Type I Interferons in Autoimmune Disease · 03.11.2019 · Annual Review of Pathology: Mechanisms of Disease Type I Interferons in Autoimmune Disease Mary K. Crow, Mikhail Olferiev,

PM14CH15_Crow ARI 8 December 2018 14:56

Annual Review of Pathology: Mechanisms of Disease

Type I Interferons inAutoimmune DiseaseMary K. Crow, Mikhail Olferiev, and Kyriakos A. KirouMary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York,New York 10021, USA; email: [email protected]

Annu. Rev. Pathol. Mech. Dis. 2019. 14:369–93

First published as a Review in Advance onOctober 17, 2018

The Annual Review of Pathology: Mechanisms ofDisease is online at pathol.annualreviews.org

https://doi.org/10.1146/annurev-pathol-020117-043952

Copyright c© 2019 by Annual Reviews.All rights reserved

Keywords

systemic lupus erythematosus, systemic autoimmune disease, type Iinterferon, interferon-α, nucleic acid, Toll-like receptor

Abstract

Type I interferons, which make up the first cytokine family to be describedand are the essential mediators of antivirus host defense, have emerged ascentral elements in the immunopathology of systemic autoimmune diseases,with systemic lupus erythematosus as the prototype. Lessons from investi-gation of interferon regulation following virus infection can be applied tolupus, with the conclusion that sustained production of type I interferonshifts nearly all components of the immune system toward pathologic func-tions that result in tissue damage and disease. We review recent data, mainlyfrom studies of patients with systemic lupus erythematosus, that providenew insights into the mechanisms of induction and the immunologic con-sequences of chronic activation of the type I interferon pathway. Currentconcepts implicate endogenous nucleic acids, driving both cytosolic sensorsand endosomal Toll-like receptors, in interferon pathway activation andsuggest targets for development of novel therapeutics that may restore theimmune system to health.

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https://www.annualreviews.org/doi/full/10.1146/annurev-pathol-020117-043952


INTRODUCTION

The discovery in 1957 of type I interferon (IFN-I) as a cytokine family mediating host defenseagainst virus infection initiated 60 years of compelling investigation illuminating complex mech-anisms of immune cell function. The IFN-I locus on human chromosome 9p encodes 13 IFN-αgenes, IFN-β, IFN-ε, IFN-ω, and IFN-κ, with both gene conversion and gene duplication con-tributing to the evolution of this gene family (1). The hundreds of IFN-I-regulated gene productsthat implement a coordinated response to virus invasion, along with the multiple regulatory mech-anisms that control this response, have a dark side; they are recognized to be important mediatorsin two categories of disease that are not obviously attributable to virus infection: systemic au-toimmune disease and the monogenic interferonopathies. Studies of patients with the prototypesystemic autoimmune disease systemic lupus erythematosus (SLE), along with studies of rare pa-tients with Aicardi-Goutieres syndrome (AGS), continue to enhance our understanding of theimmunopathogenesis of those disorders, as well as the mechanisms of activation and control ofthe innate and adaptive immune response in health and disease.

The notion that IFN-I might play a pathogenic role in SLE was first raised in 1969 in an insight-ful and prescient paper by Steinberg et al. (2) describing the acceleration of autoimmune disease inthe (NZB × NZW) F1 murine lupus model following administration of polyinosinic:polycytidylicacid, an inducer of IFN-I. The authors suggested a role for nucleic acid as a driver of IFN-I pro-duction in lupus and identified an association between IFN-I and the induction of anti-RNA au-toantibodies, two observations that are supported by studies performed decades later. Skurkovichand colleagues (3, 4) and then Hooks et al. (5) documented elevated IFN-I in the serum of patientswith SLE as well as other systemic autoimmune diseases, including rheumatoid arthritis, systemicsclerosis and Sjogren’s syndrome. Additional early studies demonstrated the capacity of immunecomplexes containing antigen and antibody to induce IFN-I by immune system cells (6). Thishas proved to be an important mechanism relevant to the high levels of circulating IFN-I seen inpatients with RNA-containing immune complexes and documented in an important series of invitro studies led by Ronnblom (7) and later supported by studies from our group demonstratinga strong association between the presence of autoantibodies targeting RNA-binding proteins andactivation of the IFN-I pathway (8).

A role for IFN-I in the tissue pathology of SLE was suggested by the studies of Rich andcolleagues (9, 10), which demonstrated the capacity of both recombinant IFN-α and SLE sera toinduce intracellular microtubular structures that were termed lupus inclusions. These structureshad been observed in the glomerular endothelial cells of patients with SLE and dermatomyositis(11), and Rich et al.’s studies implicated IFN-I rather than virus in their development (10). Manysubsequent studies, in spontaneous murine models of lupus and in lupus patients, supported apathogenic rather than a protective role of IFN-I in many systemic autoimmune diseases. Over-expression of IFN-α using an adenovirus construct accelerated autoimmunity and disease in the(NZB × NZW) F1 model and implicated an essential role for T cells in that effect, indicating thatIFN-I has broad immune system effects (12). Serendipitous observations of the development oflupus autoantibodies and clinical lupus-like disease in some patients receiving recombinant IFN-αprovided a similar demonstration in human patients that IFN-I could play a pathogenic role inSLE but also suggested that the genetic profile of the recipient of IFN-α is a determinant ofwhether pathology developed (13).

THE INTERFERON SIGNATURE

This robust record of investigation implicating IFN-I in the pathogenesis of SLE, and to someextent in other systemic autoimmune diseases, drew attention to the IFN-I cytokine family as a

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likely contributor to the immunopathology of those diseases. However, it was the availability ofmicroarray platforms for assessment of global gene expression that led researchers to considerIFN-I, along with its broad signature of IFN-I-induced gene products, as a core mechanism inthe immunopathogenesis of SLE. In 2003, three laboratories used microarray analysis of geneexpression in peripheral blood cells of patients with SLE to demonstrate a striking overexpressionof hundreds of gene transcripts that suggested induction by IFN-I (14–16). The following year, weused real-time polymerase chain reaction analysis of transcripts preferentially induced by eitherIFN-I (IFN-α) or IFN-γ to demonstrate that the observed transcript profile in microarray-basedstudies was attributable to IFN-I rather than IFN-γ and that the induced gene transcripts arecoordinately expressed in the cells of lupus patients. Expression of each of the transcripts highlycorrelated with expression of the others, suggesting that IFN-α, or a stimulus that behaved in asimilar manner to IFN-α, was responsible for the striking interferon signature present in most SLEpatients studied (17) (Figure 1a). The contribution of IFN-α to the IFN-I signature was confirmedwhen assay of IFN-I activity in sera from SLE patients was measured using a reporter cell line,WISH cells, that express the IFN-I receptor, IFNAR, and respond to IFN-I with expression ofIFN-I-induced gene transcripts (18). When an antibody specific to IFN-α was included in the assayculture, most of the IFN-I activity was inhibited, whereas anti-IFN-γ did not significantly reducethe capacity of the sera to induce IFN-I-regulated gene products. The demonstration of the IFNsignature has not only provided a tool for assessing involvement of the IFN-I pathway in SLE andrelated autoimmune diseases, as well as in the monogenic interferonopathies, but has also drivennew understanding of the mechanisms that account for the protean immunologic alterations that

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Figure 1Expression and induction of the type I interferon (IFN-I) signature. (a) IFN-I-induced gene expression wasassessed in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus(SLE) by reverse transcription polymerase chain reaction analysis of IFIT1, IFI44, MX1, and PKR.Coordinate expression of the IFN-I-regulated genes is shown based on relative expression compared tohousekeeping gene controls. (b) Healthy donor (HD) PBMCs were cultured with plasma from HDs or SLEpatients expressing autoantibodies (Abs) specific to RNA-binding proteins (anti-RBP) and/or DNA, andinduction of IFN-I was measured.

www.annualreviews.org • Type I Interferons in Autoimmune Disease 371

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characterize patients with lupus. Investigation of the inducers of the IFN signature has identifiedseveral rational therapeutic targets that are now under study, and significant therapeutic trials oftargeted therapies will soon be completed. Based on extensive study of the induction, regulation,and impact of the IFN-I signature in SLE, it is our view that activation of the IFN-I pathwayrepresents a fundamental feature of lupus pathogenesis, as well as an important but perhaps lesscentral contributor to the immunopathogenesis of Sjogren’s syndrome, systemic sclerosis, anddermatomyositis and perhaps other systemic autoimmune diseases (19).

