.
A family of interferon (IFN) regulatory factors (IRFs) The virus-induced expression of interferon (IFN) genes in infected cells involves interplay of several constitutively expressed and virus-activated transcriptional factors (1). Two of these factors binding to the virus-inducible element of the IFN-3 gene have been proposed to play a crucial role in the regulation of expression of IFN-a and IFN-,3 genes. Interferon regulatory factor 1 (IRF-1) was shown to act as an activator, and the closely related IRF-2 was a repressor (2). It was proposed that induction of the IFN-,3 gene was the result of the removal of repressor IRF-2 and the subsequent binding of the activator IRF-1 (3). Several observations supported this model. Expression of IRF-1 was found to be upregulated in virus-infected cells. The IRF-1 binding sites were identified in the IFN-3 gene promoter region and reporter plasmids with multiple repeats of the AAGTGA hexanucleotides (which are the strong IRF-1 binding site) were inducible by overexpression of IRF-1. This transactivation could be repressed by (2). In embryonal carcinoma cells, overexpression of IRF-1 induced both the transfected and the endogenous IFN-a and -,B genes (4). Moreover, a decrease in IFN-,B induction was observed in cells expressing the IRF-1 antisense mRNA (5).
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system, and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal, and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review novel information that deals with 1) genes associated with disease expression, 2) immune cell molecular abnormalities that lead to autoimmune pathology, 3) the role of hormones and sex chromosomes in the development of disease, 4) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we emphasize molecular defects intimately associated with the disease process of SLE that represent ideal therapeutic targets and disease biomarkers.
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the −180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the −180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the −180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.
Systemic lupus erythematosus (SLE) is an autoimmune/inflammatory disease characterized by autoantibody production and abnormal T cells that infiltrate tissues through not well-known mechanisms. We report that SLE T lymphocytes display increased levels of CD44, ezrin, radixin, and moesin (ERM) phosphorylation, stronger actin polymerization, higher polar cap formation, and enhanced adhesion and chemotactic migration compared with T cells from patients with rheumatoid arthritis and normal individuals. Silencing of CD44 by CD44 small interfering RNA in SLE T cells inhibited significantly their ability to adhere and migrate as did treatment with Rho kinase and actin polymerization inhibitors. Forced expression of T567D-ezrin, a phosphorylation-mimic form, enhanced remarkably the adhesion and migration rate of normal T cells. Anti-CD3/TCR autoantibodies present in SLE sera caused increased ERM phosphorylation, adhesion, and migration in normal T cells. pERM and CD44 are highly expressed in T cells infiltrating in the kidneys of patients with lupus nephritis. These data prove that increased ERM phosphorylation represents a key molecular abnormality that guides T cell adhesion and migration in SLE patients.
Background: Expression levels of both IL-17A and transcription factor CREM␣ are increased in T cells from SLE patients. Results: In primary human T cells, CREM␣ binds to the proximal IL17A promoter and induces IL-17A expression by transcriptional activation and epigenetic modifications. Conclusion: CREM␣ promotes IL-17A expression. Significance: Suppression of CREM␣ expression should mitigate IL-17A-driven inflammatory responses.
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