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Review
Type I interferons in host defence and inflammatory diseases
  1. Mary K. Crow1 and
  2. Lars Ronnblom2
  1. 1Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, Weill Cornell Medical College, New York City, New York, USA
  2. 2Section of Rheumatology, Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Mary K. Crow; crowm{at}hss.edu

Abstract

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as ‘friend’ or ‘foe’, within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

  • systemic lupus erythematosus
  • interferon
  • autoimmune diseases

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https://doi.org/10.1136/lupus-2019-000336

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    Introduction

    Type I interferons (IFN) are a major line of host defence against viruses and other microorganisms.1 However, it is now clear that type I IFNs can also drive context-specific responses to infection, which may be either beneficial or detrimental to the host.2–4 Furthermore, dysregulation of the type I IFN system can elicit autoimmune diseases, perhaps best exemplified by interferonopathies and SLE.5 All 17 type I IFNs signal through the IFN alpha receptor (IFNAR) and induce a type I IFN gene signature (IFNGS), which is present in a proportion of patients with SLE and other autoimmune diseases such as myositis, Sjögren’s syndrome, systemic sclerosis and rheumatoid arthritis.6 7 Recent evidence also implicates type I IFN-dependent signalling as a key inflammatory driver in non-autoimmune diseases such as certain solid tumours and myocardial infarction.8 9

    The second International Summit on Interferons in Inflammatory Diseases, sponsored by AstraZeneca, was held in Gaithersburg, Maryland, USA (17–18 May 2018) and united 26 international expert clinicians and scientists with diverse backgrounds in basic science, translational science and clinical medicine. In this review, we build on the content of the inaugural meeting10 by reviewing high-impact research on the role of type I IFNs in autoimmune and other inflammatory diseases published in recent years.

    Overview of the type I IFN system in host defence

    The primary (or ‘professional’) IFN-producing cells in antiviral innate immunity are plasmacytoid dendritic cells (pDC).11 Type I IFN expression is triggered by nucleic acid-sensing pattern recognition receptors, such as endosomal membrane-bound toll-like receptors (TLR; DNA and RNA sensors),12 the cytosolic retinoic acid-inducible gene 1 (RIG-I)-like family of receptors (RNA sensors)13 and cyclic GMP-AMP synthase (cGAS; DNA sensors).14 Type I IFNs induce an IFNGS via IFNAR-dependent activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT).15

    Although they signal through the same receptor, type I IFN subtypes (eg, IFN-α and IFN-β) can have both separate and overlapping roles in host defence.16 Their role in a particular context is determined by differences in timing, signal magnitude and source of the type I IFN subtype. For example, cGAS stimulation preferentially elicits an IFN-β response, whereas TLR stimulation predominately increases IFN-α expression.17 Type I IFNs have pleiotropic effects, which include promoting the maturation of dendritic cells into antigen-presenting cells18 and B cell and T cell survival, activation and differentiation,19 20 in turn promoting further IFN production from pDCs.21 22 Type I IFNs also induce differentiation of B cells into a distinct proinflammatory subset of plasma cells that secrete ISG15.23 Dysregulation of these self-amplifying loops is a hallmark of SLE and other IFN-driven diseases.

    Type I IFNs in autoimmune diseases

    SLE and interferonopathies

    SLE is a chronic inflammatory autoimmune disease that affects many organ systems.24 Although rare forms of monogenic lupus occur, more often a variety of environmental factors trigger SLE in genetically predisposed individuals. It is well established that dysregulation in the type I IFN system is a key driver in SLE pathogenesis and that the interaction of type I IFN with immune cells can induce multifaceted aspects of lupus (table 1).5 6 25–27 Up to 87% of paediatric and adult patients with SLE have an IFNGS.28–31 It remains unclear how the signature relates to the phenotype and disease progression at the cohort and/or individual patient level in established SLE. However, an IFN score was recently shown to predict the development of SLE in at-risk individuals.32 Alternative biomarkers of type I IFN activity have been evaluated and include the IFN-α response protein, sialic acid-binding Ig-like lectin 1, which is expressed exclusively on tissue-resident monocyte-derived dendritic cells and tissue-resident macrophages.33 Other gene signatures, such as plasmablast and neutrophil signatures, may correlate better with SLE disease activity than the IFNGS at the individual level.31

    View this table:
    Table 1

    Cellular effects of type I IFN that may contribute to the pathogenesis of lupus

    The primary source of type I IFNs in patients with lupus is most likely pDCs, though a role for ‘nonprofessional’ IFN-producing cells (essentially all other nucleated cells, including macrophages) cannot be ruled out. The stimulus for type I IFN production in these patients has not been resolved but may include extracellular and intracellular accumulation of endogenous nucleic acids via increased production (eg, extensive cell damage, apoptosis and NETosis) and/or impaired clearance.34 35 Monocyte-derived macrophages transfected with a small non-coding Y RNA or stimulated with immune complexes were shown to produce IFN-α and IFN-β mRNA transcripts.36 Furthermore, tumour necrosis factor (TNF) can induce macrophages to produce modest amounts of type I IFN, thereby triggering expression of IFN-stimulated genes and a proinflammatory autocrine loop,37 and prolonged exposure to type I IFNs may prime monocytes from patients with SLE to produce a strong inflammasome response to TLR activation.38 This hyperactivity would predispose a patient with SLE to elicit an exaggerated inflammatory response to a subsequent viral infection.

    Transposable elements represent nearly half of the human genome and are a significant source of potentially stimulatory self-nucleic acids. In SLE, the expression of transposable elements, such as long interspersed nuclear element type 1 (L1), is dysregulated in tissue and cell-specific patterns and can trigger TLR or cytosolic receptor-dependent type I IFN production.39–42 Overexpression of transposable element RNA may be related to impaired heat shock protein 90 expression in patients with SLE.39

    Both endosomal and cytosolic nucleic acid sensors have been implicated in the pathogenesis of SLE; however, it remains unknown if overactivation of either sensor type alone is sufficient to drive disease activity. In neonatal mice, infection with the RNA virus, lymphocytic choriomeningitis virus (LCMV), induces lupus-like disease by 2–5 months of age via both endosomal TLR and cytosolic mitochondrial antiviral signalling (MAVS) protein-dependent type I IFN production.43 LCMV-induced lupus was pDC and endosomal TLR dependent; MAVS signalling alone was insufficient to induce lupus-like symptoms. Recent evidence suggests that exogenous (eg, viral) or endogenous cytosolic RNA may stimulate the DNA sensor, cGAS, by inducing mitochondrial DNA release, cGAS activation and IFN-β production.44 45

    Type I IFN and anti-nucleic acid antibodies may collectively set preconditions for altered handling of damaged DNA. Neutrophils primed with type I IFNs and exposed to TLR-activating autoantibodies retain and extrude oxidised mitochondrial DNA, a potent inducer of type I IFN production by pDCs.46 47 Spontaneous activation of MAVS protein in lymphocytes from patients with SLE correlates with mitochondrial oxidative stress and serum type I IFN levels.48 Delineating the nucleic acid triggers in SLE and interferonopathies may inform on novel drug targets. For example, pathway elements that potential therapies could target have been identified in an in vitro model of Aicardi-Goutières syndrome, including the activation of cGAS-dependent type I IFN production by increased cytosolic reverse-transcribed DNA (figure 1A).49 Thus, reverse transcriptase inhibition may be a potential strategy to treat patients with this disease.

    Figure 1
    Figure 1

    Comparison of nucleic acid signalling pathways leading to type I interferon (IFN) production in an autoimmune disease and bacterial infection. (A) In vitro model of Aicardi-Goutières syndrome. Mutations in antiviral genes, including three-prime repair exonuclease 1 (TREX1), can cause Aicardi-Goutières syndrome, an autosomal recessive progressive inflammatory disorder. TREX1-deficient human neurons accumulate long interspersed element-1 (L1) ssDNA, which is produced by the reverse transcription of L1 retrotransposon transcripts. L1 ssDNA stimulates the cGAS-STING pathway, resulting in the production of neurotoxic IFN. Neurotoxicity could be blocked by reverse transcriptase inhibitors (RTis) and IFN-α receptor (IFNAR) blockers.49 Reprinted with permission from Elsevier and Thomas CA, et al.49 (B) Type I IFN induction through alternative pathways during Mycobacterium tuberculosis infection. Mycobacterial (Mtb) infection results in the production of microbial products and products associated with mitochondrial stress that stimulate pattern recognition receptors, including TLR4, NOD2 and cGAS, to activate type I IFN gene transcription (adapted from Moreira-Teixeira et al [96]). cGAS, cyclic GMP-AMP synthase; IFN, interferon; IFNAR, IFN alpha receptor; IRF, IFN regulatory factor; STING, stimulator of IFN gene; TLR, toll-like receptor.

