Prominent Renal Expression of a Murine Leukemia Retrovirus in Experimental Systemic Lupus Erythematosus

Alexander, Jessy J.; Saxena, Amit; Bao, Lihua; Haas, Mark; Quigg, Richard J.

doi:10.1097/01.asn.0000036868.73317.7a

Cited by 17 publications

(7 citation statements)

References 46 publications

(40 reference statements)

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“…Some of these have used animal models, such as for alopecia areata [7] and experimental systemic lupus erythematosus (SLE) [10]. In human autoimmunity, biopsy samples from tissues such as rheumatoid synovium [6,9] and skin [7] have yielded disease insights.…”

Section: Approach To the Study Of Autoimmune Diseasementioning

confidence: 99%

Untitled

2004

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120 IDDM = insulin-dependent diabetes mellitus; IFN = interferon; IL = interleukin; MS = multiple sclerosis; PCR = polymerase chain reaction; PBMC = peripheral blood mononuclear cell; RA = rheumatoid arthritis; SDA = Symbolic discriminant analysis; SLE = systemic lupus erythematosus; SLEDAI = SLE disease activity index. Arthritis Research & TherapyVol 6 No 3 Olsen et al. IntroductionThe relatively new technology of DNA microarrays has made it feasible to measure the expression levels of thousands of genes in small biological samples [1]. It has been suggested that this methodology might be especially useful in analyzing the complex and parallel changes that occur within cells and tissues of the immune system in normal and pathologic states [2]. Much of the early work using DNA microarrays was in the field of oncology; other studies have examined host responses to infectious agents or drugs [3]. The gene array approach is especially wellsuited to the type of multifactorial analysis that is needed to unravel the causes of human autoimmune disorders that involve both complex genetics and environmental factors [4,5]. Studies in autoimmune disease have included the use of biopsy samples from affected patients, targeting tissues such as synovium, brain or skin [6][7][8][9]. While this approach can offer insights for some disease subsets, it does not permit study of all afflicted patients and cannot be applied to early phases of disease when therapeutic interventions are most likely to be useful. As an alternative, we and others have hypothesized that due to the systemic nature of autoimmune disease, clinically relevant changes in gene expression should be observed in peripheral blood mononuclear cells (PBMCs). Using peripheral blood as the source of gene expression material offers the possibility of sampling any individual at any time and also has the potential to detect early pathogenetic and prognostic factors. This review will examine studies in autoimmune disease, focusing on the utility of peripheral blood samples to identify genes of interest. The potential for this approach to provide insights into disease pathogenesis and to aid with diagnosis and management are also discussed. Approach to the study of autoimmune diseaseA relatively small number of microarray studies in autoimmunity have been reported [3]. Some of these have AbstractThe relatively new technology of DNA microarrays offers the possibility to probe the human genome for clues to the pathogenesis and treatment of human disease. While early studies using this approach were largely in oncology, many new reports are emerging in other fields including infectious diseases and pharmacology, and applications in autoimmunity have been recently reported by our group and others. Some of these investigations have examined animal models of autoimmune disease, but a number of human studies have also been carried out. Of special interest are those that have used peripheral blood samples because, unlike tissue biopsies, these are readily available from all subje...

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Section: Approach To the Study Of Autoimmune Diseasementioning

confidence: 99%

Untitled

2004

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“…Nevertheless, much remains unknown about the pathogenesis of SLE, particularly at the level of nucleic acid accumulation and dysregulated gene expression. Dysregulated gene expression, with the accumulation of aberrant transcripts, could theoretically contribute to apoptosis or increased type I interferon expression and has been shown to mimic lupus [4], [5], [6], [7], [8], [9].…”

Section: Introductionmentioning

confidence: 99%

The SLE Transcriptome Exhibits Evidence of Chronic Endotoxin Exposure and Has Widespread Dysregulation of Non-Coding and Coding RNAs

et al. 2014

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BackgroundGene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutières syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE.MethodsPurified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA.ResultsWe found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients.ConclusionsMonocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism.

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“…21), a highly heterogeneous group in whom clinical manifestations vary widely. In the only reported study carried out using (NZB ϫ NZW)F 1 mice, nephritic kidneys of these mice were compared with kidneys of healthy NZW controls (22). Because SLE is a systemic autoimmune disease, we were interested in the gene expression profile of immune cells, and our analyses of the SLE-prone mouse model were therefore carried out in spleens.…”

Section: Elmann Et Almentioning

confidence: 99%

“…In the only reported such study in (NZB ϫ NZW)F 1 mice, widely used as a model of SLE, the gene profile of nephritic (NZB ϫ NZW)F 1 mouse kidneys was compared with that in kidneys of nondiseased NZW control mice (22). The most highly up-regulated gene (EDV; 5.5-fold) in the kidneys (but not in the spleens) of diseased mice corresponded to an endogenous retrovirus related to the Duplan strain (EDV, L08395).…”

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confidence: 99%

Altered gene expression in mice with lupus treated with edratide, a peptide that ameliorates the disease manifestations

Elmann¹,

Sharabi²,

Dayan³

et al. 2007

Arthritis & Rheumatism

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Objective. To identify genes that are differently expressed in (NZB ؋ NZW)F 1 mice with established lupus compared with healthy controls, and to determine how gene expression is affected by treatment with hCDR1 (Edratide), a peptide synthesized on the basis of the sequence of the first complementarity-determining region (CDR1) of an autoantibody.Methods. RNA was extracted from spleen cells of young, disease-free mice and of older mice with systemic lupus erythematosus (SLE) that were treated with hCDR1 or with vehicle alone. Gene expression was assessed using the DNA microarray technique and verified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).Results. In mice with SLE, numerous genes showed increased or decreased expression relative to that in the disease-free controls. Treatment with hCDR1 restored the expression of many of these genes to control levels. Real-time RT-PCR verified that in diseased mice RNA transcripts of Tnfsf4, Il5ra, Zbtb20, and Nid1 were up-regulated, while transcripts of Tfpi and S100a8 were down-regulated, and confirmed the effects of hCDR1 on the expression of those genes. Kidney immunostaining demonstrated that the up-regulated expression of OX40 ligand, which is a protein product of the gene tumor necrosis factor (ligand) superfamily member 4, in diseased mice was reduced by hCDR1. Conclusion. Expression of numerous genes inmice with SLE differs from that in young, disease-free control mice. Treatment with hCDR1 restores the expression of 22% of these genes to levels similar to those in controls. Thus, one of the mechanisms by which hCDR1 exerts its beneficial effects on the clinical symptoms of SLE is through regulation of gene expression.

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Prominent Renal Expression of a Murine Leukemia Retrovirus in Experimental Systemic Lupus Erythematosus

Cited by 17 publications

References 46 publications

Untitled

Untitled

The SLE Transcriptome Exhibits Evidence of Chronic Endotoxin Exposure and Has Widespread Dysregulation of Non-Coding and Coding RNAs

Altered gene expression in mice with lupus treated with edratide, a peptide that ameliorates the disease manifestations

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