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


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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    • "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.
    Frontiers in Immunology 10/2013; 4:319. DOI:10.3389/fimmu.2013.00319
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    • "Many lines of evidence underscore the importance of cytokines in SLE susceptibility. Circulating interferon alpha (IFN-í µí»¼) levels are high in many SLE patients [2] [3]. One of the most direct lines of evidence suggesting that high IFN-í µí»¼ is a primary pathogenic factor is that some individuals treated with recombinant interferon alpha (IFN-í µí»¼) for viral hepatitis develop de novo SLE, which typically resolves when IFN-í µí»¼ treatment is discontinued [4] [5]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF- α ) levels. We explored circulating TNF- α levels in SLE families to determine whether high levels of TNF- α were clustered in a heritable pattern. We measured TNF- α in 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF- α trait were assessed. SLE-affected individuals had the highest TNF- α levels, and TNF- α was significantly higher in unaffected first degree relatives than healthy unrelated subjects (P = 0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF- α levels, resulting in a first degree relative recurrence risk of 4.48 (P = 2.9 × 10(-5)). Interestingly, the median TNF- α value in spouses was similar to that of the first degree relatives. Concordance of the TNF- α trait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF- α in SLE pathogenesis, and TNF- α levels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.
    Clinical and Developmental Immunology 09/2013; 2013:267430. DOI:10.1155/2013/267430 · 2.93 Impact Factor
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    • "High levels of circulating IFN-α are common in SLE patients 7. We have previously demonstrated that serum IFN-α levels are abnormally high in SLE family members, supporting the idea that high circulating IFN-α is a heritable risk factor for SLE 8, 9. "
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    ABSTRACT: Background Alleles of IRF8 have been associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. Objectives We investigated whether the IRF8 alleles were associated with differences in serum IFN in SLE or MS. Methods Single nucleotide polymorphisms (SNPs) in IRF8 (associated with SLE and MS respectively) were genotyped in 627 SLE patients of African-American, European-American, and Cretan origin, 73 MS patients, and matched controls. Serum type I IFN was measured using a functional reporter cell assay. Results The MS-associated rs17445836 G allele was associated with the presence of anti-dsDNA autoantibodies in SLE patients across all ancestral backgrounds (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and the subgroup of MS patients with secondary progressive MS. The rs17445836 G allele was associated with decreased type I IFN-induced gene expression in PBMC from SLE patients who lacked anti-dsDNA antibodies. No associations were observed with the rs12444486 allele. Conclusions The rs17445836 G allele was associated with decreased type I IFN responses in both SLE and MS patients. The association of this allele with low IFN SLE and with MS, a condition characterized by low circulating type I IFN levels, suggests that this allele is associated with autoimmunity in the setting of low type I IFN levels. These data also suggest a role for this allele in humoral autoimmune responses. Disclosure of Interest None Declared
    Genes and immunity 08/2013; 14(8). DOI:10.1038/gene.2013.42 · 2.91 Impact Factor
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