Activation of the type I interferon pathway in primary Sjogren’s syndrome

Mavragani, Clio P.; Crow, Mary K.

doi:10.1016/j.jaut.2010.06.012

Cited by 168 publications

(107 citation statements)

References 60 publications

(65 reference statements)

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“…IRF and TRIM21 expression in Sjögren's syndrome Sjö gren's syndrome is an autoimmune disease with increased levels of type 1 IFN and overexpression of type I IFN-stimulated genes, the so-called IFN signature (48)(49)(50). Using PBMCs from patients with a verified IFN signature, we found that TRIM21 is indeed expressed at higher levels compared with healthy controls (Fig.…”

Section: Irf4 and Irf8 Block The Irf1-mediated Induction Of Trim21 Exmentioning

confidence: 84%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ–activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element–dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4−/− cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren’s syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ–mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1−/− cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.

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Section: Irf4 and Irf8 Block The Irf1-mediated Induction Of Trim21 Exmentioning

confidence: 84%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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show abstract

“…The fact that the serum IFN bioactivity could be inhibited by neutralizing antibodies directed against IFN and IFN , provides evidence for a role of both type I IFNs in the induction of IFN type I response activity in RA (Mavragani et al, 2009). Upregulation of type I IFN-response genes has now been observed in peripheral blood cells and/or target tissues of (a subset of) patients with autoimmune diseases such as RA, SLE (Baechler et al 2005), SSc (Tan et al, 2006;Bos et al, 2009), SS (Mavragani & Crow, 2010), multiple sclerosis (Van Baarsen et al, 2006) and type 1 diabetes. These findings suggest that an activated IFN response gene expression program is a common denominator in chronic inflammatory diseases in general.…”

Section: A Type I Ifn Response Signature In the Peripheral Blood Of Amentioning

confidence: 99%

Gene Expression Profiling in Rheumatoid Arthritis

Verweij¹,

Vosslamber²

2012

Insights and Perspectives in Rheumatology

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“…The etiology of Sjogren's syndrome remains unidentified (16). Interactions between environmental contributors such as viruses or stress in conjunction with genetic susceptibility factors and hormonal effects are currently believed to result in disease development (16,17).…”

Section: Aetiology and Pathogenesismentioning

confidence: 99%

“…Interactions between environmental contributors such as viruses or stress in conjunction with genetic susceptibility factors and hormonal effects are currently believed to result in disease development (16,17). Intrinsic activation of epithelium in various target organs was demonstrated (18), based on inappropriate expression of MHC molecules, overexpression of costimulatory molecules and capacity for cytokine production, and the term "autoimmune epithelitis" was proposed (19 (16,20) However, the mechanisms that account for the epithelial activation remain stil unclear (16). Recent data suggest the central role of the type I interferon (IFN) system in the pathogenesis of many autoimmune disorders including SS (16).…”

Section: Aetiology and Pathogenesismentioning

confidence: 99%

Oral Aspects of Sjögren’s Syndrome

Ergün¹

2012

Insights and Perspectives in Rheumatology

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Activation of the type I interferon pathway in primary Sjogren’s syndrome

Cited by 168 publications

References 60 publications

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Gene Expression Profiling in Rheumatoid Arthritis

Oral Aspects of Sjögren’s Syndrome

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