    Recent reports provide insight into the genetic background that increases type I IFN expression and contributes to SLE risk. A global transancestral association study of SLE using genomic data from more than 27 000 individuals, including 11 590 patients with SLE, confirmed that SLE risk has both ancestry-dependent and ancestry-independent contributors.50 Hagberg et al demonstrated increased T cell STAT4 responsiveness to interleukin (IL)-12 and IFN-α in patients with SLE carrying the STAT4 risk allele.51 Furthermore, healthy individuals with the risk gene variant have normal STAT4 responsiveness to IL-12, which can become ‘lupus like’ if cells from these individuals are exposed to IFN-α.52 The presence of the purine nucleoside phosphorylase risk allele was associated with increased type I IFN-induced mRNA expression in B cells derived from patients with SLE.53

    Epigenetic mechanisms alter gene expression and contribute to SLE heterogeneity.54 DNA methylation profiles were analysed in an epigenome-wide association study of more than 500 patients with SLE and a similar number of controls.55 Differential methylation of type I IFN-regulated genes was most notable for patients with active versus inactive disease. In SLE-discordant twins, differential methylation was present in type I IFN-regulated genes for T and B cells, monocytes and granulocytes, and hypomethylation of these genes was associated with increased SLE flare risk.56 Park et al57 employed a comprehensive epigenomics approach to examine cross-regulation of TLR responses at the level of chromatin in macrophages by TNF and type I IFNs.57 TNF-induced silencing of TLR signalling was prevented by type I IFN-induced priming of chromatin. These data may explain why some patients with chronic inflammatory diseases become severely ill when they develop a subsequent infection.

    Sjögren’s syndrome

    Sjögren’s syndrome is an autoimmune disease that primarily affects the exocrine glands, with strong evidence that dysregulation of the type I IFN system is a key driver of inflammation.58 59 However, the effects of type I IFNs in Sjögren’s syndrome may be subtype specific. IFN-β may reduce the expression of proinflammatory mediators in peripheral blood mononuclear cells isolated from patients with Sjögren’s syndrome.60 Like SLE, patients with Sjögren’s syndrome can be stratified by those who do and do not have an IFNGS. Patients with the signature have increased B cell activating factor (BAFF) expression,61 which is involved in B cell activation, and a higher prevalence of autoantibodies to Sjögren’s syndrome-related antigen A (SSA; also called anti-Ro/SSA) and B (SSB; also called anti-La/SSB) than those without the signature.62 Patient stratification also may be possible based on the presence or absence of a type II IFNGS.63 In a phase 2 study, to evaluate the effects of belimumab, an anti-BAFF antibody, on exocrine inflammation in patients with Sjögren’s syndrome,64 a low blood and salivary count of natural killer cells was the only predictor of response to belimumab. The authors proposed that two subpopulations of patients with Sjögren’s syndrome may exist: one with a predominant type I IFN-BAFF-B cell axis (ie, belimumab responders) and another with a predominant type II IFN axis associated with natural killer cell activity.

    Systemic sclerosis

    Systemic sclerosis is an atypical autoimmune disease in that both inflammatory (ie, vasculopathy) and non-inflammatory (ie, dermal and visceral fibrosis) processes contribute to clinical manifestations.65 Dermal pDCs and a dysregulated type I IFN system are implicated in the clinical manifestations of systemic sclerosis, including fibrosis,66–70 and an IFNGS is present in more than 68% of patients.28 pDCs in the skin of patients with systemic sclerosis aberrantly express TLR8, which is responsible for pDC secretion of chemokine (C-X-C motif) ligand 4 (CXCL4; also called platelet factor 4), and TLR8 and TLR9-induced type I IFN production by pDCs is potentiated by CXCL4.70 Aberrant TLR8 expression and subsequent secretion of both CXCL4 and IFN-α by pDCs may partially explain why two IFN-driven diseases, lupus and systemic sclerosis, can have such distinct clinical manifestations. Targeting pDCs rather than a specific IFN may be a more effective approach to treating patients with systemic sclerosis.

    Myositis

    Idiopathic inflammatory myopathies are heterogeneous, systemic autoimmune diseases with muscle (and often skin) as the primary target(s) and include polymyositis and dermatomyositis.71 Muscle biopsies from patients with dermatomyositis are characterised by overlapping distributions of large numbers of pDCs, a prominent IFNGS and abundant type I IFN-inducible protein, myxovirus resistance protein 1, underscoring the potential role of type I IFNs in driving disease activity.72 Furthermore, the IFNGS and levels of type I IFN-regulated chemokines in blood correlate with disease activity in patients with dermatomyositis. IFN-β is the predominant type I IFN subtype in the sera of patients with dermatomyositis and correlates with the IFNGS.73 Consistent with these findings, severe dermatomyositis can be triggered by IFN-β therapy for multiple sclerosis (MS).74 Although IFN-β predominates, IFN-α has also been implicated in the pathogenesis of dermatomyositis. Piper et al75 have shown that IFN-α drives the expansion of an immature transitional B cell population with a proinflammatory phenotype in juvenile dermatomyositis.75

    Rheumatoid arthritis

    Rheumatoid arthritis is a chronic inflammatory autoimmune disease that primarily affects the joints, but as a systemic disease it has extra-articular manifestations in the eyes, heart, lungs and other organs.76 pDCs and IFN-α/β levels are increased in the rheumatoid arthritis synovium compared with the joints of healthy individuals,77–79 and up to 50% of patients with rheumatoid arthritis have a peripheral blood IFNGS.28 80 Baseline type I IFN activity (quantified as type I IFN protein and IFNGS expression) may predict clinical responders to TNF antagonists and non-responders to rituximab in patients with rheumatoid arthritis.81–83 However, the IFNGS may not reflect rheumatoid arthritis disease activity,84 and whether there is a causal relationship between IFNGS and rheumatoid arthritis pathogenesis is currently unclear. Indeed, recent evidence suggests that pDCs from drug-naïve patients with early rheumatoid arthritis differentially expressed genes suggestive of enhanced tolerogenic function.85

    Autoimmune regulator-deficient patients

    Autoimmune regulator (AIRE) is a transcriptional regulator that promotes clonal depletion of self-reactive T cells. Highlighting this role, AIRE deficiency causes autoimmune polyglandular syndrome type 1 (APS-1; also known as autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy/dysplasia).86 AIRE-deficient individuals have autoreactivity against self-antigens, including those typically associated with MS, SLE, type I diabetes mellitus and rheumatoid arthritis. Paradoxically, it is not clear that MS and SLE have ever been described, and the other two conditions are more rare in AIRE-deficient individuals than might have been expected. Casting light on this, Meyer et al87 performed protoarray analyses and additional techniques to investigate sera from patients with APS-1 and controls.87 88 In addition to global loss of T cell tolerance, patients with APS-1 had two types of B cell dysregulation: (1) diverse or ‘private’ reactivities of up to 100 diverse gene products, many of which were AIRE regulated; and (2) shared reactivities to steroidogenic enzymes and selected cytokines, none of which were obviously AIRE regulated. Remarkably, high-affinity antibodies to IFN-α were present in almost all patients, preventing IFNAR-dependent signalling, and were negatively correlated with the prevalence of type I diabetes mellitus in patients who carried other pathognomonic features, such as antibodies to glutamic acid decarboxylase (GAD)65 and GAD67. Thus, specific autoantibodies may actively limit certain diseases in AIRE-deficient individuals. Interestingly, the presence of anti-IFN-α antibodies did not predispose patients with APS-1 to severe viral infections, which may reflect preserved antiviral protection from IFN-β or other IFNs. The high-affinity anti-IFN antibodies obtained from the blood of patients with APS-1 have been useful in providing tools of unprecedented sensitivity for measuring IFN-α levels in human body fluids.89

