Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MKActivation of the interferon-alpha 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.
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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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    • "individuals [14e16]. This increased ISG expression also correlates with greater disease activity and particular autoantibody profiles and disease phenotypes in SLE patients [12]. Moreover, this upregulation of ISG expression may be useful in distinguishing between different autoimmune diseases and other febrile conditions [17]. "
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    ABSTRACT: Background Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. Objectives In this study we examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Methods Peripheral blood was collected and run on 208 Illumina HumanHT-12 V4 expression BeadChip arrays. Subjects included 21 African-American (AA) and 21 European-American (EA) SLE patients, 5 AA and 5 EA controls. CD4+ T-cells, CD8+ T-cells, monocytes and B cells were purified by flow sorting. Each cell subset from each subject was run on a separate array. Differentially expressed genes (DEGs) were determined by comparing cases and controls of the same ancestral background. Results The overlap in DEG lists between different cell types from the same ancestral background was very modest (<1%). Typically between 5-10% of DEGs were shared when comparing the same cell type between different ancestral backgrounds. Global IFN-stimulated gene (ISG) expression revealed that AA subjects demonstrated more concordance across all studied cell types. Two subgroups of patients were identified based on the ISG expression profiles. One subgroup showed higher ISGs expression in all cell types, and the other subgroup had higher ISG expression only in T and B lymphocytes but not in monocytes. Conclusions We find striking differences in gene expression between different immune cell subsets and between ancestral backgrounds in SLE patients. The IFN signature is diverse, with different transcripts represented in different cell populations, and signature-positive cell subsets differed in EA vs. AA patients. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5291
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