Article

Network Analysis of Associations Between Serum Interferon-alpha Activity, Autoantibodies, and Clinical Features in Systemic Lupus Erythematosus

University of Chicago, Chicago, IL, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 04/2011; 63(4):1044-53. DOI: 10.1002/art.30187
Source: PubMed

ABSTRACT

Interferon-α (IFNα) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFNα levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. This study was undertaken to detect associations between clinical and serologic disease manifestations and serum IFNα activity in a large diverse SLE cohort, using multivariate and network analyses.
We studied 1,089 SLE patients (387 African American, 186 Hispanic American, and 516 European American patients). The presence or absence of individual American College of Rheumatology (ACR) clinical criteria for SLE, autoantibodies, and serum IFNα activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each ancestral background group separately to establish the network of associations between variables that were independently significant following Bonferroni correction.
In all ancestral backgrounds, high IFNα activity was associated with anti-Ro and anti-double-stranded DNA antibodies (P = 4.6 × 10(-18) and P = 2.9 × 10(-16) , respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFNα activity (P ≤ 6.7 × 10(-4) ). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared among >1 ancestral background. Associations between clinical criteria were different for different ancestral backgrounds, while autoantibody-IFNα relationships were similar across backgrounds. IFNα activity and autoantibodies were not associated with ACR clinical features in multivariate models.
Our findings indicate that serum IFNα activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFNα may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.

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Available from: Jennifer A Kelly, Dec 12, 2014
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    • "The overlap of these DEGs between AA and EA subjects was modest, even when comparing the same cell type between ancestral backgrounds. When examining IFN pathway genes represented in our study, we also found differences in ISG expression between the two ancestral backgrounds, supporting diversity in IFN pathway activation between different ancestral backgrounds which has been suggested by our previous studies [13] [39] [43]. We found that different ISGs were expressed in different cell types, supporting the idea that each cell type contributes a particular panel of genes to the previously reported overall PBMC or whole blood IFN signature. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. We examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Peripheral blood was collected from African-American (AA) and European-American (EA) SLE patients and controls. CD4 T-cells, CD8 T-cells, monocytes, and B cells were purified by flow sorting, and each cell subset from each subject was run on a genome-wide expression array. Cases were compared to controls of the same ancestral background. The overlap in differentially expressed gene (DEG) lists between different cell types from the same ancestral background was modest (<10%), and only 5-8% overlap in DEG lists was observed when comparing the same cell type between different ancestral backgrounds. IFN-stimulated gene (ISG) expression was not up-regulated synchronously in all cell types from a given patient, for example a given subject could have high ISG expression in T and B cells, but not in monocytes. AA subjects demonstrated more concordance in ISG expression between cell types from the same individual, and AA patients demonstrated significant down-regulation of metabolic gene expression which was not observed in EA patients. ISG expression was significantly decreased in B cells in patients taking immunosuppressants, while ISGs in other cell types did not differ with medication use. In conclusion, gene expression was strikingly different between immune cell subsets and between ancestral backgrounds in SLE patients. These findings emphasize the critical importance of studying multiple ancestral backgrounds and multiple cell types in gene expression studies. Ancestral backgrounds which are not studied will not benefit from personalized medicine strategies in SLE. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Journal of Autoimmunity
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    • "The overlap of these DEGs between AA and EA subjects was modest, even when comparing the same cell type between ancestral backgrounds. When examining IFN pathway genes represented in our study, we also found differences in ISG expression between the two ancestral backgrounds, supporting diversity in IFN pathway activation between different ancestral backgrounds which has been suggested by our previous studies [13] [39] [43]. We found that different ISGs were expressed in different cell types, supporting the idea that each cell type contributes a particular panel of genes to the previously reported overall PBMC or whole blood IFN signature. "
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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
    Full-text · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    • "Many patients with SLE have high circulating levels of type I IFN (11). Some individuals treated with IFN-α for chronic viral infections developed de novo SLE that was resolved when IFN-α was withdrawn (12, 13). "
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    ABSTRACT: The characteristic serologic feature of systemic lupus erythematosus (SLE) is autoantibodies against one's own nucleic acid or nucleic acid-binding proteins - DNA and RNA-binding nuclear proteins. Circulating autoantibodies can deposit in the tissue, causing inflammation and production of cytokines such as type 1 interferon (IFN). Investigations in human patients and animal models have implicated environmental as well as genetic factors in the biology of the SLE autoimmune response. Viral/Bacterial nucleic acid is a potent stimulant of innate immunity by both toll-like receptor (TLR) and non-TLR signaling cascades. Additionally, foreign DNA may act as an immunogen to drive an antigen-specific antibody response. Self nucleic acid is normally restricted to the nucleus or the mitochondria, away from the DNA/RNA sensors, and mechanisms exist to differentiate between foreign and self nucleic acid. In normal immunity, a diverse range of DNA and RNA sensors in different cell types form a dynamic and integrated molecular network to prevent viral infection. In SLE, pathologic activation of these sensors occurs via immune complexes consisting of autoantibodies bound to DNA or to nucleic acid-protein complexes. In this review, we will discuss recent studies outlining how mismanaged nucleic acid sensing networks promote autoimmunity and result in the over-production of type I IFN. This information is critical for improving therapeutic strategies for SLE disease.
    Full-text · Article · Oct 2013 · Frontiers in Immunology
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