    The type I IFN system in non-autoimmune diseases

    Tuberculosis

    Infection with Mycobacterium tuberculosis is the leading cause of mortality from infectious diseases.90 91 In most individuals, M. tuberculosis infection is controlled by the host immune response, with CD4+ T cells, IL-12, IFN-γ and TNF as the most critical factors.92 It remains unclear why some people are not protected from developing active tuberculosis (TB). Patients with active TB can be distinguished from those with latent TB by the presence of a peripheral blood gene signature with increased expression of type I IFN-inducible genes and decreased expression of IFNG and TBX21.93 Furthermore, the type I IFN-induced components of the gene signature correlate with radiographic evidence of active TB and diminish with successful treatment.94 95 These findings and the body of evidence from mouse models of TB support a role for type I IFNs in the pathogenesis of TB.96

    Distinct strains of M. tuberculosis variably induce type I IFN. Recognition of one particular strain by TLR4 was associated with production of IFN-β and increased virulence, with lung pathology observed early in the course of infection.97 Specific M. tuberculosis strains can differ in their capacity to induce mitochondrial stress, generation of reactive oxygen species and release of host mitochondrial DNA into the cytosol.98 The release of mitochondrial DNA contributes to cGAS and stimulator of IFN gene (STING)-dependent production of IFN-β after M. tuberculosis infection98–101 (figure 1B).

    Type I IFN effects on TB are context specific. In mouse models of TB, type I IFNs induce the production of the immunosuppressive cytokine IL-10, reduce production of protective cytokines such as IL-1 and impair the macrophage response to type II IFN (IFN-γ). This contributes to decreased induction of Th1 adaptive immunity, increased bacterial loads and shorter survival times.102–107 In contrast to data from the murine models, several clinical studies have reported beneficial effects of type I IFN administration in the setting of well-established M. tuberculosis infections.108 109 Additionally, in a low IFN-γ state or in the setting of reduced IFN-γ signalling, low levels of type I IFN may maintain the function of classically activated protective macrophages by inhibiting Arg1 expression and the related conversion of protective macrophages to an alternatively activated, less protective phenotype.110 111

    Understanding the mechanisms responsible for switching from acute to sustained type I IFN expression in chronic M. tuberculosis infection may be informative for autoimmune diseases, such as SLE, in which activation of latent Epstein-Barr virus has been suggested as a factor that can trigger autoimmunity in a genetically predisposed individual.112 113

    HIV infection

    HIV infection results in profound immune system dysfunction, classically characterised by progressive CD4+ T cell depletion.114 Despite the availability of improved treatments, many patients experience chronic inflammation associated with sustained production of type I IFN and its sequelae.114 The effects of type I IFN in the setting of HIV-1-induced inflammation may be IFN subtype specific. In the HIV-exposed brain, IFN-α promotes neuropathology, whereas IFN-β is neuroprotective.115 A relationship may exist between the sustained IFNGS and disease progression. Simian immunodeficiency virus (SIV) infection is non-progressive in African green monkeys and is associated with a transient IFNGS after acute infection. In contrast, SIV infection in Asian macaques is progressive and associated with a sustained IFNGS.116 It remains unclear if this relationship is correlative or causative.

    HIV-1 pathogenesis, including the role of pDCs and type I IFNs, has been studied in humanised mice, which are immunodeficient animals stably reconstituted with human immune cells/tissues to provide an in vivo functional human immune system that is tolerant to both human and mouse antigens.117 In this model, the pDC/type I IFN axis has distinct roles in acute and chronic HIV infection. HIV enters pDCs through CD4-dependent endocytosis and induces type I IFN production primarily through RNA-mediated activation of TLR7.118 In acute HIV infection, pDCs contribute to suppression of HIV replication and promote priming of anti-HIV-1 T cells.119 In chronic HIV infection, sustained type I IFN production from pDCs contributes to depleting/exhausting T cells.119–121 Thus, pDCs can have opposing roles depending on the stage of HIV infection.

    During treatment with antiretroviral agents, HIV replication is suppressed and viral antigen production decreases below detectable levels in the blood and other tissues. Cells with HIV-1 DNA persist in tissue, and, if antiviral treatment ceases, viral replication rebounds within 2 weeks. The dependence on combination antiretroviral therapy (cART) for viral replication suppression can be replicated in the humanised mouse models. These models have been used to determine if targeting the pDC/type I IFN axis in the treatment of patients with organ inflammation resulting from chronic HIV infection could also prevent viral rebound on cART withdrawal. IFNAR blockade in HIV-1-infected humanised mice fully reversed HIV-1-induced immune hyperactivation, rescued anti-HIV-1 immune responses in T cells, decreased HIV-1 reservoir size and delayed rebound after stopping cART.121 Theoretically, an anti-type I IFN approach to treating chronic HIV would not require lifelong treatment because the goal is to rescue the T cell population, augmenting elimination or control of the virus. If recovery of T cell function can be sustained, future studies might assess whether anti-type I IFN therapy diminishes viral reservoirs and eliminates viral replication, a situation that might be considered a ‘functional cure’.

    Oncology

    Antigenicity, adjuvanticity and homeostatic feedback are major discriminatory functions of the immune system that are critical in cancer biology and regulated, in part, by the type I IFN system.122 Low levels of type I IFN in the tumour have an anticancerous effect by activating T cell-dependent adaptive immunity, whereas higher levels are effective by inhibiting angiogenesis.123 Conventional cancer therapies, such as radiation, chemotherapy and epigenetic drugs, can activate the type I IFN system and stimulate the immune response to cancer.122 124 Genotoxic cancer therapies lead to breaks in genomic DNA, which in turn can act as stimuli for the pattern recognition receptor, cGAS, and induce IFN signalling.124

    Recent evidence suggests that type I IFN signalling also may have a detrimental role in the immune tumour microenvironment. Patients with IFNGS-positive breast cancer tumours are more likely to fail chemotherapy than patients with IFNGS-negative tumours.125 In its unshielded state, RN7SL1A, a prominent stromal fibroblast RNA, can elicit a RIG-I-dependent IFNGS.126 127 Carcinoma-associated basement membrane disruptions promote fibroblast production of exosomes containing unshielded RN7SL1A, which in turn transfer the unshielded RNA to neighbouring breast cancer cells.126 127 In breast cancer cells, RIG-I-dependent activation of STAT1 elicits a NOTCH3-dependent pathway that can expand therapy resistance, progression and metastasis in breast cancer.127 In another study, relapse after radiation therapy and anti-cytotoxic T-lymphocyte-associated protein 4 treatment was associated with prolonged type I IFN signalling in mice.128 In summary, IFN can have a positive or negative influence on cancer growth, and this influence may depend on various factors including treatment, cancer type, tumour microenvironment and level of IFN stimulation.

    Myocardial infarction

    Coronary atherosclerosis develops asymptomatically until acute myocardial infarction elicits chest pain, forcing patients to seek medical care.129 In the first few days after infarct, cardiomyocyte cell death is followed by a sterile inflammatory response that eventually resolves into fibrosis.129 130 Understanding the mechanisms of pathological ventricular remodelling is an area of intense research effort.

    On myocardial ischaemia, with events including double-stranded DNA breaks,131 damage-associated molecular patterns (DAMPs) may be liberated after the ischaemia event and may contribute to the inflammatory response by inducing type I IFN. In a mouse model of myocardial ischaemia, an IFN regulatory factor 3 (IRF3)-dependent IFNGS was upregulated in cardiac macrophages 4 days after infarction.9 The IFNGS required cGAS and IFNAR, implicating endogenous nucleic acids as the trigger for a type I IFN response. Self-DNA was released by injured cardiomyocytes and taken up by macrophages. IRF3 or IFNAR-deficient mice had improved survival rates after the injury. Administration of an anti-IFNAR antibody within 48 hours after myocardial ischaemia decreased the inflammatory response, reduced ventricular dilation and improved cardiac performance compared with mice that did not receive treatment. Thus, anti-type I IFN drugs may be beneficial in the acute postmyocardial ischaemia period.

