Kirou, K. A. et al. Activation of the interferon- pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 52, 1491-1503

Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, New York, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 05/2005; 52(5):1491-503. DOI: 10.1002/art.21031
Source: PubMed


Gene-expression studies have demonstrated increased expression of interferon (IFN)-inducible genes (IFIGs) in peripheral blood mononuclear cells (PBMCs) of many patients with systemic lupus erythematosus (SLE), with a predominant effect of type I IFN. This study examined the hypothesis that increased disease severity and activity, as well as distinct autoantibody specificities, characterize SLE patients with activation of the type I IFN pathway.
Freshly isolated PBMCs from 77 SLE patients, 22 disease controls, and 28 healthy donors were subjected to real-time polymerase chain reaction for 3 IFIGs that are preferentially induced by IFNalpha, and the data were used to derive IFNalpha scores for all individuals. Expression of IFIGs was significantly higher in SLE patients compared with disease controls or healthy donors. SLE patients with high and low IFNalpha scores were compared for clinical manifestations of disease, disease severity, disease activity, serologic features, and potential confounders, by bivariate and multivariate analyses.
SLE patients with a high IFNalpha score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did SLE patients with low IFNalpha scores. Patients with high scores showed increased disease activity, as measured by lower C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score. The presence of antibodies specific for Ro, U1 RNP, Sm, and dsDNA, but not phospholipids, was significantly associated with a high IFNalpha score. Logistic regression analysis confirmed that renal disease, higher SDI scores, low complement levels, and presence of anti-RNA binding protein (RBP) autoantibodies were associated with a high IFNalpha score.
Activation of the IFNalpha pathway defines a subgroup of SLE patients whose condition is characterized by increased disease severity, including renal disease, increased disease activity, reflected in complement activation, and autoreactivity to RBP.

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Available from: Kyriakos Kirou, Feb 06, 2015
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    • "All of these data indicate that estrogens may regulate TLR expressions and the activation of TLRmediated signaling pathways in B cells. As is well known, interferon-α (IFN-α) has been identified as a critical cytokine in the pathogenesis of SLE [25] [26]. IFN-α can induce and accelerate the SLE symptoms in patients and mice [27] [28]. "
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    ABSTRACT: The activation of IFN-α signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Many studies suggest that estrogens are closely related to the gender difference in the prevalence of SLE. However, the underlying mechanism of the interaction between estrogens and the activation of IFN-α signaling in SLE B cells remains incompletely understood. In the present study, we first found that healthy female mice showed an up-regulated type I IFN-induced gene signature in B cells compared with age-matched male mice, and in vivo study revealed that the gender difference was related to 17β-estradiol. Moreover, we found that 17β-estradiol could enhance the activation of IFN-α signaling in an ERα-dependent manner by down-regulating the expression of three microRNAs, including let-7e-5p, miR-98-5p and miR-145a-5p. These microRNAs could target the 3'UTR of the IKKε-encoding gene IKBKE directly and regulate the expression of IKKε, which can promote the activation of IFN-α signaling. In addition, compared with age-matched male mice, female mice showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p in B cells. Moreover, peripheral blood mononuclear cells from women showed a higher level of IKKε and lower levels of let-7e-5p, miR-98-5p and miR-145a-5p compared with those from age-matched men. These data suggest that 17β-estradiol amplifies the activation of IFN-α signaling in B cells via IKKε by down-regulating the expression of let-7e-5p, miR-98-5p and miR-145a-5p. Our findings may provide a new perspective for understanding the mechanism underlying the gender difference in the prevalence of SLE. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; 1852(8). DOI:10.1016/j.bbadis.2015.04.019 · 4.66 Impact Factor
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    • "We then performed quantitative RT-PCR to investigate the expression status of selected transcripting altered genes including PRF1, IFI44, IRF7, PLCL1, RASGRF2, SLC16A7, NLRP2, CD300LB and S1PR3 in a larger cohort of 40 samples (10 for each group). This analysis included genes, such as PRF1 and IFI44, for which increased expression in SLE has been described [24] [39]. Our analysis confirmed elevated and reduced levels of gene expression in our collection of SLE sample, consistent with the transcriptome-seq data (Fig. 3C). "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease well known for its clinical heterogeneity, and its etiology secondary to a cross-talk involving genetic predisposition and environmental stimuli. Although genome-wide analysis has contributed greatly to our understanding of the genetic basis of SLE, there is increasing evidence for a role of epigenetics. Indeed, recent data have demonstrated that in patients with SLE, there are striking alterations of DNA methylation, histone modifications, and deregulated microRNA expression, the sum of which contribute to over-expression of select autoimmune-related genes and loss of tolerance. To address this issue at the level of clinical phenotype, we performed DNA methylation, mRNA and microRNA expression screening using high-throughput sequencing of purified CD4+ T cells from patients with SLE, compared to age and sex matched controls. In particular, we studied 42 patients with SLE and divided this group into three clinical phenotypes: a) the presence of skin lesions without signs of systemic pathology; b) skin lesions but also chronic renal pathology; and c) skin lesions, chronic renal pathology and polyarticular disease. Interestingly, and as expected, sequencing data revealed changes in DNA methylation in SLE compared to controls. However, and more importantly, although there were common methylation changes found in all groups of SLE compared to controls, there was specific DNA methylation changes that correlated with clinical phenotype. These included changes in the novel key target genes NLRP2, CD300LB and S1PR3, as well as changes in the critical pathways, including the adherens junction and leukocyte transendothelial migration. We also noted that a significant proportion of genes undergoing DNA methylation changes were inversely correlated with gene expression and that miRNA screening revealed the existence of subsets with changes in expression. Integrated analysis of this data highlights specific sets of miRNAs controlled by DNA methylation, and genes that are altered by methylation and targeted by miRNAs. In conclusion, our findings suggest select epigenetic mechanisms that contribute to clinical phenotypes and further shed light on a new venue for basic SLE research.
    Journal of Autoimmunity 08/2014; 54. DOI:10.1016/j.jaut.2014.07.002 · 8.41 Impact Factor
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    • "A hallmark of systemic autoimmune diseases is the increased expression of interferon (IFN) type I in both blood and disease-affected tissues [2]. About half of the SLE patients exhibit an IFN type I signature or upregulation of IFN type I-induced genes (IFIGs), which have been found to correlate with disease activity and severity [3-5]. "
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    ABSTRACT: A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21 and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6+ memory T helper cells producing IL-17A, IL-17F, IL-21 and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature. In total, 25 SLE patients and 15 healthy controls (HC) were included. SLE patients were divided into IFN type I signature positive (IFN+) (n = 16) and negative (IFN-) (n = 9) patients as assessed by mRNA expression of IFN inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21 and IL-22 by CD4+CD45RO+CCR6+ T cells (CCR6+ cells) was measured by flow cytometry and compared between IFN+, IFN- patients and HC. Increased percentages of IL-17A and IL-17A/IL-17F double producing CCR6+ cells were observed in IFN+ patients compared with IFN- patients and HC. IL-17A and IL-17F expression within CCR6+ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B cell activating factor of the tumour necrosis family (BAFF) - a factor strongly correlating with IFN type I - and IL-21 producing CCR6+ cells. We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double producing CCR6+ memory T helper cells in IFN+ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis.
    Arthritis research & therapy 03/2014; 16(2):R62. DOI:10.1186/ar4499 · 3.75 Impact Factor
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