EXOGENOUS AND ENDOGENOUS TRIGGERSOF TYPE I INTERFERON

Endosomal Toll-Like Receptor Ligands

Among the most significant challenges that limit understanding of the etiology of SLE is character-ization of the stimuli and pathways through which production of IFN-I is induced. Two categoriesof receptors and related molecular pathways—the endosomal Toll-like receptors (TLRs) and thecytosolic nucleic acid sensors—suggest triggers that are potentially relevant to lupus pathogenesis.A common theme is that nucleic acids, both RNA and DNA, have the potential to drive IFN-Iproduction.

Historically, as suggested by the insightful 1969 paper by Steinberg et al. (2), researchers con-sidered viruses to be the most obvious inducers of innate immune system activation. It is possiblethat activation of latent Epstein-Barr virus (EBV) could be responsible for production of IFN-I(20, 21). Recent studies show that expression of latent membrane protein 1 (LMP1), but not otherEBV-encoded transcripts, is correlated with expression of IFN-I-regulated genes, and SLE pa-tients have increased levels of antibodies against EBV early antigen, suggestive of reactivation (22).Potential mechanisms whereby EBV might induce IFN-I are suggested by the demonstration thatintact EBV can trigger TLR9 in a major histocompatibility complex (MHC) class II–dependentmanner, and small RNAs encoded by EBV, EBERs, activate TLR7 and stimulate IFN-I pro-duction (23–25). At least at the level of EBV-specific CD8+ T cells, which are impaired in theiranti-EBV cytotoxic function, flare of lupus disease activity precedes EBV reactivation (26). It isthus not clear if the functional effects of EBV on the IFN-I pathway and other immune systemfunctions reflect a primary etiologic role for EBV or are a consequence of lupus disease.

While viral nucleic acids, whether related to acute or to reactivated latent infection, may induceIFN-I expression, the significant insight relevant to SLE pathogenesis is that endogenous nucleicacid can also trigger IFN-I expression and the IFN-I signature. The laboratory of Lars Ronnblomperformed a series of experiments that documented the capacity of immune complexes containingmaterial derived from necrotic and apoptotic cells, along with SLE immunoglobulin G (IgG), toinduce production of IFN-α by plasmacytoid dendritic cells (pDCs) (7, 27). The activity of thenecrotic material depended on the presence of RNA, and the activity of the SLE IgG correlatedwith the presence of antibodies specific for RNA-binding proteins. In our laboratory, we studiedplasma derived from patients with autoantibodies specific for RNA-binding proteins (RBPs; Ro,La, Sm, or RNP) and/or anti-double-stranded DNA autoantibodies and found that induction ofIFN-I in healthy donor peripheral blood mononuclear cells (PBMCs) depended on the presenceof anti-RBP autoantibodies (Figure 1b). Barrat et al. implicated endosomal TLR7 and TLR9in this response to nucleic acid–containing immune complexes using novel TLR oligonucleotideinhibitors (28). Identification of lupus-associated genetic polymorphisms in the IFN regulatoryfactor 5 (IRF5) gene, a transcription factor that is phosphorylated after endosomal TLR activation,further implicated this pathway as important in IFN-I production (29). Our demonstration that, in


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patients expressing anti-RBP or anti-DNA antibodies, the risk allele of IRF5 was associated withincreased serum IFN-I activity further supported the significant role played by the endosomalTLR pathway in the IFN-I produced by many SLE patients (30). MyD88, IRAK1, IRAK4, IRF7,IKKβ, and prolyl isomerase 1 are additional components of the TLR7 signaling pathway thatparticipate in driving IFN-I production (31–35). More recent studies have shown that both T andB lymphocytes can amplify the production of IFN-I by immune complex–activated pDCs (36, 37),and IgE and the kallikrein–kinin system can inhibit that pathway (38, 39). Given these results, aswell as those of studies of anti-RBP antibody, the current view is that TLR7 recognizes cell debris–associated RNA. In the case of SLE, RNA is in the form of immune complexes that access the TLR7compartment after engaging cell surface Fc receptors on pDCs and act as immunopathogenicmediators that drive IFN-α production (Figure 2a). While mitochondrial DNA can activateTLR9, stimulate its downstream signaling components, and induce IFN-I, it is not yet clear howTLR9-induced IFN-I contributes to the IFN-I signature in vivo (40). However, rare mutationsin DNASE1, encoding an extracellular protein that degrades circulating DNA, or in DNASE1L3,encoding an enzyme that digests DNA confined in microparticles, are associated with productionof anti-DNA antibodies, and the DNA may be recognized by TLR9 (41, 42). This important bodyof work established new roles for autoantibodies and the complexes that they form beyond theirwell-established contribution to disease through passive deposition in target organs such as thekidney.

Ligands of Cytosolic Nucleic Acid Sensor Signaling Pathways

In addition to the clear contribution of RNA-containing immune complexes to IFN-I productionin patients with SLE, advances in defining sensors of cytosolic nucleic acids and their ligandshave raised the possibility that alterations in nucleic acid localization or degradation might engagecytosolic pathways that can induce IFN-I (43). However, in contrast to the well-documented roleof lupus immune complexes in driving endosomal TLRs, defining the most relevant ligands forthe cytosolic RNA and DNA sensors is a work in progress. The retinoic acid–inducible gene I(RIG-I)-like receptors (RLRs) recognize replicating RNA viruses and induce IFN-I through asignaling pathway that involves mitochondrial antiviral signaling protein (MAVS), an adaptor thatassociates with mitochondria and then activates TANK binding kinase 1 (TBK1) and nuclear factorκ B (NF-κB) subunit 1. Cyclic GMP–AMP synthase (cGAS) recognizes cytosolic DNA, generates2′,3′-cyclic GMP–AMP (cGAMP) and activates the adaptor STING, encoded by TMEM173, alsoresulting in TBK1 activation and, ultimately, transcription of IFN-β and other proinflammatorygenes (44) (Figure 2b).

A current research focus is the investigation of a potential role for these cytosolic nucleicacid sensing pathways in the immunopathogenesis of SLE. Some similarities between the clinicalmanifestations of AGS and SLE, with common features including high levels of IFN-I, centralnervous system disease, skin lesions, and some autoantibodies, have suggested that, in some patientswith SLE, single-gene mutations in mediators of nucleic acid degradation or signaling mightcontribute to innate immune activation and autoimmunity (45). Mutations in TREX-1 (DNASE3);SAMHD1; RNASEH2A, B, or C; or ADAR have all been associated with AGS and are associatedin various ways with defects in nucleic acid degradation or metabolism. Only a small percentageof SLE patients have been documented to have damaging mutations in AGS-associated genes(46–48), but the collective data on AGS point to a need for studies of cytosolic nucleic acids andthe signaling pathways that they trigger in patients with SLE.