    Conclusions

    SLE remains the prototypic type I IFN-driven disease, and evidence is accumulating for targeting the type I IFN pathway as a rational therapeutic approach. In recent years, there has been considerable effort to develop drugs for SLE and interferonopathies, and clinical trial data support the strategy of targeting signalling components downstream of type I IFNs for the treatment of type I IFN-driven diseases. Anifrolumab, a fully human monoclonal antibody against the IFNAR, plus standard of care neutralised the IFNGS, decreased SLE disease activity relative to placebo and was well tolerated in a phase 2b trial with patients with SLE.29 Baricitinib, a JAK inhibitor, decreased SLE disease activity in patients with SLE in a phase 2 trial132 and improved symptoms, decreased corticosteroid dosage and neutralised the IFNGS in patients with other type I interferonopathies, including chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures and STING-associated vasculopathy with onset in infancy.133

    The presence of an IFNGS may predict clinical responders to treatment, but patients without a strong IFNGS remain an important subpopulation with clinically significant disease activity. To date, serious treatment-related adverse events have not been observed in patients receiving anti-type I IFN-targeted therapy, which is intriguing because the type I IFN system is fundamental to both innate and acquired immunity.29 132 pDC depletion may be a more selective approach to controlling excessive type I IFN production in autoimmune diseases because the ‘nonprofessional’ IFN-producing cell populations would be spared. At the same time, the community will benefit in the near future from a better understanding of the heterogeneity of pDCs. BIIB059, a humanised monoclonal antibody to blood dendritic cell antigen 2 (a pDC-specific receptor), is currently being developed for the treatment of SLE. In a phase 1 study, it demonstrated a favourable safety profile, decreased IFN-response gene expression and reduced skin disease activity.134

    Substantially more research is needed to discern the mechanisms of induction and response to type I IFNs across autoimmune and non-autoimmune inflammatory diseases, especially with regards to identifying the drivers of type I IFN production and the effects of these cytokines on T cell populations. Sustained type I IFN production in chronic infections contrasts with the transient and well-controlled response after acute viral infections but may be mechanistically similar to the dysregulation observed in the type I IFN system for IFN-driven autoimmune diseases.

    The role of type I IFNs in cancer and chronic infections is complex and context specific—at times they are ‘friend’ and at other times they are ‘foe’—but this does not preclude therapeutically targeting the type I IFN pathway at an appropriate stage of the disease process. The potential efficacy of targeting the type I IFN pathway in humans is evident from the correlates of anti-IFN antibodies and clinical symptoms in subcohorts of patients with APS-1. Patient phenotyping will be critical to successful intervention and will be helped by the bourgeoning capacity to accurately measure type I IFN-α. Given the prevalence of cancer and chronic TB/HIV infections, identifying drug targets along the type I IFN system for these therapeutic areas has the potential to yield treatments that would greatly impact human health around the world.

    Supplemental material

    Acknowledgments

    The second International Summit on Interferons in Inflammatory Diseases was sponsored by AstraZeneca. Editorial support was provided by Francis Golder, BVSc, PhD, and Alan Saltzman, PhD, of JK Associates. We thank the IFN summit attendees (online supplementary appendix table 1) for their participation and help in reviewing this manuscript.

