The type I interferon system in the etiopathogenesis of autoimmune diseases

Rönnblom, Lars

doi:10.3109/03009734.2011.624649

Cited by 106 publications

(92 citation statements)

References 99 publications

(107 reference statements)

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“…These cells, known as plasmacytoid DCs (pDCs), are the most potent producers of type I IFNs, a functional characteristic attributed to constitutive expression of TLR7, TLR9, and IRF7 and likely signaling from a unique intracellular compartment (24)(25)(26)(27). The involvement of pDCs in lupus is further suggested by the reduced frequency of these cells in patient blood together with increases in afflicted organs, presumably caused by the attraction of activated pDCs to inflammatory sites (10). Similar increases have been noted in inflammatory tissues of patients with Sjögren's syndrome (28), rheumatoid arthritis (29,30), dermatomyositis (31), and psoriasis (32).…”

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confidence: 99%

“…These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9)(10)(11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9,12,13).…”

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Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

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In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas lpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.E xtensive evidence suggests that type I IFNs are major pathogenic effectors in lupus-associated systemic autoimmunity. A well-documented pattern of expression of type I IFN-inducible genes occurs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE) (1-3), and reduced disease is observed in some lupus-predisposed mice that either lack the common receptor (IFNAR) for these cytokines (4, 5) or have been treated with IFNAR-blocking antibody (6). Consequently, attention has focused on defining the cell subsets and signaling processes involved in type I IFN production, the mechanisms by which these mediators accelerate disease, and approaches to interfere with these pathogenic events.Early in vitro studies showed that type I IFN production can be induced in normal blood leukocytes by SLE autoantibodies complexed with nucleic acid-containing apoptotic/necrotic cell material, and further work demonstrated that this activity is sensitive to RNase and DNase digestion (7,8). These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9-11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9, 12, 13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14-20), and in Unc93b1 (3d) mutant mice i...

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confidence: 99%

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confidence: 99%

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

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“…However, recent studies have demonstrated that IFN-I signaling could play deleterious roles in some normal biological functions, especially when cells undergo excessive activated IFN-I signaling. It has been reported that uncontrolled activated IFN-I signaling contributes to autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Aicardi-Goutières syndrome (6,7). IFN-I also has important effects on lethality in diverse models of sepsis or endotoxic shock (8).…”

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confidence: 99%

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

Qian

Zuo

et al. 2016

Journal of Biological Chemistry

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Edited by George DeMartinoAdenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys 48 -linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase ␤ transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between ␤ transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.

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“…This family consists of different a genes (Ifna), 13 in humans and 14 in mice, and one b IFN gene (Ifnb), both of which signal through the heterodimeric receptor complex, consisting of IFNAR1 and IFNAR2. Type I IFNs have been associated with autoimmune diseases because type I IFN-inducible genes are upregulated in some autoimmune diseases, displaying a so-called IFN signature (13)(14)(15). This is an upregulation of type I IFN-inducible genes or genes containing IFN-sensitive response elements (ISREs) found in tissues such as skin lesions in psoriasis and the inflamed joints of rheumatoid arthritis patients (16)(17)(18)(19).…”

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confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.

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The type I interferon system in the etiopathogenesis of autoimmune diseases

Cited by 106 publications

References 99 publications

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

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