Polymorphisms in interferon induced with helicase domain 1 (IFIH1), encoding the RNAsensor MDA5, are associated with SLE and increased IFN-I and CXCL10 production (49–51).


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Figure 2 (Figure appears on preceding page)

Molecular pathways mediating induction of IFN-I. (a) TLR-mediated induction of IFN-I. pDCs are themost active producers of IFN-I induced by activation of endosomal TLRs (TLR7 and TLR9 in pDCs;TLR8 in monocytes). ssRNAs (e.g., EBERs; U1 or hY RNA associated with RBPs and anti-RBP Abs) ordouble-stranded DNAs (e.g., viral DNA; DNA derived from apoptotic cells or mitochondrial DNAassociated with anti-DNA Abs; DNA in the context of NETs) access TLR7 or TLR9, respectively, in an Fcreceptor–dependent manner. A signaling cascade involving MyD88, IRAK4, IRAK1, TRAF6, and TRAF3results in activation and translocation of NF-κB p50 and p65, along with IRF5 and IRF7, to the nucleus andtranscription of IFN-α. (b) Cytosolic sensor–mediated induction of IFN-I. Small RNAs (e.g., Alu RNA,potentially associated with Ro60; L1-encoded RNA; EBERs; viral RNA) may bind directly to RNA sensorRIG-I or MDA5 or may promote increased permeability of mitochondria and release of oxidizedmitochondrial DNA into the cytosol. Cytosolic DNA can interact with the DNA sensor cGAS. The RNAsensing pathway induces IFN-β after activating mitochondria-associated MAVS and activating TRAF3,TRAF6, TBK1/IKKε, and NF-κB. DNA induces IFN-β after generation of cGAMP and activation ofSTING and TBK1/IKKε. Mutations in genes associated with Aicardi-Goutieres syndrome (e.g., TREX1,SAMHD1, RNASEH2A, RNASEH2B, RNASEH2C, and ADAR) may augment available cytosolic nucleicacids and drive increased signaling through RNA and DNA sensors. Abbreviations: Ab, antibody; cGAS,cyclic GMP–AMP synthase; cGAMP, cyclic GMP–AMP; dsRNA, double-stranded RNA; EBER,EBV-encoded small RNA; EBV, Epstein-Barr virus; IFN, interferon; IKKε, inhibitor of NF-κB kinasesubunit ε; IRF3, interferon regulatory factor 3; IRAK1, interleukin 1 receptor associated kinase 1; L1, longinterspersed nuclear elements; MDA5, melanoma differentiation-associated protein 5; MAVS,mitochondrial antiviral signaling protein; MyD88, myeloid differentiation primary response 88; NETs,neutrophil-derived extracellular traps; NF-κB, nuclear factor κB; pDC, plasmacytoid dendritic cell; RBP,RNA-binding protein; RIG-I, retinoic acid–inducible gene I; ssRNA, single-stranded RNA; TLR, Toll-likereceptor; TRAF3, tumor necrosis factor associated factor 3.

In addition to the association with IFIH1 mutations, a rare loss-of-function genetic variant inMAVS has been associated with clinical SLE characterized by relatively low serum IFN-I activityand absence of anti-RBP autoantibodies, suggesting that alternative signaling pathways mightgenerate a distinct lupus phenotype (52). Of great interest are the studies of prion-like MAVSaggregation observed in the PBMCs of one-third of SLE patients studied (53). MAVS aggregationwas associated with elevated IFN-β, as well as anti-Sm and -U1RNP autoantibodies. WhileMAVS is typically engaged by RNA-activated RIG-I, a RIG-I-independent pathway of MAVSactivation and aggregation can be induced by mitochondrial oxidative stress (54). The relevance ofRNA sensing and MAVS to cell function is supported by a recent study of bone marrow–derivedmesenchymal stem cells from SLE patients (55). MAVS expression was highly correlated withIFN-β and was associated with activation of DNA damage pathways, and silencing of MAVSreduced IFN-β and p53.

The DNA-triggered cGAS signaling pathway is also under current study in SLE. Keith Elkon’slaboratory has documented increased expression of cGAS in PBMCs of SLE patients and a cor-relation of cGAS levels with IFN-I signature score (56). As cGAS is an IFN-I-stimulated geneproduct, its elevated expression could merely be a reflection of IFN-I pathway activation, althoughit should be noted that 15% of the patients studied also showed detectable cGAMP, an activa-tor of STING. However, a study of a family with members expressing lupus-like autoimmunedisease and increased IFN-I production found a gain-of-function mutation in TMEM173 that re-sulted in constitutive activation of STING, providing a proof of principle that the cGAS–STINGpathway can contribute to a lupus phenotype (57). cGAMP can also provide a priming signal tothe AIM2 inflammasome, an innate immune system pathway that generates caspase-1-dependentinterleukin-1β (58). As is noted above for the RNA sensing pathway, oxidative modification ofDNA can promote induction of IFN-I due to the DNA’s resistance to TREX1 degradation, sug-gesting that environmental factors generating reactive oxygen species could also augment the


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likelihood that the cGAS–STING pathway might be activated and trigger IFN-I production (59).Extracellular sources of oxidized mitochondrial DNA can derive from neutrophils that have un-dergone NETosis and stimulate cGAS if the material gains access to the intracellular compartment(60–63).

The potential role of STING in the immunopathogenesis of SLE is complicated by recent dataidentifying an isoform of STING, STING-β, that inhibits binding of TBK1 and 2′,3′-cGAMPto STING-α and is inversely related to IFN-β levels (64). STING-β levels were reduced in cellsfrom SLE patients, indicating a mechanism that might allow more robust IFN-I production. Noinformation is currently available on how the relative expression of the two relevant isoforms ofSTING are regulated and whether STING-β deficiency might be a significant contributor toIFN-I pathway activation in SLE.

In spite of tremendous progress in defining the sensors and related signaling pathways thatinduce IFN-I, the nucleic acid ligands for those pathways that are most relevant to SLE are notknown. Perhaps the most compelling potential ligand is oxidized mitochondrial DNA, which, asnoted above, is particularly resistant to degradation and can activate cGAS and STING and driveTBK1 and IRF3 activation (59). In contrast to nuclear DNA, mitochondrial DNA is relativelyhypomethylated, similar to microbial DNA. Herpesvirus infection can induce mitochondrial DNAstress, which is of interest with regard to the potential mechanisms by which EBV infection mightmediate IFN-I pathway activation in SLE (65, 66).

An intriguing mechanism of IFN-I induction implicates genome-derived retroelements thatare either nuclear DNA or mitochondrial DNA derived. A recent study of mechanisms of tissuedamage in age-related macular degeneration provides a model system for considering contribu-tions of genomic elements to inflammatory disease (67). In that condition, a relative deficiencyof DICER (ribonuclease III) in the retinal pigment epithelium results in expression of RNAsencoded by Alu retroelements, members of the short interspersed nuclear element repetitive el-ement family. These RNAs increase the permeability of mitochondrial pores, allowing escape ofmitochondrial DNA into the cytosol, activation of cGAS, and induction of IFN-β in a STING-dependent manner. In this system, the release of mitochondrial DNA results in activation of thenoncanonical NLRP3 inflammasome pathway and inflammation-mediated tissue damage. A sim-ilar mechanism involving both RNA and DNA sensing pathways is suggested by the host responseto dengue virus, an RNA virus (68). Dengue RNA, like the Alu RNAs described above, mediatesrelease of mitochondrial DNA, providing ligands for the cGAS pathway and induction of IFN-β.Thus, in addition to mitochondrial stress, Alu RNA and, perhaps, some virus RNAs can contributeto cGAS activation by altering mitochondrial pore permeability and extrusion of mitochondrialDNA, a ligand for cGAS. A role for Alu RNAs in the IFN-I response has also been demonstratedin ADAR1-deficient human cells (69). ADAR1 is required for editing of RNA polymerase II–transcribed RNAs, including Alus, and deficiency of ADAR1 is associated with MDA5-dependentspontaneous IFN-I production. Notably, Alu RNA is bound by Ro60, a common autoantigentargeted by autoantibodies in SLE, Sjogren’s syndrome, and rheumatoid arthritis, and is foundin SLE immune complexes (70). Ro60 deletion results in increased Alu and IFN-I-induced geneexpression, suggesting a regulatory role for Ro60.

