The type I interferon system in systemic lupus erythematosus

Rönnblom, Lars; Eloranta, Maija‐Leena; Alm, Gunnar V.

doi:10.1002/art.21571

Cited by 304 publications

(258 citation statements)

References 116 publications

(120 reference statements)

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“…5 High serum IFN activity had also been shown in a proportion of anti-SS-A antibody-positive patients with primary SS or SLE. 8 An activation of the type I IFN system is a feature shared between patients with primary SS and patients with SLE, 9 and the observation that IRF5 and STAT4 associates to both diseases further links these two conditions to each other.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the production of antiviral proteins, type I IFN action has several immunomodulatory effects, such as maturation of dendritic cells, activation of Th1 and Tc cells, as well as increased immunoglobulin production by B cells. 9 Stimuli for type I IFN production can be either exogenous (for example, viral DNA or RNA) or endogenous immune complexes consisting of nucleic acids and autoantibodies, which bind to FcgRIIa on plasmacytoid dendritic cells, followed by internalization and binding to toll-like receptors 7 and 9. 10 This process activates several transcription factors, including IRF5, which ultimately leads to transcription of type I IFN genes and other genes involved in cell-cycle regulation, apoptosis and a proinflammatory immune response.…”

Section: Introductionmentioning

confidence: 99%

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Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

et al. 2008

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Primary Sjö gren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) 41.4 and P-values o0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P ¼ 2.5 Â 10 À9 . The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

et al. 2008

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“…Plasmapheresis probably also reduces levels of IFN by removing IFN-inducing circulating immune complexes (24). Moreover, new approaches targeting type I IFN-like antibodies against IFN, soluble IFN receptors, monoclonal antibodies (mAb) against blood dendritic cell antigen 2, and others are under development (3,25).…”

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confidence: 99%

Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

Biesen¹,

Demir²,

Barkhudarova³

et al. 2008

Arthritis & Rheumatism

175

149

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Objective. Type I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and is therefore considered a potential therapeutic target. This study was undertaken to establish a feasible biomarker for IFN effects with respect to disease activity and effectiveness of IFN-suppressive therapy in SLE patients.Methods. Transcriptomes of purified monocytes from 9 SLE patients and 7 healthy controls were analyzed by Affymetrix GeneChip technology. Levels of sialic acid-binding Ig-like lectin 1 (Siglec-1) (sialoadhesin, CD169) in inflammatory and resident monocytes were determined at the protein level in 38 healthy controls and 52 SLE patients, using multicolor flow cytometry.Results. Transcriptomes of peripheral monocytes from SLE patients revealed a dominant type I IFN signature. Siglec-1 was identified as one of the most prominent type I IFN-regulated candidate genes. At the protein level, the frequency of Siglec-1-expressing monocyte subsets was correlated with disease activity (as measured by the SLE Disease Activity Index) and was inversely correlated with levels of complement factors. Most interestingly, levels of anti-doublestranded DNA (anti-dsDNA) antibodies were highly correlated with the percentage of resident monocytes, but not inflammatory monocytes, expressing Siglec-1. High-dose glucocorticoid treatment resulted in a dramatic reduction of Siglec-1 expression in cells from patients with active SLE.Conclusion. Our findings indicate that Siglec-1 expression in resident blood monocytes is a potential biomarker for monitoring disease activity, displaying type I IFN responses, and estimating levels of antidsDNA antibodies. Moreover, our results suggest that resident and inflammatory monocytes contribute differently to the process of autoantibody formation in SLE.

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“…For instance, they cause maturation of dendritic cells, promote T cell activation, and stimulate B cell development and production of antibodies. Data from previous studies indicate that the type I IFN system plays a pivotal role when self tolerance is broken and autoimmune reactions develop (2). Accordingly, the type I IFN system is activated in many autoimmune diseases, including systemic lupus erythematosus (SLE) (2), pri-mary Sjögren's syndrome (3), psoriasis (4), polymyositis (5), and type 1 diabetes mellitus (6).…”

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confidence: 99%

“…The association of the single-nucleotide polymorphisms (SNPs) in the IRF-5 gene with SLE has recently been convincingly replicated in 4 independent case-control studies (8). A causative role of type I IFN in the initiation and maintenance of autoimmunity is suggested by the finding that up to 19% of IFN␣-treated patients with a malignant disease ultimately developed an autoimmune disorder (2). Development of rheumatoid arthritis (RA [MIM no.…”

mentioning

confidence: 99%

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

Sigurðsson¹,

Padyukov²,

Kurreeman³

et al. 2007

Arthritis & Rheumatism

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172

127

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Objective. To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA).Methods. Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP).Results. Four of the 5 SNPs located in the 5 region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of ϳ0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort.Conclusion. Given the fact that anti-CCPnegative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.The type I interferons (IFNs) comprise a large family of cytokines that are typically produced during viral infections, mainly by plasmacytoid dendritic cells (1). In addition to direct antiviral effects, type I IFNs have many important immunomodulatory functions (1). For instance, they cause maturation of dendritic cells, promote T cell activation, and stimulate B cell development and production of antibodies. Data from previous studies indicate that the type I IFN system plays a pivotal role when self tolerance is broken and autoimmune reactions develop (2). Accordingly, the type I IFN system is activated in many autoimmune diseases, including systemic lupus erythematosus (SLE) (2), priDr. Sigurdsson

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The type I interferon system in systemic lupus erythematosus

Cited by 304 publications

References 116 publications

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

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