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Down-regulation of Interferon signature in systemic lupus erythematosus patients by active immunization with Interferon alpha-Kinoid

ABSTRACT: We performed a phase I/II, randomized, double-blind, placebo-controlled dose-escalation study to examine the safety, immunogenicity, and biological effects of active immunization with interferon alpha-Kinoid (IFN-K) in systemic lupus erythematosus (SLE) patients. Women 18-50 years of age with mild to moderate SLE were immunized with three (n=10) or four doses (n=9) of 30, 60, 120, 240 microgram IFN-K or saline. Anti-IFNalpha antibodies were detected in all IFN-K-immunized patients. Transcriptomic analysis separated patients at baseline into type I IFN signature-positive and -negative groups. IFN-K induced higher anti-IFNalpha titers in signature-positive than in signature-negative patients and, in signature-positive patients, reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFNalpha antibody titers, and with baseline IFN score.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39088 | GEO | 2012/11/01

SECONDARY ACCESSION(S): PRJNA170074

REPOSITORIES: GEO

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Down-regulation of Interferon signature in systemic lupus erythematosus patients by active immunization with Interferon alpha-Kinoid

Project description:We performed a phase I/II, randomized, double-blind, placebo-controlled dose-escalation study to examine the safety, immunogenicity, and biological effects of active immunization with interferon alpha-Kinoid (IFN-K) in systemic lupus erythematosus (SLE) patients. Women 18-50 years of age with mild to moderate SLE were immunized with three (n=10) or four doses (n=9) of 30, 60, 120, 240 microgram IFN-K or saline. Anti-IFNalpha antibodies were detected in all IFN-K-immunized patients. Transcriptomic analysis separated patients at baseline into type I IFN signature-positive and -negative groups. IFN-K induced higher anti-IFNalpha titers in signature-positive than in signature-negative patients and, in signature-positive patients, reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFNalpha antibody titers, and with baseline IFN score. IFN-K or placebo was administered at day 0, day 7, day 28 in all patients. Half the subjects received a fourth injection at day 84 (see treatment protocol)

2012-11-01 | E-GEOD-39088 | biostudies-arrayexpress

Down-regulation of Interferon signature in systemic lupus erythematosus patients by active immunization with Interferon alpha-Kinoid extended follow-up

Project description:Interferon-alpha Kinoid (IFN-K) is a therapeutic vaccine composed of IFN-alpha2b coupled to a carrier protein. In a phase I/II placebo-controlled trial, we observed that IFN-K significantly decreases the IFN gene signature in whole blood RNA samples from SLE patients (see GSE39088). Here, we analyzed extended follow-up data from IFN-K-treated patients, in terms of persistence of neutralizing anti-IFNÂ± Abs, gene expression profiling and safety. Follow-up analyses in six patients confirmed a significant correlation between neutralizing anti-IFNalpha Ab titers and decrease in IFN scores compared to baseline. These analyses also revealed an inhibitory effect of IFNÂ± blockade on the expression of B cell associated transcripts. Extended clinical (SLEDAI, BILAG, Physician Global Assessment) and biological (binding and neutralizing anti-IFNalpha Ab titers, C3 concentrations and anti double-stranded (ds)DNA Ab titers) follow-up data were collected in 6 IFN-K-treated patients. In these patients, whole blood samples were collected in PAXgene Blood RNA tubes (Qiagen) every 6 months after completion of the initial study. RNA was extracted from these samples, and was also re-extracted from baseline (month 0) and day 168 (month 6) PAXgene tubes stored at -80Â° from the same patients, and from 10 healthy volunteers.

2016-02-29 | E-GEOD-72754 | biostudies-arrayexpress

Down-regulation of Interferon signature in systemic lupus erythematosus patients by active immunization with Interferon alpha-Kinoid extended follow-up

2016-02-29 | GSE72754 | GEO

Transcriptomic profiling of interferon signature in Systemic Lupus Erythematosus

Project description:The establishment of an interferon (IFN) signature to subset SLE patients on disease severity has led to therapeutics targeting IFNa. Here, we investigate IFN signaling in SLE by first determining the IFN signature for SLE patients (n=81) from the Stanford Lupus Registry using fluidigm qPCR. We measured 44 previously determined IFN-inducible transcripts to subset patients as IFN-high (IFN-H) or IFN-low (IFN-L).

2022-02-23 | GSE193174 | GEO

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent.

Project description:Most systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.