We have studied a different family of retroelements, long interspersed nuclear elements (L1or LINE-1), in blood and tissue samples from patients with SLE and Sjogren’s syndrome (71).In contrast to Alu elements, full-length L1 are present in multiple copies (approximately 70, butvariable from person to person) in the genome, and those full-length elements can be transcribed togenerate a full-length mRNA with two open reading frames that encode an RBP, an endonuclease,and a reverse transcriptase. Suspecting that impaired regulation of L1 might contribute to innateimmune system activation, we demonstrated expression of L1 transcripts in kidney tissue from


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patients with class IV lupus glomerulonephritis and in salivary gland tissue from patients withSjogren’s syndrome (72). While we documented decreased methylation of several of the CpGelements in the 5′ regulatory region of L1 in DNA from patient samples, additional alterations inmechanisms that control L1 transcription are also possible (73). L1 RNA expression was highlycorrelated with IFN-α transcripts, and in vitro transcribed RNA derived from the 5′ untranslatedregion of L1 induced expression of IFN-I mRNA and protein. Although the cellular sensors thatrecognize the L1 RNA have not been identified, a TBK1 inhibitor abrogated the induction of IFN-I by the in vitro–transcribed L1 RNA, suggesting that RNA sensors and MAVS might be involved(72). Alternatively, as was observed in the age-related macular degeneration scenario describedabove, L1 RNA might have the capacity to promote transfer of cell-intrinsic mitochondrial DNAto the cytosol, providing ligands for the cGAS pathway.

Many contributors and mechanisms relevant to the induction of IFN-I by endogenous nucleicacids remain to be elucidated. The nature of the nucleic acid ligands for cytosolic RNA and DNAsensors, the regulatory mechanisms that lead to impaired control of endogenous retroelementsin systemic autoimmune disease, the fidelity of the regulators of metabolism and degradation ofendogenous stimulatory nucleic acids, and the role of mitochondrial integrity in allowing accessof mitochondrial DNA are all topics needing further investigation. Our view is that, while eachindividual with a systemic autoimmune disease, for which we use SLE as a prototype, may takea distinct route toward activation of the IFN-I pathway, the excessive and sustained productionof IFN-I represents a core pathogenic mechanism, at least in SLE. We also suspect that bothendosomal TLR and cytosolic nucleic acid sensing pathways are active in these diseases. Therecent accumulating data implicating genomic retroelements and mitochondria in IFN-I pathwayactivation suggest productive new directions that might ultimately provide new insights into therole of environmental stressors in inducing or amplifying innate immune system activation. BarbaraMcClintock (74) first conceived of activation of endogenous retrotransposons as a genomic defensemechanism that responded to environmental stresses, providing a mechanism to generate genomicdiversity. While, at the population level, these stress responses may be beneficial, at the individuallevel, sensing of self-nucleic acids can represent a trigger for autoimmunity and inflammation.

CELLS PRODUCING TYPE I INTERFERON

The major IFN-I-producing cells were first isolated by Siegal et al. (75) in 1999 and describedas type 2 dendritic cell precursors and later as pDCs. Reizis and colleagues (76, 77) have studiedthe development of pDCs in detail and concluded that they have a common origin with antigen-presenting DCs, with the transcription factor TCF4 (E2-2) determining their differentiationprogram. pDCs express BDCA2, a type II C-type lectin that inhibits IFN-I production whenligated, and ILT7, and their extraordinarily abundant production of IFN-I is facilitated by theirexpression of IRF7. Their development is dependent on Flt3 and mTOR, and treatment withrapamycin, an mTOR inhibitor, can impact their development (78).

The important role of pDCs as the major producers of IFN-α is generally accepted, andgenetic studies in mice support the theory that pDCs are the most significant cell populationresponsible for production of IFN-I in lupus (79, 80). pDCs have also been implicated in studiesof skin and blood from patients with systemic sclerosis, although in this case, TLR8 rather thanTLR7 mediates cell activation and induction of IFN-I (81). A recent study using a sensitive assayfor IFN-α confirmed that pDCs were the major producers of IFN-α in several autoimmunediseases but also implicated monocytes in patients with gain-of-function STING mutations (82).Neutrophils stimulated with immune complexes may also contribute to production of IFN-α (83).Identification and study of pDCs are challenging due to their low numbers in peripheral blood;


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Ronnblom’s laboratory documented decreased numbers of circulating IFN-I-producing cells inSLE blood samples and proposed that those cells had been recruited to tissue following activationby an inducer of IFN-I—nucleic acid–containing immune complexes—in serum (84).

Although IFN-α is the major IFN-I found in SLE patient sera, there is also increasing interestin the contribution of the protein products of other IFN-I genes and their cell sources to theimmunopathogenesis of systemic autoimmune disease. IFN-β is of particular interest; its tran-scripts have been demonstrated in mesenchymal stem cells (55), and serum levels of IFN-β arehighly correlated with disease activity in patients with dermatomyositis (85). Mavragani et al. (72)stained salivary gland tissue of patients with Sjogren’s syndrome and renal tissue from patientswith lupus nephritis and observed IFN-β protein in glandular epithelial cells and renal tubularcells, respectively. Study of skin from patients with cutaneous lupus shows production of IFN-κby keratinocytes (86). IFN-λ, a type III IFN, can be produced by gut and lung epithelial cells, aswell as by myeloid dendritic cells, and while it is probably not a product of pDCs, it can influencetheir production of IFN-I (87).

Identifying the most relevant cells producing IFN-I and the subspecies of IFN-I that theygenerate will help to unravel the impact of the IFNs on the immunopathogenesis of disease anddesign of effective therapeutics. For example, although the families of IFN-I-regulated genestranscribed in response to IFN-α and IFN-β are largely the same, some studies point to thespecial capacity of IFN-β, but not other IFN-Is, to induce the immunosuppressive moleculesIL-10 and PD-L1 (88). In murine models of virus infection, IFN-α and IFN-β appear to havedistinct roles in control of virus dissemination early in the course of the infection. While promot-ing an immunosuppressive T cell phenotype might intuitively seem desirable in an autoimmunedisease characterized by chronic immune system activation, the specific roles of IFN-α versusIFN-β activity in the immunopathogenesis of systemic autoimmune diseases require further study.Monoclonal antibodies specific to BDCA2 target pDCs and would be likely to preferentially in-hibit IFN-α production. Although IFN-α may be the most abundantly produced IFN-I in mostof the systemic autoimmune diseases, current data suggest that a therapeutic approach that morebroadly targets the IFN-I family, including IFN-β and IFN-ω, may be more efficacious (89).

