Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus

Bauer, JW; Baechler, Emily C.; Petri, Michelle; Batliwalla, Franak; Crawford, Dianna; Ortmann, Ward; Espe, Karl J.; Li, Wentian; Patel, Dhavalkumar D.; Gregersen, Peter K.; Behrens, Timothy W.

doi:10.1371/journal.pmed.0030491

Cited by 276 publications

(280 citation statements)

References 46 publications

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“…It has been reported through a survey of the serologic proteome in human SLE that a set of IFNregulated inflammatory chemokines had highly coordinated upregulation and their levels correlated strongly with clinical and laboratory measures of disease activity, thus, may function as biomarkers for active human SLE. 55 In this study, the complex interactions of cytokines and chemokines underlying IFN-a treatment were suggested. Of a panel of chemokines and cytokines overexpressed in NZB/W mice after IFN-a treatment in vitro, the disparity in the basal and stimulated level of CXCL10 compared to the other two strains was striking.…”

Section: Discussionmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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Section: Discussionmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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“…Comprehensive profiling of gene expression in peripheral blood mononuclear cells (PBMCs) and protein expression in sera from patients has consistently shown the upregulation of IFN-inducible genes in SLE compared with normal controls. 10,11,13,[49][50][51][52] IFN signature in PBMCs Baechler et al 10 studied gene expression microarray profiles in 48 SLE patients and 42 controls to identify pathways that might be dysregulated in PBMCs of SLE patients. Several immune-related genes were up-regulated in the SLE patients including Fc receptor for IgA (FCAR, CD89), Fc receptor for IgG such as FcgRIIA (CD32) and FcgRI (CD64), TNFRSF6 (Fas/CD95), and three molecules in the inflammatory IL-1 cytokine pathway: IL-1b, IL-1 receptor II (IL-1RII) and IL-1 receptor antagonist.…”

Section: Expression Profiling Of Ifn-responsive Genes In Slementioning

confidence: 99%

“…Inspired by the transcriptome analyses, Bauer et al 13 examined the levels of 160 serum proteins in 15 IFNhigh, 15 IFN-low SLE patients and 15 healthy controls using a high-throughput protein microarray technology, Luminex. Luminex assays are based on custom dualantibody sandwich immunoassay arrays using xMAP technology (multi-analyte profiling beads) enabling the detection and quantification of multiple protein targets simultaneously.…”

Section: Ifn Signature In Serum Proteinmentioning

confidence: 99%

“…[10][11][12] Furthermore, protein microarray experiments revealed IFN-inducible protein expression profile in serum from SLE patients. 13 High-throughput SNP typing platforms such as Illumina (Illumina Inc., San Diego, CA, USA) and Sequenom (Sequenom Inc., San Diego, CA, USA) enabled us to carry out B0.5 million genotypes a day with high fidelity. Together with a great effort in the recruitment of DNA samples from patients and controls, an increasing number of large-scale genetic association studies are being carried out.…”

Section: Introduction/historical Perspectivementioning

confidence: 99%

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A compass that points to lupus: genetic studies on type I interferon pathway

Kyogoku

Tsuchiya

2007

Genes Immun

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It was more than 20 years ago that patients with systemic lupus erythematosus (SLE) were first reported to display elevated serum levels of type I interferon (IFN). Since then, extensive studies revealed a crucial role for type I IFN in SLE pathogenesis. The current model proposes that small increase of type I IFN production by plasmacytoid dendritic cells (pDCs) is sufficient to induce unabated activation of immature peripheral DCs. IFN-matured DCs select and activate autoreactive T cells and B cells, rather than deleting them, resulting in peripheral tolerance breakdown, a characteristic feature of SLE. Furthermore, immune complexes provide an amplification loop to pDCs for further IFN production. In the past 5 years, high-throughput technologies such as expression profiling and single-nucleotide polymorphism (SNP) typing established the role of altered type I IFN system in SLE, and a detailed picture of its molecular mechanisms is beginning to emerge. In this review, we discuss two major lines of genetics studies on type I IFN pathway related to human SLE: (1) expression profiling of IFN-responsive genes and (2) disease-associated SNPs of IFN-related genes, especially IRF5 (IFN-regulatory factor 5). Lastly, we discuss how such genetic alterations in type I IFN pathway fit in the current model of SLE pathogenesis.

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“…Similarly, Fu et al [61] and Bauer et al [62] also identified chemokines and cytokines whose gene expression was different in SLE than in healthy controls. Where available we should include antibodies to these proteins if they are cell-membranebound or to their receptors in our cell-capture array.…”

Section: Other Markersmentioning

confidence: 84%

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

Lin

Adelstein

et al. 2010

Proteomics Clinical Apps

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease that has heterogeneous clinical manifestation with diverse patterns of organ involvement, autoantibody profiles and varying degrees of severity of disease. Research and clinical experience indicate that different subtypes of SLE patients will likely benefit from more tailored treatment regimes, but we currently lack a fast and objective test with high enough sensitivity to enable us to perform such sub‐grouping for clinical use. In this article, we review how proteomic technologies could be used as such an objective test. In particular, we extensively review many leukocyte surface markers that are known to have an association with the pathogenesis of SLE, and we discuss how these markers can be used in the further development of a novel SLE‐specific antibody leukocyte capture microarray. In addition, we review some bioinformatics challenges and current methods for using the data generated by these cell‐capture microarrays in clinical use. In a broader context, we hope our experience in developing a disease specific cell‐capture microarray for clinical application can be a guide to other proteomic practitioners who intend to extend their technologies to develop clinical diagnostic and prognostic tests for complex diseases.

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Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus

Cited by 276 publications

References 46 publications

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

A compass that points to lupus: genetic studies on type I interferon pathway

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

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