    References

    1. 1.↵
      1. Stetson DB,
      2. Medzhitov R
      . Type I interferons in host defense. Immunity2006;25:373–81.doi:10.1016/j.immuni.2006.08.007
      OpenUrlCrossRefPubMedWeb of Science
    2. 2.↵
      1. Boxx GM,
      2. Cheng G
      . The roles of type I interferon in bacterial infection. Cell Host Microbe2016;19:760–9.doi:10.1016/j.chom.2016.05.016
      OpenUrlCrossRef
    3. 3.↵
      1. Soper A,
      2. Kimura I,
      3. Nagaoka S, et al
      . Type I interferon responses by HIV-1 infection: association with disease progression and control. Front Immunol1823;2017.
    4. 4.↵
      1. Murira A,
      2. Lamarre A
      . Type-I interferon responses: from Friend to foe in the battle against chronic viral infection. Front Immunol2016;7.doi:10.3389/fimmu.2016.00609
    5. 5.↵
      1. Bengtsson AA,
      2. Rönnblom L
      . Role of interferons in SLE. Best Pract Res Clin Rheumatol2017;31:415–28.doi:10.1016/j.berh.2017.10.003
      OpenUrl
    6. 6.↵
      1. Rönnblom L,
      2. Eloranta M-L
      . The interferon signature in autoimmune diseases. Curr Opin Rheumatol2013;25:248–53.doi:10.1097/BOR.0b013e32835c7e32
      OpenUrlCrossRefPubMed
    7. 7.↵
      1. Li H,
      2. Ice JA,
      3. Lessard CJ, et al
      . Interferons in Sjögren’s Syndrome: Genes, Mechanisms, and Effects. Front Immunol2013;4.doi:10.3389/fimmu.2013.00290
    8. 8.↵
      1. Budhwani M,
      2. Mazzieri R,
      3. Dolcetti R
      . Plasticity of type I interferon-mediated responses in cancer therapy: from anti-tumor immunity to resistance. Front. Oncol.2018;8.doi:10.3389/fonc.2018.00322
    9. 9.↵
      1. King KR,
      2. Aguirre AD,
      3. Ye Y-X, et al
      . IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med2017;23:1481–7.doi:10.1038/nm.4428
      OpenUrlCrossRefPubMed
    10. 10.↵
      1. Crow MK,
      2. Rönnblom L
      . Report of the inaugural interferon research Summit: interferon in inflammatory diseases. Lupus Sci Med2018;5.doi:10.1136/lupus-2018-000276
    11. 11.↵
      1. Swiecki M,
      2. Colonna M
      . The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol2015;15:471–85.doi:10.1038/nri3865
      OpenUrlCrossRefPubMed
    12. 12.↵
      1. Arpaia N,
      2. Barton GM
      . Toll-like receptors: key players in antiviral immunity. Curr Opin Virol2011;1:447–54.doi:10.1016/j.coviro.2011.10.006
      OpenUrlCrossRefPubMed
    13. 13.↵
      1. Dixit E,
      2. Kagan JC
      . Intracellular pathogen detection by RIG-I-like receptors. Adv Immunol2013;117:99–125.
      OpenUrlCrossRefPubMed
    14. 14.↵
      1. Sun L,
      2. Wu J,
      3. Du F, et al
      . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science2013;339:786–91.doi:10.1126/science.1232458
      OpenUrlAbstract/FREE Full Text
    15. 15.↵
      1. Ivashkiv LB,
      2. Donlin LT
      . Regulation of type I interferon responses. Nat Rev Immunol2014;14:36–49.doi:10.1038/nri3581
      OpenUrlCrossRefPubMed
    16. 16.↵
      1. CT N,
      2. Mendoza JL,
      3. Garcia KC, et al
      . Alpha and beta type 1 interferon signaling: Passage for diverse biologic outcomes. Cell2016;164:349–52.
      OpenUrl
    17. 17.↵
      1. Hoffmann H-H,
      2. Schneider WM,
      3. Rice CM
      . Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol2015;36:124–38.doi:10.1016/j.it.2015.01.004
      OpenUrlCrossRefPubMed
    18. 18.↵
      1. Gallucci S,
      2. Lolkema M,
      3. Matzinger P
      . Natural adjuvants: endogenous activators of dendritic cells. Nat Med1999;5:1249–55.doi:10.1038/15200
      OpenUrlCrossRefPubMedWeb of Science
    19. 19.↵
      1. Kiefer K,
      2. Oropallo MA,
      3. Cancro MP, et al
      . Role of type I interferons in the activation of autoreactive B cells. Immunol Cell Biol2012;90:498–504.doi:10.1038/icb.2012.10
      OpenUrlCrossRefPubMedWeb of Science
    20. 20.↵
      1. Crouse J,
      2. Kalinke U,
      3. Oxenius A
      . Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol2015;15:231–42.doi:10.1038/nri3806
      OpenUrlCrossRefPubMed
    21. 21.↵
      1. Leonard D,
      2. Eloranta M-L,
      3. Hagberg N, et al
      . Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes. Ann Rheum Dis2016;75:1728–34.doi:10.1136/annrheumdis-2015-208055
      OpenUrlAbstract/FREE Full Text
    22. 22.↵
      1. Berggren O,
      2. Hagberg N,
      3. Weber G, et al
      . B lymphocytes enhance interferon-α production by plasmacytoid dendritic cells. Arthritis Rheum2012;64:3409–19.doi:10.1002/art.34599
      OpenUrlCrossRefPubMedWeb of Science
    23. 23.↵
      1. Care MA,
      2. Stephenson SJ,
      3. Barnes NA, et al
      . Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity. J Immunol2016;197:1447–59.doi:10.4049/jimmunol.1600624
      OpenUrlAbstract/FREE Full Text
    24. 24.↵
      1. Kaul A,
      2. Gordon C,
      3. Crow MK, et al
      . Systemic lupus erythematosus. Nat Rev Dis Primers2016;2.doi:10.1038/nrdp.2016.39
    25. 25.↵
      1. Rönnblom L,
      2. Alm GV,
      3. Eloranta M-L
      . Type I interferon and lupus. Curr Opin Rheumatol2009;21:471–7.doi:10.1097/BOR.0b013e32832e089e
      OpenUrlCrossRefPubMedWeb of Science
    26. 26.↵
      1. Crow MK
      . Type I interferon in the pathogenesis of lupus. J Immunol2014;192:5459–68.doi:10.4049/jimmunol.1002795
      OpenUrlAbstract/FREE Full Text
    27. 27.↵
      1. Chasset F,
      2. Arnaud L
      . Targeting interferons and their pathways in systemic lupus erythematosus. Autoimmun Rev2018;17:44–52.doi:10.1016/j.autrev.2017.11.009
      OpenUrl
    28. 28.↵
      1. Higgs BW,
      2. Liu Z,
      3. White B, et al
      . Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis2011;70:2029–36.doi:10.1136/ard.2011.150326
      OpenUrlAbstract/FREE Full Text
    29. 29.↵
      1. Furie R,
      2. Khamashta M,
      3. Merrill JT, et al
      . Anifrolumab, an Anti-Interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol2017;69:376–86.doi:10.1002/art.39962
      OpenUrl
    30. 30.↵
      1. Chiche L,
      2. Jourde-Chiche N,
      3. Whalen E, et al
      . Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol2014;66:1583–95.doi:10.1002/art.38628
      OpenUrl
    31. 31.↵
      1. Banchereau R,
      2. Hong S,
      3. Cantarel B, et al
      . Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell2016;165:551–65.doi:10.1016/j.cell.2016.03.008
      OpenUrlCrossRefPubMed
    32. 32.↵
      1. Md Yusof MY,
      2. Psarras A,
      3. El-Sherbiny YM, et al
      . Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status. Ann Rheum Dis2018;77:1432–9.
      OpenUrl
    33. 33.↵
      1. Oliveira JJ,
      2. Karrar S,
      3. Rainbow DB, et al
      . The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus. Arthritis Res Ther2018;20.doi:10.1186/s13075-018-1649-1
    34. 34.↵
      1. Barrat FJ,
      2. Elkon KB,
      3. Fitzgerald KA
      . Importance of nucleic acid recognition in inflammation and autoimmunity. Annu Rev Med2016;67:323–36.doi:10.1146/annurev-med-052814-023338
      OpenUrlCrossRefPubMed
    35. 35.↵
      1. Mahajan A,
      2. Herrmann M,
      3. Muñoz LE
      . Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol2016;7.doi:10.3389/fimmu.2016.00035
    36. 36.↵
      1. Clancy RM,
      2. Markham AJ,
      3. Reed JH, et al
      . Targeting downstream transcription factors and epigenetic modifications following Toll-like receptor 7/8 ligation to forestall tissue injury in anti-Ro60 associated heart block. J Autoimmun2016;67:36–45.doi:10.1016/j.jaut.2015.09.003
      OpenUrlCrossRefPubMed
    37. 37.↵
      1. Yarilina A,
      2. Park-Min K-H,
      3. Antoniv T, et al
      . TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat Immunol2008;9:378–87.doi:10.1038/ni1576
      OpenUrlCrossRefPubMedWeb of Science
    38. 38.↵
      1. Liu J,
      2. Berthier CC,
      3. Kahlenberg JM
      . Enhanced inflammasome activity in systemic lupus erythematosus is mediated via type I interferon-induced up-regulation of interferon regulatory factor 1. Arthritis Rheumatol2017;69:1840–9.doi:10.1002/art.40166
      OpenUrl
    39. 39.↵
      1. Kelly M,
      2. Lihua S,
      3. Zhe Z, et al
      . Transposable element dysregulation in systemic lupus erythematosus and regulation by histone conformation and Hsp90. Clin Immunol2018;197:6–18.doi:10.1016/j.clim.2018.08.011
      OpenUrl
    40. 40.↵