THE TYPE I INTERFERON RECEPTOR AND THECELLULAR RESPONSE

The heterodimeric IFN-I receptor comprises two transmembrane proteins, IFNAR2, which hashigh binding affinity for the cytokine, and IFNAR1, which has lower affinity (90, 91). Althoughthe differences between them may be subtle, each of the IFN-I subspecies and subtypes is likely tohave a different binding profile, with IFN-β having the highest affinity (92). IFNAR is expressedon most cells, although, as is relevant to mechanisms of neuropsychiatric lupus, expression ofIFNAR2 is relatively low in the human brain (91). Our unpublished data indicate that expressionof both IFNAR1 and IFNAR2 transcripts are comparable in PBMCs, as well as in isolated CD4and CD8 T cells and B cells from SLE patients and healthy donors, although these data donot rule out differences in stability, trafficking, or degradation of the receptor. Binding of ligandto the receptor activates the Janus family kinases Jak1 and Tyk2, leading to phosphorylation ofassociated members of the signal transducer and activator of transcription (STAT) family. Inantiviral responses, STAT1 and STAT2 are mainly involved in signaling downstream, associatingwith IRF9 to regulate hundreds of IFN-I-induced genes, but other STATs, as well as MAP kinases,may also be involved in IFNAR signaling in a manner that may differ in different cell types.Engagement of IFNAR by IFN-I leads to induction of SOCS genes and a negative feedback looplimiting signaling through IFNAR, but the documented decrease in SOCS1 expression in SLE


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patients and in murine lupus models suggests reduced negative regulation of IFNAR signaling (93).Ubiquitin-specific protease 18 (USP18) is an additional gene product regulating IFN-I signalingthat is potentially relevant to altered signaling in systemic autoimmune disease and is interestingin that it preferentially blocks signaling by IFN-α while sparing inhibition of signaling inducedby IFN-β (94).

INTERFERON-INDUCED GENES AND THEIRFUNCTIONAL SIGNIFICANCE

After binding to its receptor and triggering the Jak–STAT signaling pathway, IFN-I induces tran-scription of hundreds of genes. Many have antiviral activity and can be categorized based on theirimpact on inhibition of translation, degradation of RNA, and other important functions relevantto control of viral load and infectivity (Figure 3). Other IFN-I-induced genes are more involvedin regulatory activity relevant to immune function, including antiproliferative activity. In contrast

Antiproliferative andimmunomodulatory(tunable; fluctuate in SLE)e.g., CXCL10, DDX58, IFIH1, BST2, ISG20

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Figure 3Induction of type I IFN–inducible genes. Type I IFNs bind to IFNAR, the type I IFN receptor, with IFN-βhaving a higher affinity for IFNAR than does IFN-α. In general, binding to IFNAR initiates a signalingcascade through Jak1 and Tyk2, activating STAT1 and STAT2, which translocate to the nucleus inassociation with IRF9 and induce new gene transcription. In some cases additional STATs may be activated,or protein kinase B may mediate gene transcription initiated by IFNAR binding. Studies of IFN-inducedgene expression have identified two general categories of IFN-induced genes, those that are readily inducedand mediate many antiviral effects and those that mediate antiproliferative and immunomodulatoryfunctions. The antiviral or robust IFN-induced genes tend to be expressed in a relatively stable manner overtime in many SLE patients. Expression of the immunomodulatory or tunable IFN-induced genes canfluctuate over time in relation to lupus disease activity. Abbreviations: IFN, interferon; IRF9, interferonregulatory factor 9; ISRE, interferon-sensitive response element; Jak1, Janus kinase 1; Tyk2, tyrosine kinase2; SLE, systemic lupus erythematosus; STAT1/2, signal transducer and activator of transcription 1/2.


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to those genes with antiviral activity, which often depend on regulation by STAT1/STAT2/IRF9complexes binding to interferon-sensitive response elements in gene promoters, IFN-I-inducedgenes with antiproliferative and immune-modulating activity may use other regulatory elementsand may be more dependent on higher concentrations of IFN-I.

A study led by Gideon Schreiber used a mutant IFN-α that bound well to IFNAR2 but not toIFNAR1 to characterize IFN-I-induced genes as either antiviral (robust) or antiproliferative andimmunomodulatory (tunable) (95). Antiviral IFN-I-regulated genes include some that are well-known components of the IFN-I signature assessed by many investigators (e.g., MX1, IFIT1), andthe antiproliferative genes include some of those encoding inflammatory mediators (e.g., CXCL10,IL8). The SOCS1 protein, an inhibitor of IFN-α signaling, is among the products of the antiviral(robust) IFN-I-induced genes.

Chiche et al. (96) analyzed gene expression data from microarray analysis of blood cells fromSLE patients and identified three distinct modules of IFN-regulated gene transcripts. Two ofthe modules are IFN-I related, with module M1.2 generally comparable to the robust moduledescribed above and present in most SLE patients. Module M3.4 was less prevalent, fluctuatedover time, and was described as including transcripts induced by IFN-β in other studies. Whiletranscripts in module M3.4 are of interest, it appears that they are not specific to IFN-β. Weperformed K-means clustering of differentially expressed transcripts in SLE compared to healthydonor PBMCs based on the Affymetrix microarray platform and also defined two IFN-I clusterswith considerable overlap with the robust and tunable transcripts defined by Schreiber’s group (M.Olferiev & M.K. Crow, unpublished data). In addition to genes encoding chemokines and otherproinflammatory mediators (e.g., CXCL10, CXCL11), the cluster resembling Schreiber’s tunabletranscripts included transcripts involved in signaling or regulation of the cytosolic nucleic acid sens-ing pathway (e.g., DDX58/RIG-I, ADAR, TREX1), as well as transcripts documented to regulate ex-pression of genomic retroelements (e.g., APOBEC3A, BST2, ISG20). While they were often highlyexpressed early in the course of lupus disease, transcripts in this second cluster sometimes peakedin expression weeks or months prior to a clinical disease flare. Detailed analysis of the longitudinalexpression of these IFN-I-related transcripts is ongoing in our laboratory, but transcripts studiedto date support the relevance of the cytosolic nucleic acid sensing pathways to the immunopatho-genesis of SLE and warrant further longitudinal study to relate regulation of those transcripts toserologic features of autoimmunity, protein biomarkers, and clinical manifestations of disease.

THE CONTRIBUTION OF TYPE I INTERFERON TO HOST DEFENSEAND IMMUNOPATHOLOGY

Chronic activation of the IFN-I pathway, as demonstrated in most patients with SLE, has nu-merous and complex effects on both innate and adaptive immune system function, as well as ontarget organ pathology (97–99) (Figure 4). The capacity of IFN-I to alter antigen-presenting cellfunction, B cell differentiation and class switching, and chemokine production has been well docu-mented (100–102), but the impact of IFN-I on T effector cell function and tissue immunopathol-ogy is still being investigated. In that regard, murine models of chronic virus infection, as wellas studies of patients with chronic HIV infection, have been particularly informative in dissect-ing the effects of acute versus sustained expression of IFN-I on immune regulation and tissuedamage (103–107). In fact, the many parallels between the immunopathogenic mechanisms de-scribed in HIV-infected patients and those in SLE patients are striking. Nucleic acid–containingimmune complexes are potent inducers of IFN-I through TLR7 in pDCs of SLE patients, andvirus-containing immune complexes drive IFN-I production by pDCs in HIV-infected patientsin a TLR7-dependent manner (108).


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TYPE

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• Autoimmunity• Neuropsychiatric manifestations• Premature atherosclerosis• Preeclampsia• Inflammation, including synovial and renal inflammation• Skin rash

• Immune complex–mediated multiorgan pathology,including glomerulonephritis

• Antibody-mediated cytopenias• Cellular infiltration contributes to organ damage

Innate immune functions• Augments APC function• Activates microglial cells• Alters endothelial cell function• Inhibits angiogenesis• Induces chemokines and myeloid cell recruitment• Promotes apoptosis

B cell functions• Promotes B cell differentiation and

immunoglobulin class switching

T cell functions• Promotes T follicular helper cell expansion• Induces partial CD8 T cell exhaustion• Regulates NK cell function

• Promotes autoimmunity• Impairs antiviral immunity• Cellular infiltration contributes to organ damage

Figure 4Protean immunopathologic effects of type I interferon contribute to many of the clinical and pathologicmanifestations of disease in systemic lupus erythematosus. Abbreviations: APC, antigen-presenting cell;NK, natural killer.