2020-04-13 | GSE148535 | GEO

Modular repertoire analyses identify dynamic type I and type II interferon transcriptional signatures in adult SLE patients

Project description:Gene expression profiling (compared to healthy controls) to identify patients with active SLE disease and patients with quiescent disease 157 “SLE” and 20 “Healthy controls of SLE were followed up for up to 3 years. Clinical assessment, current treatment, laboratory results and SLEDAI score were collected at each visit (V1, V2...). SLE patients are compared to control groups.

2014-04-01 | E-GEOD-49454 | biostudies-arrayexpress

Expression data from purified human platelets

Project description:Patients with systemic lupus erythematosus (SLE) have a markedly increased risk to develop cardiovascular disease, and traditional cardiovascular risk factors fail to account for this increased risk. We used microarray to probe the platelet transcriptome in individuals with SLE and healthy controls, and the gene and protein expression of a subset of differentially expressed genes was further investigated and correlated to platelet activation status. Real-time PCR was used to confirm a type I interferon (IFN) gene signature in patients with SLE, and the IFN-regulated proteins PRKRA, IFITM1 and CD69 (p<0.0001) were found to be up-regulated in platelets from SLE patients as compared to healthy volunteers. Notably, patients with a history of vascular disease had increased expression of type I IFN-regulated proteins as well as more activated platelets as compared with patients without vascular disease. We suggest that interferogenic immune complexes stimulate production of IFNα which up-regulates the megakaryocytic type I IFN-regulated genes and proteins. This could affect platelet activation and contribute to development of vascular disease in SLE. In addition, platelets with type I IFN signature could be a novel marker for vascular disease in SLE. Platelets were purified from SLE patients (n=10) and age and sex-matched healthy volunteers (n=10). cDNA was generated for each individual. For the microarray analysis, cDNA from the 10 SLE patients were pooled, as well as the cDNA from the 10 healthy volunteers to represent a mean mRNA expression level from 10 individuals.

2010-06-04 | E-GEOD-22132 | biostudies-arrayexpress

Expression data from purified human platelets

2010-06-05 | GSE22132 | GEO

Leukocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases.

Project description:Objectives Type 1 interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-I on mixed cell populations. We aimed to define modules of IFN-I associated genes in purified leukocyte populations and use these as a basis for a detailed comparative analysis. Methods CD4+ and CD8+ T-cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers (HV)and gene expression determined by microarray. Modules of IFN-I associated genes were defined using weighted gene coexpression network analysis. The composition and expression of these modules was analysed. Results 1,150 of 1,288 IFN-I associated genes were specific to myeloid subsets, compared with 11 genes unique to T-cells. IFN-I genes were more highly expressed in myeloid subsets compared to T-cells. A subset of neutrophil samples from HV and conditions not classically associated with IFN-I signatures displayed increased IFN-I gene expression, whereas upregulation of IFN-I associated genes in T-cells was restricted to SLE. Conclusions Given the broad upregulation of IFN-I genes in neutrophils including in some HV, investigators reporting IFN-I signatures on the basis of whole blood samples should be cautious about interpreting this as evidence of bona fide IFN-I mediated pathology. Instead, specific upregulation of IFN-I associated genes in T-cells may be a useful biomarker and a further mechanism by which elevated IFN-I contributes to autoimmunity in SLE.

2016-06-01 | E-MTAB-2713 | biostudies-arrayexpress

Activation of the Interferon Pathway is Dependent upon Autoantibodies in African-American SLE Patients, but not in European-American SLE Patients

Project description:Systemic lupus erythematosus (SLE) is a heterogeneous disease which leads to different levels of serum autoantibodies to RNA-binding proteins (anti-RBP) and interferon-Î± (IFN-Î±), which plays an important pathogenic role in SLE, between European-American (EA) and African-American (AA) patients. We aimed to explore how IFN-related gene expression pathways differ in patients according to their ancestry and anti-RBP profile Whole blood from 33 female SLE patients and 16 matched controls from EA and AA ancestral backgrounds was analyzed through Affymetrix Gene 1.0 ST gene expression arrays and the data were further studied through Ingenuity Pathways Analysis for canonical pathway comparison. An independent replication cohort of more than 100 SLE patient samples and 30 controls was used to test the hypotheses generated by the microarray data, using qPCR to quantify gene expression.

2013-11-15 | E-GEOD-50635 | biostudies-arrayexpress

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