      1. Kassiotis G,
      2. Stoye JP
      . Immune responses to endogenous retroelements: taking the bad with the good. Nat Rev Immunol2016;16:207–19.doi:10.1038/nri.2016.27
      OpenUrlCrossRefPubMed
    41. 41.↵
      1. Mavragani CP,
      2. Sagalovskiy I,
      3. Guo Q, et al
      . Expression of long interspersed nuclear element 1 retroelements and induction of type I interferon in patients with systemic autoimmune disease. Arthritis Rheumatol2016;68:2686–96.doi:10.1002/art.39795
      OpenUrlCrossRef
    42. 42.↵
      1. Li P,
      2. Du J,
      3. Goodier JL, et al
      . Aicardi–Goutières syndrome protein TREX1 suppresses L1 and maintains genome integrity through exonuclease-independent ORF1p depletion. Nucleic Acids Res2017;45:4619–31.doi:10.1093/nar/gkx178
      OpenUrl
    43. 43.↵
      1. Gonzalez-Quintial R,
      2. Nguyen A,
      3. Kono DH, et al
      . Lupus acceleration by a MAVS-activating RNA virus requires endosomal TLR signaling and host genetic predisposition. Plos One2018;13:e0203118.doi:10.1371/journal.pone.0203118
    44. 44.↵
      1. Kerur N,
      2. Fukuda S,
      3. Banerjee D, et al
      . cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med2018;24:50–61.doi:10.1038/nm.4450
      OpenUrlPubMed
    45. 45.↵
      1. Sun B,
      2. Sundström KB,
      3. Chew JJ, et al
      . Dengue virus activates cGAS through the release of mitochondrial DNA. Sci Rep2017;7.doi:10.1038/s41598-017-03932-1
    46. 46.↵
      1. Caielli S,
      2. Athale S,
      3. Domic B, et al
      . Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med2016;213:697–713.doi:10.1084/jem.20151876
      OpenUrlAbstract/FREE Full Text
    47. 47.↵
      1. Lood C,
      2. Blanco LP,
      3. Purmalek MM, et al
      . Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med2016;22:146–53.doi:10.1038/nm.4027
      OpenUrlCrossRefPubMed
    48. 48.↵
      1. Buskiewicz IA,
      2. Montgomery T,
      3. Yasewicz EC, et al
      . Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus. Sci Signal2016;9.doi:10.1126/scisignal.aaf1933
    49. 49.↵
      1. Thomas CA,
      2. Tejwani L,
      3. Trujillo CA, et al
      . Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell2017;21:319–31.doi:10.1016/j.stem.2017.07.009
      OpenUrlCrossRef
    50. 50.↵
      1. Langefeld CD,
      2. Ainsworth HC,
      3. Graham DSC, et al
      . Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun2017;8.doi:10.1038/ncomms16021
    51. 51.↵
      1. Hagberg N,
      2. Joelsson M,
      3. Leonard D, et al
      . The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE. Ann Rheum Dis2018;77:1070–7.doi:10.1136/annrheumdis-2017-212794
      OpenUrlAbstract/FREE Full Text
    52. 52.↵
      1. Hagberg N,
      2. Ronnblom L
      . Interferon-alpha enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T]. Ann Rheum Dis2018.
    53. 53.↵
      1. Ghodke-Puranik Y,
      2. Dorschner JM,
      3. Vsetecka DM, et al
      . Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells. Arthritis Rheumatol2017;69:2328–37.doi:10.1002/art.40304
      OpenUrl
    54. 54.↵
      1. Hedrich CM
      . Epigenetics in SLE. Curr Rheumatol Rep2017;19.doi:10.1007/s11926-017-0685-1
    55. 55.↵
      1. Imgenberg-Kreuz J,
      2. Carlsson Almlöf J,
      3. Leonard D, et al
      . DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Ann Rheum Dis2018;77:736–43.doi:10.1136/annrheumdis-2017-212379
      OpenUrlAbstract/FREE Full Text
    56. 56.↵
      1. Ulff-Møller CJ,
      2. Asmar F,
      3. Liu Y, et al
      . Twin DNA methylation profiling reveals flare-dependent interferon signature and B cell promoter hypermethylation in systemic lupus erythematosus. Arthritis Rheumatol2018;70:878–90.doi:10.1002/art.40422
      OpenUrl
    57. 57.↵
      1. Park SH,
      2. Kang K,
      3. Giannopoulou E, et al
      . Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat Immunol2017;18:1104–16.doi:10.1038/ni.3818
      OpenUrlCrossRefPubMed
    58. 58.↵
      1. Brito-Zerón P,
      2. Baldini C,
      3. Bootsma H, et al
      . Sjögren syndrome. Nat Rev Dis Primers2016;2.doi:10.1038/nrdp.2016.47
    59. 59.↵
      1. Thorlacius GE,
      2. Wahren-Herlenius M,
      3. Ronnblom L
      . An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome. Curr Opin Rheumatol2018;30:471–81.
      OpenUrl
    60. 60.↵
      1. Benchabane S,
      2. Belkhelfa M,
      3. Belguendouz H, et al
      . Interferon-β inhibits inflammatory responses mediators via suppression of iNOS signaling pathway in PBMCs from patients with primary Sjögren's syndrome. Inflammopharmacology2018;26:1165–74.doi:10.1007/s10787-018-0499-4
      OpenUrl
    61. 61.↵
      1. Brkic Z,
      2. Maria NI,
      3. van Helden-Meeuwsen CG, et al
      . Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis2013;72:728–35.doi:10.1136/annrheumdis-2012-201381
      OpenUrlAbstract/FREE Full Text
    62. 62.↵
      1. Bodewes ILA,
      2. Al-Ali S,
      3. van Helden-Meeuwsen CG, et al
      . Systemic interferon type I and type II signatures in primary Sjögren’s syndrome reveal differences in biological disease activity. Rheumatology2018;57:921–30.doi:10.1093/rheumatology/kex490
      OpenUrl
    63. 63.↵
      1. Nezos A,
      2. Gravani F,
      3. Tassidou A, et al
      . Type I and II interferon signatures in Sjogren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis. J Autoimmun2015;63:47–58.doi:10.1016/j.jaut.2015.07.002
      OpenUrlCrossRefPubMed
    64. 64.↵
      1. Seror R,
      2. Nocturne G,
      3. Lazure T, et al
      . Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjögren’s syndrome: results of the BELISS study. Arthritis Res Ther2015;17.doi:10.1186/s13075-015-0750-y
    65. 65.↵
      1. Allanore Y,
      2. Simms R,
      3. Distler O, et al
      . Systemic sclerosis. Nat Rev Dis Primers2015;1.doi:10.1038/nrdp.2015.2
    66. 66.↵
      1. Christmann RB,
      2. Sampaio-Barros P,
      3. Stifano G, et al
      . Association of interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol2014;66:714–25.doi:10.1002/art.38288
      OpenUrl
    67. 67.↵
      1. Wang B,
      2. Higgs BW,
      3. Chang L, et al
      . Pharmacogenomics and translational simulations to bridge indications for an Anti-Interferon-α receptor antibody. Clin Pharmacol Ther2013;93:483–92.doi:10.1038/clpt.2013.35
      OpenUrlCrossRefPubMed
    68. 68.↵
      1. Guo X,
      2. Higgs BW,
      3. Bay-Jensen AC, et al
      . Suppression of T cell activation and collagen accumulation by an anti-IFNAR1 mAb, anifrolumab, in adult patients with systemic sclerosis. J Invest Dermatol2015;135:2402–9.doi:10.1038/jid.2015.188
      OpenUrlCrossRefPubMed
    69. 69.↵
      1. George PM,
      2. Oliver E,
      3. Dorfmuller P, et al
      . Evidence for the involvement of type I interferon in pulmonary arterial hypertension. Circ Res2014;114:677–88.doi:10.1161/CIRCRESAHA.114.302221
      OpenUrlAbstract/FREE Full Text
    70. 70.↵
      1. Ah Kioon MD,
      2. Tripodo C,
      3. Fernandez D, et al
      . Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Sci Transl Med2018;10. doi:doi:10.1126/scitranslmed.aam8458
    71. 71.↵
      1. Dimachkie MM,
      2. Barohn RJ,
      3. Amato AA
      . Idiopathic inflammatory myopathies. Neurol Clin2014;32:595–628. vii.doi:10.1016/j.ncl.2014.04.007
      OpenUrl
    72. 72.↵
      1. Greenberg SA,
      2. Pinkus JL,
      3. Pinkus GS, et al
      . Interferon-α/β-mediated innate immune mechanisms in dermatomyositis. Ann Neurol2005;57:664–78.doi:10.1002/ana.20464
      OpenUrlCrossRefPubMedWeb of Science
    73. 73.↵
      1. Liao AP,
      2. Salajegheh M,
      3. Nazareno R, et al
      . Interferon β is associated with type 1 interferon-inducible gene expression in dermatomyositis. Ann Rheum Dis2011;70:831–6.doi:10.1136/ard.2010.139949
      OpenUrlAbstract/FREE Full Text
    74. 74.↵
      1. Somani A-K,
      2. Swick AR,
      3. Cooper KD, et al
      . Severe dermatomyositis triggered by interferon beta-1a therapy and associated with enhanced type I interferon signaling. Arch Dermatol2008;144:1341–9.doi:10.1001/archderm.144.10.1341
      OpenUrlCrossRefPubMedWeb of Science
    75. 75.↵
      1. Piper CJM,
      2. Wilkinson MGL,
      3. Deakin CT, et al
      . CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α. Front Immunol2018;9.doi:10.3389/fimmu.2018.01372
    76. 76.↵