Murine models of chronic lymphocytic choriomeningitis virus (LCMV) and HIV infectionhave been particularly informative in dissecting the broad immune-modulating effects of chronicIFN-I exposure. Many studies from the Ahmed and Oldstone laboratories have made importantcontributions to understanding how chronic virus infection, and the accompanying sustainedIFN-I production, can shape the T cell effector profile to promote T cell–dependent B celldifferentiation and inflammation (88, 104, 109), and several recent reviews summarize the immunedysregulation associated with chronic IFN-I availability (97–99). Chronic IFN-I production mayshift the CD4 T cell effector phenotype from a Th1 functional phenotype toward a dominant Tfollicular helper cell phenotype, promoting B cell differentiation, and may also directly or indirectlycontribute to the partially exhausted CD8 T cell phenotype that has been observed in SLE (CD4+

Th1 cells are necessary for effective development of CD8 cytotoxic T cells). The lessons learnedfrom these murine studies are highly relevant to the development of hypotheses regarding thecontribution of IFN-I to altered immune system function in SLE and other autoimmune diseasesassociated with an IFN-I signature.

Two studies comparing the pathology induced by two LCMV strains—clone 13 andArmstrong—are particularly notable (103, 104). While the production of IFN-I after virus in-fection is rapidly controlled in mice infected with the Armstrong strain, clone 13 leads to long-term elevation of IFN-I and tissue pathology. In these studies, blockade of IFNAR in the animalsinfected with clone 13 reduced levels of proinflammatory mediators and corrected alterations insplenic architecture, reducing tissue pathology. Two additional studies published in 2017 usedhumanized mice infected with HIV to show that blockade of IFNAR, together with antiretroviraltherapy, during chronic infection decreased markers of CD8 T cell exhaustion; reduced the extentof HIV replication, perhaps due to improved CD8 T cell function; and decreased the reservoirof cells harboring HIV (105, 106). Together, these and other studies of chronic virus infectionindicate that the immune dysregulation and tissue pathology associated with sustained IFN-I pro-duction can be corrected by inhibition of IFNAR, an important lesson that is highly relevant to thedesign of therapeutics for SLE and other systemic autoimmune diseases characterized by IFN-Ipathway activation.


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TISSUE PATHOLOGY AND DISEASE MANIFESTATIONSASSOCIATED WITH TYPE I INTERFERON

Production of IFN-I in target tissues and organs in patients with SLE and related diseases isconsistent with the documented contribution of the IFN-I pathway to the inflammation anddisruption of the architecture of lymphoid tissue in murine models characterized by sustainedIFN-I production. pDCs have been observed in skin and renal tissue from SLE patients, andexpression of the protein products of IFN-I-induced genes—typically MX1—are documented inthose tissues (72, 80, 110–112). Ultraviolet light, a well-known inducer of lupus flare, promotesrecruitment of pDCs to skin (113). Mavragani et al. (72) stained kidney tissue from patientswith lupus nephritis and salivary gland tissue from patients with Sjogren’s syndrome with anti-BDCA2 antibody to identify pDCs, and they observed infiltration of pDCs in both tissues. BothIFN-α and IFN-β can be seen in both tissues. Keratinocyte-derived IFN-κ is present in skinof patients with cutaneous lupus, and synovial tissue from SLE patients with arthritis is stronglypositive for IFN-I-regulated gene transcripts (86, 114). IFN-I likely contributes to the prematureatherosclerosis that is characteristic of patients with SLE, and the IFN-I signature is associatedwith impaired endothelial function, accelerated thrombosis, and platelet activation (115, 116).Neuropsychiatric lupus is one of the more prevalent manifestations of the disease, and it has asignificant impact on quality of life. Recent studies implicate IFN-I generated in the peripheryin microglial activation and altered synaptic pruning in murine lupus, and preliminary data frompathologic brain specimens from patients with SLE indicate increased microglial activation andsynaptic pruning (117). Elevated levels of IFN-I are also associated with risk of preeclampsia andpoor pregnancy outcomes in patients with SLE (118).

Collectively, the broad expression of IFN-I and IFN-I-regulated gene products, in associationwith most of the clinical manifestations that characterize SLE, provides strong support for theimmunopathologic relevance of this cytokine family. It is likely that all subspecies of IFN-I areimplicated, although some questions remain regarding the relative roles of IFN-α and IFN-βin the different organs affected. This issue could be of clinical significance, as IFN-I may playprotective as well as pathogenic roles in the central nervous system (119).

While the documentation of local production of IFN-I is not as extensive in other systemicautoimmune diseases as it is in SLE, it is likely that IFN-I also contributes to immune dysregulationin those disorders that are characterized by autoantibodies targeting nucleic acids and nucleic acid–binding proteins. As noted above, IFN-α and IFN-β are expressed in Sjogren’s syndrome salivaryglands, with immunohistochemistry data suggesting that IFN-α is primarily expressed in pDCs,while IFN-β is present in glandular epithelial cells (72, 120). The IFN-I signature is also present inPBMCs from those patients. Muscle tissue from patients with dermatomyositis shows the presenceof IFN-I and IFN-I-induced protein; IFN-β is proposed to be the predominant species of IFN-Iin this disease (85, 121, 122). The role of the IFN-I pathway in systemic sclerosis is an area of activecurrent investigation (123); pDCs are likely to be the important producers, but they may act via anunusual signaling pathway transduced through TLR8 (81). The IFN-I signature is not prominentin most patients with rheumatoid arthritis, although the signature has been demonstrated intreatment-naive patients and may identify patients refractory to initial therapy (124). A commontheme that applies to several, if not most, of these systemic autoimmune diseases is the associationof IFN-I pathway activation and the IFN-I signature with autoantibodies targeting RNA andRNA-associated proteins (8, 125, 126). These observations support the significant role of nucleicacid–containing immune complexes in driving production of IFN-I, with pDCs and TLR7 likelyplaying a key role.


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RELATIONSHIP BETWEEN THE TYPE I INTERFERON SIGNATUREAND DISEASE ACTIVITY

Early studies in patients with SLE showed a statistical association of the IFN-I signature inperipheral blood with important clinical manifestations of disease, such as lupus nephritis, and anassociation with the SLE disease activity index in cross-sectional data (14, 17). However, morerecent data have questioned the utility of the IFN-I signature as a biomarker of disease activity,as longitudinal data demonstrate stability of the IFN-I score over time in most patients (127). Inour view, the assessment of a relationship between the IFN-I signature and clinical disease activityand lupus flare requires further study. In studies that evaluated all patients meeting classificationcriteria for a diagnosis of SLE, most participants show stability of the IFN-I score. However, ina study designed by Kyriakos Kirou that selected SLE patients to enrich the study populationin those who demonstrated a disease flare in the year prior to enrollment and that analyzedmultiple longitudinal samples, several longitudinal patterns of IFN-I pathway activation werefound (Figure 5) (K.A. Kirou, M. Olferiev & M.K. Crow, unpublished data). Stable patterns ofIFN-I score in relation to disease activity were observed, but 40% of patients studied showed apeak in IFN-I score 1–6 months before an increase in disease activity. Some patients did showconcurrence of the IFN-I score and disease activity scores, suggesting, at least, that exogenousor endogenous drivers of IFN-I production might contribute to the immune dysregulation thatresults in the clinical manifestations of disease.

While we do see stable expression of the IFN-I score in many patients, more refined dissec-tion of the IFN-I pathway may reveal clinically relevant associations. As described above, theIFN-I-regulated transcripts can be clustered into groups of transcripts that can be differentiatedstatistically, and transcripts from the cluster described by Schreiber’s group as robust, roughlycomparable to Chiche’s module M1.2, are often used to measure activation of the IFN-I pathway(95, 96). A characteristic of these transcripts is that they are sensitive to induction and relatively

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Figure 5Longitudinal expression of an IFN-I signature in relation to disease activity in patients with SLE. An IFN-I score was generated basedon RT-PCR analysis of three genes (IFIT1, IFI44, and PKR) in longitudinal PBMC samples from two patients with SLE, and this wasrelated to disease activity scores (SLEDAI and BILAG). (a) Patient IF2 demonstrated an IFN-I score that paralleled the disease activity.(b) Patient IF6 initially had inactive disease and a limited autoantibody profile (anti-Ro). The patient developed community-acquiredpneumonia approximately 5 months after recruitment into the study, developed an acute IFN-I spike approximately 8 months afterrecruitment, and extended the autoantibody profile to include anti-Sm/RNP 16 months after recruitment. The asterisks indicate thepeak of disease activity. Abbreviations: BILAG, British Isles Lupus Assessment Group; IFN-I, type I interferon; PBMC, peripheralblood mononuclear cell; RT-PCR, reverse transcription polymerase chain reaction; SLE, systemic lupus erythematosus; SLEDAI,systemic lupus erythematosus disease activity index.


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stable over time, regardless of disease activity. A second cluster of IFN-I-regulated transcripts thatwe have defined using K-means clustering, which has some overlap with the Schreiber group’s (95)tunable transcript cluster and includes representatives from Chiche et al.’s (96) modules M3.4 andM5.12, may be more useful in predicting future disease flares, as we have observed that these tran-scripts fluctuate over time. We are currently analyzing extensive longitudinal data to understandthe relationship of those transcripts to serologic and clinical measures of disease activity.

One subpopulation of patients that requires further study includes those that do not demon-strate an IFN-I signature. Observations from interventional clinical trials, most notably the studyof the anti-IFNAR monoclonal antibody anifrolumab (89), demonstrated a significant responseto the agent in patients with a high IFN-I score, but not in those with a score that overlappedwith that of healthy donors, compared with patients treated with placebo. In view of the nearlyuniversal presence of an IFN-I signature in pediatric lupus patients prior to therapy, it remainspossible that acquired alterations in the immune system might contribute to a blunting of theIFN-I signature in some adult lupus patients. In most studies describing patients considered tohave a low IFN-I score, many still show a level of IFN-I pathway activation that is greater than thatof healthy individuals. One potential mechanism that might account for consistently low IFN-Iactivity in patients bearing a clear diagnosis of SLE is the development of endogenous anti-IFN-Iantibodies. These antibodies have been identified in patients with rare mutations in the autoim-mune regulator AIRE but are also documented among the anticytokine antibodies detected inpatients with SLE and Sjogren’s syndrome (128–130). Some data have documented a low IFN-Iscore in some SLE patients with anti-IFN-I antibodies (129), but additional investigation will beneeded to determine the role of these antibodies in the IFN-I-low patient group more gener-ally. Of interest, one therapeutic approach in current clinical trials aims to induce endogenousanti-IFN-I antibody using a vaccination protocol (131).

THERAPEUTIC APPROACHES TARGETING THE TYPE IINTERFERON PATHWAY

The strong evidence that IFN-I is a central mediator of the immunopathogenesis of SLE, andperhaps of additional systemic autoimmune diseases, is driving active preclinical and clinical drugdevelopment programs, including testing of agents that might address afferent and efferent armsof the IFN-I pathway. We do not provide a comprehensive summary of the therapeutic agentsrelevant to this cytokine pathway, as others have reviewed many of the agents of current interest(132). However, we highlight several therapeutic approaches based on the results of both murineand human studies, including data reviewed in this article.

Antimalarial drugs are currently used in most patients with SLE and in patients with some otherautoimmune diseases, and their utility in decreasing the frequency of future disease flares is wellestablished (133). Recent data indicate that agents in the antimalarial family can inhibit signalingthrough both TLR and cytosolic sensor pathways (134). If these drugs could be made more potent,then they could prove even more efficacious than the commonly used hydroxychloroquine. Thepotential promise of targeting pDCs is suggested by the abundant IFN-α produced by those cells,the association of IFN-I production with RNA-containing immune complexes that stimulate pDCsthrough TLR7, and genetic studies in murine systems that demonstrate abrogation of disease whenpDCs are diminished. Anti-BDCA2 antibodies are specific for pDCs, so they might deplete and/orhave the potential to provide an inhibitory signal to those cells (135). Kinases involved in the TLR7signaling pathway are also of interest (136). Inhibitors of IRAK4 have been tested in murine lupusmodels and reduce disease through actions on multiple pathogenic pathways (137). The cytosolicnucleic acid sensors and their signaling pathways also represent promising therapeutic targets in


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view of the recognition that intracellular nucleic acids, as well as extracellular immune complexes,can serve as relevant drivers of IFN-I production. cGAS inhibitors are in development, and severalstudies have provided support for inhibition of TBK1 as an approach to reduce the IFN-I-regulatedgene signature (138, 139).

Inhibitors of the efferent arm of the IFN-I pathway are particularly promising for the treatmentof autoimmune diseases because they can target IFN-I signaling, as well as signaling induced byother cytokine ligands. Jak1 inhibitors have been used in patients with monogenic disorders ofIFN-I pathway regulation and are currently being studied in patients with SLE (140). TargetingJak1 should abrogate IFN-I signals but also reduce the production of IL-12, an effect that mighthave a beneficial impact on T cell function (141).

In addition, inhibition of IFNAR with the anti-IFNAR monoclonal antibody anifrolumab ispromising given its successful Phase II clinical trial, although initial reports of Phase III studiesare disappointing (89). The Phase II study met its clinical end point across multiple clinical pa-rameters and was particularly effective in patients demonstrating a high IFN-I gene signature. Inview of the protean immunologic alterations that characterize the autoimmune disease of patientswith SLE and the iterative and complex amplification of immune system alterations that typicallydevelop over time in SLE, it is more than likely that targeting only one molecular pathway, evenone as central to immunopathology as the IFN-I pathway, will not be sufficient to gain controlof this disease, as well as other related systemic autoimmune diseases associated with an IFN-Isignature. However, approaches that target components of this pathway represent the mostpromising and advanced therapeutic strategy to date.

PERSPECTIVE

The complex genomic structure of the IFN-I locus, encoding multiple members of the IFN-I cy-tokine family, reflects the ongoing struggle between the host and the multitude of viral pathogensthat challenge host integrity. In SLE and related diseases, this rigorously regulated system escapesits controls, resulting in induction of the IFN-I genes, activation of the molecular pathways thatthey trigger, and induction of the hundreds of genes that they regulate. A complex molecularprogram driven by IFN-I modulates many aspects of immune function, contributing to the au-toimmunity, inflammation, and tissue damage that play central roles in generating the clinicalmanifestations of SLE; this molecular program likely also contributes to related systemic autoim-mune diseases. A notable feature of the IFN-I pathway in SLE is that its activation is sustainedover time, raising many questions yet to be addressed. Potential roles for exogenous viral triggersor latent infection with EBV remain possibly relevant, and the potential contribution of intra-cellular nucleic acids, including those encoded by genomic repeat elements, that escape propermetabolism or degradation is only beginning to come into focus.