      1. Smolen JS,
      2. Aletaha D,
      3. Barton A, et al
      . Rheumatoid arthritis. Nat Rev Dis Primers2018;4.doi:10.1038/nrdp.2018.1
    77. 77.↵
      1. Cavanagh LL,
      2. Boyce A,
      3. Smith L, et al
      . Rheumatoid arthritis synovium contains plasmacytoid dendritic cells. Arthritis Res Ther2005;7:R230–40.doi:10.1186/ar1467
      OpenUrlCrossRefPubMedWeb of Science
    78. 78.↵
      1. van Holten J,
      2. Smeets TJM,
      3. Blankert P, et al
      . Expression of interferon beta in synovial tissue from patients with rheumatoid arthritis: comparison with patients with osteoarthritis and reactive arthritis. Ann Rheum Dis2005;64:1780–2.doi:10.1136/ard.2005.040477
      OpenUrlAbstract/FREE Full Text
    79. 79.↵
      1. Roelofs MF,
      2. Wenink MH,
      3. Brentano F, et al
      . Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (rA). Ann Rheum Dis2009;68:1486–93.doi:10.1136/ard.2007.086421
      OpenUrlAbstract/FREE Full Text
    80. 80.↵
      1. van der Pouw Kraan TCTM,
      2. Wijbrandts CA,
      3. van Baarsen LGM, et al
      . Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis2007;66:1008–14.doi:10.1136/ard.2006.063412
      OpenUrlAbstract/FREE Full Text
    81. 81.↵
      1. Mavragani CP,
      2. La DT,
      3. Stohl W, et al
      . Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-β/α ratios in rheumatoid arthritis patients: a post hoc analysis of a predominantly Hispanic cohort. Arthritis Rheum2010;62:392–401.doi:10.1002/art.27226
      OpenUrlCrossRefPubMedWeb of Science
    82. 82.↵
      1. Raterman HG,
      2. Vosslamber S,
      3. de Ridder S, et al
      . The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther2012;14.doi:10.1186/ar3819
    83. 83.↵
      1. Wampler Muskardin T,
      2. Vashisht P,
      3. Dorschner JM, et al
      . Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. Ann Rheum Dis2016;75:1757–62.doi:10.1136/annrheumdis-2015-208001
      OpenUrlAbstract/FREE Full Text
    84. 84.↵
      1. de Jong TD,
      2. Blits M,
      3. de Ridder S, et al
      . Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters. Arthritis Res Ther2016;18.doi:10.1186/s13075-016-1191-y
    85. 85.↵
      1. Cooles FAH,
      2. Anderson AE,
      3. Skelton A, et al
      . Phenotypic and transcriptomic analysis of peripheral blood plasmacytoid and conventional dendritic cells in early drug naïve rheumatoid arthritis. Front Immunol2018;9.doi:10.3389/fimmu.2018.00755
    86. 86.↵
      1. Guo C-J,
      2. Leung PSC,
      3. Zhang W, et al
      . The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1). Autoimmun Rev2018;17:78–85.doi:10.1016/j.autrev.2017.11.012
      OpenUrl
    87. 87.↵
      1. Meyer S,
      2. Woodward M,
      3. Hertel C, et al
      . AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell2016;166:582–95.doi:10.1016/j.cell.2016.06.024
      OpenUrlCrossRefPubMed
    88. 88.↵
      1. Fishman D,
      2. Kisand K,
      3. Hertel C, et al
      . Autoantibody repertoire in APECED patients targets two distinct subgroups of proteins. Front Immunol2017;8.doi:10.3389/fimmu.2017.00976
    89. 89.↵
      1. Rodero MP,
      2. Decalf J,
      3. Bondet V, et al
      . Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med2017;214:1547–55.doi:10.1084/jem.20161451
      OpenUrlAbstract/FREE Full Text
    90. 90.↵
      1. Pai M,
      2. Behr MA,
      3. Dowdy D, et al
      . Tuberculosis. Nat Rev Dis Primers2016;2.doi:10.1038/nrdp.2016.76
    91. 91.↵
      1. World Health Organization
      . Tuberculosis (TB). Available: http://www.who.int/gho/tb/en/ [Accessed 21 Aug 2018].
    92. 92.↵
      1. O'Garra A,
      2. Redford PS,
      3. McNab FW, et al
      . The immune response in tuberculosis. Annu Rev Immunol2013;31:475–527.doi:10.1146/annurev-immunol-032712-095939
      OpenUrlCrossRefPubMedWeb of Science
    93. 93.↵
      1. Singhania A,
      2. Verma R,
      3. Graham CM, et al
      . A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. Nat Commun2018;9.doi:10.1038/s41467-018-04579-w
    94. 94.↵
      1. Berry MPR,
      2. Graham CM,
      3. McNab FW, et al
      . An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature2010;466:973–7.doi:10.1038/nature09247
      OpenUrlCrossRefPubMedWeb of Science
    95. 95.↵
      1. Bloom CI,
      2. Graham CM,
      3. Berry MPR, et al
      . Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy. PLoS One2012;7:e46191.doi:10.1371/journal.pone.0046191
    96. 96.↵
      1. Moreira-Teixeira L,
      2. Mayer-Barber K,
      3. Sher A, et al
      . Type I interferons in tuberculosis: foe and occasionally Friend. J Exp Med2018;215:1273–85.doi:10.1084/jem.20180325
      OpenUrlAbstract/FREE Full Text
    97. 97.↵
      1. Carmona J,
      2. Cruz A,
      3. Moreira-Teixeira L, et al
      . Mycobacterium tuberculosis strains are differentially recognized by TLRs with an impact on the immune response. PLoS One2013;8:e67277.doi:10.1371/journal.pone.0067277
    98. 98.↵
      1. Wiens KE,
      2. Ernst JD
      . The mechanism for type I interferon induction by Mycobacterium tuberculosis is bacterial strain-dependent. PLoS Pathog2016;12:e1005809.doi:10.1371/journal.ppat.1005809
    99. 99.↵
      1. Wassermann R,
      2. Gulen MF,
      3. Sala C, et al
      . Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe2015;17:799–810.doi:10.1016/j.chom.2015.05.003
      OpenUrlCrossRefPubMed
    100. 100.↵
      1. Collins AC,
      2. Cai H,
      3. Li T, et al
      . Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe2015;17:820–8.doi:10.1016/j.chom.2015.05.005
      OpenUrlCrossRefPubMed
    101. 101.↵
      1. Watson RO,
      2. Bell SL,
      3. MacDuff DA, et al
      . The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe2015;17:811–9.doi:10.1016/j.chom.2015.05.004
      OpenUrlCrossRefPubMed
    102. 102.↵
      1. Manca C,
      2. Tsenova L,
      3. Bergtold A, et al
      . Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha /beta. Proc Natl Acad Sci U S A2001;98:5752–7.doi:10.1073/pnas.091096998
      OpenUrlAbstract/FREE Full Text
    103. 103.↵
      1. Manca C,
      2. Tsenova L,
      3. Freeman S, et al
      . Hypervirulent M. tuberculosis W/Beijing strains upregulate type I IFNs and increase expression of negative regulators of the JAK-STAT pathway. J Interferon Cytokine Res2005;25:694–701.doi:10.1089/jir.2005.25.694
      OpenUrlCrossRefPubMedWeb of Science
    104. 104.↵
      1. Antonelli LRV,
      2. Gigliotti Rothfuchs A,
      3. Gonçalves R, et al
      . Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J Clin Invest2010;120:1674–82.doi:10.1172/JCI40817
      OpenUrlCrossRefPubMedWeb of Science
    105. 105.↵
      1. Redford PS,
      2. Mayer-Barber KD,
      3. McNab FW, et al
      . Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon Receptor–Dependent pathway. J Infect Dis2014;209:270–4.doi:10.1093/infdis/jit424
      OpenUrlCrossRefPubMed
    106. 106.↵
      1. McNab FW,
      2. Ewbank J,
      3. Rajsbaum R, et al
      . TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production. J Immunol2013;191:1732–43.doi:10.4049/jimmunol.1300146
      OpenUrlAbstract/FREE Full Text
    107. 107.↵
      1. McNab FW,
      2. Ewbank J,
      3. Howes A, et al
      . Type I IFN induces IL-10 production in an IL-27-independent manner and blocks responsiveness to IFN-γ for production of IL-12 and bacterial killing in Mycobacterium tuberculosis-infected macrophages. J Immunol2014;193:3600–12.doi:10.4049/jimmunol.1401088
      OpenUrlAbstract/FREE Full Text
    108. 108.↵
      1. Giosue S,
      2. Casarini M,
      3. Alemanno L, et al
      . Effects of aerosolized interferon- α in patients with pulmonary tuberculosis. Am J Respir Crit Care Med1998;158:1156–62.doi:10.1164/ajrccm.158.4.9803065
      OpenUrlCrossRefPubMedWeb of Science
    109. 109.↵
      1. Palmero D,
      2. Eiguchi K,
      3. Rendo P, et al
      . Phase II trial of recombinant interferon-alpha2b in patients with advanced intractable multidrug-resistant pulmonary tuberculosis: long-term follow-up. Int J Tuberc Lung Dis1999;3:214–8.
      OpenUrlPubMedWeb of Science
    110. 110.↵
      1. Moreira-Teixeira L,
      2. Sousa J,
      3. McNab FW, et al
      . Type I IFN Inhibits Alternative Macrophage Activation during Mycobacterium tuberculosis Infection and Leads to Enhanced Protection in the Absence of IFN-γ Signaling. J Immunol2016;197:4714–26.doi:10.4049/jimmunol.1600584