We contend that excess IFN-I represents a core immunopathogenic mechanism in SLE. Whilethe murine models of chronic virus infection associated with sustained IFN-I production provideinformative demonstrations of the immune sequelae of excessive IFN-I signaling, additional con-cepts are needed to address the early events that might contribute to IFN-I production. We suggesta conceptual model that can guide continued investigation of the immunologic mechanisms thataccount for development of SLE, informed by the clear role for genetic variations that decrease thethreshold for immune activation and shape development of autoantibody specificities in an individ-ual patient (Figure 6). As was demonstrated in a comprehensive and insightful study combiningexamination of patients with severe malaria infection and a murine model of malaria infectionthat demonstrates similar pathology, IFN-I serves as an essential mediator determining diseaseoutcomes (142). In a first phase of disease following infection, macrophages activated by malaria


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IRF7

IRF5

Nucleus

Type I IFN,including IFN-β

TLR7

FcRFcR

Nucleic acid–containingimmune complexes

Apoptotic ornecrotic debris

Viruses

RNA

DNA

Nucleus

MitochondrialDNA

IFNAR

IFN-α

Bone marrow Blood

Stimulatorynucleic acids

(potentially derived from genomic retroelements

or a virus)RIG-I

MDA5

Monocyte Plasmacytoid dendritic cell

NETscGAS

Figure 6Proposed two-stage induction of robust type I IFN production implicates both cytosolic and TLR nucleic acid sensors. Although pDCsare the source of abundant IFN-α, they may require priming with small amounts of type I IFN, including IFN-β, produced by othercells, such as macrophages. A scenario in which activation of the innate immune response could be initiated would involve stimulationof macrophages with exogenous virus or cytosolic nucleic acid (e.g., oxidized mitochondrial DNA or genomic retroelement-derivedRNA or DNA), activating the cytosolic nucleic acid sensors and resulting in secretion of small concentrations of IFN-β. pDC primingby type I IFN would allow robust IFN-α secretion in response to activation of TLR7 by nucleic acid–containing immune complexes.Abbreviations: IFN, interferon; NETs, neutrophil-derived extracellular traps; pDC, plasmacytoid dendritic cell; TLR, Toll-likereceptor.

parasites in a STING-dependent manner, presumably based on signaling from cytosolic nucleicacid receptors, produced small amounts of IFN-I and prime pDCs to respond to malaria parasitesthrough the TLR7 pathway, resulting in robust IFN-I production, immune system activation,and tissue inflammation. Disease pathology was abrogated in the absence of IFNAR. Continuedinvestigation of patients with systemic autoimmune disease, along with murine models, may sim-ilarly demonstrate requirements for both cytosolic sensors and the endosomal TLR pathways ininitiating and perpetuating IFN-I production and its myriad downstream sequelae. Such a scenariowould provide many candidate therapeutic targets and opportunities to gain control of disease inpatients.

DISCLOSURE STATEMENT

M.K.C. has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Lilly, and Neovacs.K.A.K. serves as an investigator in clinical trials sponsored by AstraZeneca, Aurinia Pharmaceuti-cals, and the Lupus Clinical Investigators Network (LuCIN). M.O. is not aware of any affiliations,memberships, funding, or other financial holdings that might be perceived as affecting the objec-tivity of this review.

ACKNOWLEDGMENTS

The authors have received funding from the National Institutes of Health, the Lupus ResearchAlliance, and the Emerald Foundation. They acknowledge the contributions of Jing Hua, PhD,who performed experiments assessing the contributions of anti-DNA and anti-RBP antibodies toinduction of IFN-I.


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PM14_TOC ARI 21 December 2018 8:18

Annual Reviewof Pathology:Mechanisms ofDisease

Volume 14, 2019Contents

Polyglutamine Repeats in Neurodegenerative DiseasesAndrew P. Lieberman, Vikram G. Shakkottai, and Roger L. Albin � � � � � � � � � � � � � � � � � � � � � � � � 1

Epstein–Barr Virus and CancerPaul J. Farrell � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �29

Exposure to Ultraviolet Radiation in the Modulationof Human DiseasesPrue H. Hart, Mary Norval, Scott N. Byrne, and Lesley E. Rhodes � � � � � � � � � � � � � � � � � � � � � � �55

Insights into Pathogenic Interactions Among Environment, Host,and Tumor at the Crossroads of Molecular Pathology andEpidemiologyShuji Ogino, Jonathan A. Nowak, Tsuyoshi Hamada, Danny A. Milner Jr.,

and Reiko Nishihara � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �83

Pathological Issues in Dystrophinopathy in the Ageof Genetic TherapiesNazima Shahnoor, Emily M. Siebers, Kristy J. Brown, and Michael W. Lawlor � � � � � � � 105

Pathogenesis of Rickettsial Diseases: Pathogenic and ImmuneMechanisms of an Endotheliotropic InfectionAbha Sahni, Rong Fang, Sanjeev K. Sahni, and David H. Walker � � � � � � � � � � � � � � � � � � � � � 127

Innate Immune Signaling in Nonalcoholic Fatty Liver Diseaseand Cardiovascular DiseasesJingjing Cai, Meng Xu, Xiaojing Zhang, and Hongliang Li � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 153

Immunological Basis for Recurrent Fetal Lossand Pregnancy ComplicationsHitesh Deshmukh and Sing Sing Way � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 185

Opportunities for microRNAs in the Crowded Fieldof Cardiovascular BiomarkersPerry V. Halushka, Andrew J. Goodwin, and Marc K. Halushka � � � � � � � � � � � � � � � � � � � � � � � 211

Molecular Pathogenesis of the TauopathiesJurgen Gotz, Glenda Halliday, and Rebecca M. Nisbet � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 239

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PM14_TOC ARI 21 December 2018 8:18

Pathophysiology of Sickle Cell DiseasePrithu Sundd, Mark T. Gladwin, and Enrico M. Novelli � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 263

Malformations of Cerebral Cortex Development: Moleculesand MechanismsGordana Juric-Sekhar and Robert F. Hevner � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 293

Clinical Metagenomic Next-Generation Sequencingfor Pathogen DetectionWei Gu, Steve Miller, and Charles Y. Chiu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 319

Molecular Genetics of Endometrial CarcinomaDaphne W. Bell and Lora Hedrick Ellenson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 339

Type I Interferons in Autoimmune DiseaseMary K. Crow, Mikhail Olferiev, and Kyriakos A. Kirou � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 369

Systems-Wide Approaches in Induced Pluripotent Stem Cell ModelsEdward Lau, David T. Paik, and Joseph C. Wu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 395

Pathology and Pathogenesis of Chagas Heart DiseaseKevin M. Bonney, Daniel J. Luthringer, Stacey A. Kim, Nisha J. Garg,

and David M. Engman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 421

Modeling Disease with Human Inducible Pluripotent Stem CellsRodrigo Grandy, Rute A. Tomaz, and Ludovic Vallier � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 449

RNA Binding Proteins and the Pathogenesis of FrontotemporalLobar DegenerationJeffrey W. Hofmann, William W. Seeley, and Eric J. Huang � � � � � � � � � � � � � � � � � � � � � � � � � � � 469

Cellular and Molecular Mechanisms of Prion DiseaseChristina J. Sigurdson, Jason C. Bartz, and Markus Glatzel � � � � � � � � � � � � � � � � � � � � � � � � � � � � 497

Errata

An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articlesmay be found at http://www.annualreviews.org/errata/pathmechdis

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Documents

Type I Interferons in Autoimmune Disease · 03.11.2019 · Annual Review of Pathology: Mechanisms of Disease Type I Interferons in Autoimmune Disease Mary K. Crow, Mikhail Olferiev,