      OpenUrlAbstract/FREE Full Text
    111. 111.↵
      1. Ward CM,
      2. Jyonouchi H,
      3. Kotenko SV, et al
      . Adjunctive treatment of disseminated Mycobacterium avium complex infection with interferon alpha-2b in a patient with complete interferon-gamma receptor R1 deficiency. Eur J Pediatr2007;166:981–5.doi:10.1007/s00431-006-0339-1
      OpenUrlCrossRefPubMed
    112. 112.↵
      1. Harley JB,
      2. Chen X,
      3. Pujato M, et al
      . Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat Genet2018;50:699–707.doi:10.1038/s41588-018-0102-3
      OpenUrlCrossRef
    113. 113.↵
      1. Pisetsky DS
      . Role of Epstein-Barr virus infection in SLE: Gene-environment interactions at the molecular level. Ann Rheum Dis2018;77:1249–50.doi:10.1136/annrheumdis-2018-213783
      OpenUrl
    114. 114.↵
      1. Deeks SG,
      2. Overbaugh J,
      3. Phillips A, et al
      . HIV infection. Nat Rev Dis Primers2015;1.doi:10.1038/nrdp.2015.35
    115. 115.↵
      1. Thaney VE,
      2. Kaul M
      . Type I interferons in NeuroHIV. Viral Immunol2019;32.doi:10.1089/vim.2018.0085
    116. 116.↵
      1. Bosinger SE,
      2. Li Q,
      3. Gordon SN, et al
      . Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest2009;119:3556–72.doi:10.1172/JCI40115
      OpenUrlCrossRefPubMedWeb of Science
    117. 117.↵
      1. Carrillo MA,
      2. Zhen A,
      3. Kitchen SG
      . The use of the humanized mouse model in gene therapy and immunotherapy for HIV and cancer. Front Immunol2018;9.doi:10.3389/fimmu.2018.00746
    118. 118.↵
      1. O’Brien M,
      2. Manches O,
      3. Bhardwaj N
      . Plasmacytoid dendritic cells in HIV infection. Adv Exp Med Biol2013;762:71–107.
      OpenUrlCrossRefPubMed
    119. 119.↵
      1. Li G,
      2. Cheng M,
      3. Nunoya J-ichi, et al
      . Plasmacytoid dendritic cells suppress HIV-1 replication but contribute to HIV-1 induced immunopathogenesis in humanized mice. PLoS Pathog2014;10:e1004291.doi:10.1371/journal.ppat.1004291
    120. 120.↵
      1. Li G,
      2. Zhao J,
      3. Cheng L, et al
      . HIV-1 infection depletes human CD34+CD38- hematopoietic progenitor cells via pDC-dependent mechanisms. PLoS Pathog2017;13:e1006505.doi:10.1371/journal.ppat.1006505
    121. 121.↵
      1. Cheng L,
      2. Ma J,
      3. Li J, et al
      . Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J Clin Invest2017;127:269–79.doi:10.1172/JCI90745
      OpenUrl
    122. 122.↵
      1. Patel SA,
      2. Minn AJ
      . Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity2018;48:417–33.doi:10.1016/j.immuni.2018.03.007
      OpenUrl
    123. 123.↵
      1. Gajewski TF,
      2. Corrales L
      . New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev2015;26:175–8.doi:10.1016/j.cytogfr.2015.01.001
      OpenUrlCrossRefPubMed
    124. 124.↵
      1. Harding SM,
      2. Benci JL,
      3. Irianto J, et al
      . Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature2017;548:466–70.doi:10.1038/nature23470
      OpenUrlCrossRefPubMed
    125. 125.↵
      1. Weichselbaum RR,
      2. Ishwaran H,
      3. Yoon T, et al
      . An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci U S A2008;105:18490–5.doi:10.1073/pnas.0809242105
      OpenUrlAbstract/FREE Full Text
    126. 126.↵
      1. Nabet BY,
      2. Qiu Y,
      3. Shabason JE, et al
      . Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell2017;170:e13:352–66.doi:10.1016/j.cell.2017.06.031
      OpenUrl
    127. 127.↵
      1. Boelens MC,
      2. Wu TJ,
      3. Nabet BY, et al
      . Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell2014;159:499–513.doi:10.1016/j.cell.2014.09.051
      OpenUrlCrossRefPubMed
    128. 128.↵
      1. Benci JL,
      2. Xu B,
      3. Qiu Y, et al
      . Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell2016;167:e12:1540–54.doi:10.1016/j.cell.2016.11.022
      OpenUrl
    129. 129.↵
      1. Buja LM,
      2. Vander Heide RS
      . Pathobiology of ischemic heart disease: past, present and future. Cardiovasc Pathol2016;25:214–20.doi:10.1016/j.carpath.2016.01.007
      OpenUrl
    130. 130.↵
      1. Konstam MA,
      2. Kramer DG,
      3. Patel AR, et al
      . Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging2011;4:98–108.doi:10.1016/j.jcmg.2010.10.008
      OpenUrlAbstract/FREE Full Text
    131. 131.↵
      1. Corbucci GG,
      2. Perrino C,
      3. Donato G, et al
      . Transient and reversible deoxyribonucleic acid damage in human left ventricle under controlled ischemia and reperfusion. J Am Coll Cardiol2004;43:1992–9.doi:10.1016/j.jacc.2004.01.040
      OpenUrlFREE Full Text
    132. 132.↵
      1. Wallace DJ,
      2. Furie RA,
      3. Tanaka Y, et al
      . Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet2018;392:222–31.doi:10.1016/S0140-6736(18)31363-1
      OpenUrl
    133. 133.↵
      1. Sanchez GAM,
      2. Reinhardt A,
      3. Ramsey S, et al
      . JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest2018;128:3041–52.doi:10.1172/JCI98814
      OpenUrl
    134. 134.↵
      1. Furie R,
      2. Werth VP,
      3. Merola JF, et al
      . Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest2019;129:1359–71.doi:10.1172/JCI124466
      OpenUrl
    135. 135.
      1. McNab F,
      2. Mayer-Barber K,
      3. Sher A, et al
      . Type I interferons in infectious disease. Nat Rev Immunol2015;15:87–103.doi:10.1038/nri3787
      OpenUrlCrossRefPubMed
    136. 136.
      1. González-Navajas JM,
      2. Lee J,
      3. David M, et al
      . Immunomodulatory functions of type I interferons. Nat Rev Immunol2012;12:125–35.doi:10.1038/nri3133
      OpenUrlCrossRefPubMed
    137. 137.
      1. Aman MJ,
      2. Tretter T,
      3. Eisenbeis I, et al
      . Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes. Blood1996;87:4731–6.
      OpenUrlAbstract/FREE Full Text
    138. 138.
      1. Alunno A,
      2. Bartoloni E,
      3. Bistoni O, et al
      . Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new. Clin Dev Immunol2012;2012:1–5.doi:10.1155/2012/823085
      OpenUrlCrossRef
    139. 139.
      1. López P,
      2. Rodríguez-Carrio J,
      3. Caminal-Montero L, et al
      . A pathogenic IFNα, BLyS and IL-17 axis in systemic lupus erythematosus patients. Sci Rep2016;6.doi:10.1038/srep20651
    140. 140.
      1. Fitzgerald-Bocarsly P,
      2. Feng D
      . The role of type I interferon production by dendritic cells in host defense. Biochimie2007;89:843–55.doi:10.1016/j.biochi.2007.04.018
      OpenUrlCrossRefPubMed
    141. 141.
      1. Swiecki M,
      2. Colonna M
      . Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev2010;234:142–62.doi:10.1111/j.0105-2896.2009.00881.x
      OpenUrlCrossRefPubMedWeb of Science
    142. 142.
      1. Jackson SW,
      2. Kolhatkar NS,
      3. Rawlings DJ
      . B cells take the front seat: dysregulated B cell signals orchestrate loss of tolerance and autoantibody production. Curr Opin Immunol2015;33:70–7.doi:10.1016/j.coi.2015.01.018
      OpenUrlCrossRefPubMed
    143. 143.
      1. Vazquez MI,
      2. Catalan-Dibene J,
      3. Zlotnik A
      . B cells responses and cytokine production are regulated by their immune microenvironment. Cytokine2015;74:318–26.doi:10.1016/j.cyto.2015.02.007
      OpenUrlCrossRef
    144. 144.
      1. Thacker SG,
      2. Zhao W,
      3. Smith CK, et al
      . Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum2012;64:2975–85.doi:10.1002/art.34504
      OpenUrlCrossRefPubMedWeb of Science
    145. 145.
      1. Knight JS,
      2. Kaplan MJ
      . Cardiovascular disease in lupus: insights and updates. Curr Opin Rheumatol2013;25:597–605.
      OpenUrlCrossRefPubMed
    146. 146.
      1. Bialas AR,
      2. Presumey J,
      3. Das A, et al
      . Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature2017;546:539–43.doi:10.1038/nature22821
      OpenUrlCrossRefPubMed

    Footnotes

    • Funding This study was supported by AstraZeneca.

    • Competing interests MC and LR, as well as the meeting participants, received fees for their time in preparing for and presenting at/attending the IFN Summit meeting. They received no fees for their work as authors of the manuscript.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Data availability statement No additional data are available.