Clinical Reviews in Allergy & Immunology

https://doi.org/10.1007/s12016-020-08798-2

Type I Interferons in the Pathogenesis and Treatment

of Autoimmune Diseases
Jiao Jiang 1,2 & Ming Zhao 1,2 & Christopher Chang 3,4 & Haijing Wu 1,2 & Qianjin Lu 1,2

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Type I interferons (IFN-Is) are a very important group of cytokines that are produced by innate immune cells but also act on
adaptive immune cells. IFN-Is possess antiviral, antitumor, and anti-proliferative effects, as well are associated with the initiation
and maintenance of autoimmune disorders. Studies have shown that aberrantly expressed IFN-Is and/or type I IFN-inducible
gene signatures in the serum or tissues of patients with autoimmune disorders are linked to their pathogenesis, clinical manifes-
tations, and disease activity. Type I interferonopathies with mutations in genes impacting the type I IFN signaling pathway have
shown symptoms and characteristics similar to those of systemic lupus erythematosus (SLE). Furthermore, both interventions in
animal models and clinical trials of therapies targeting the type I IFN signaling pathway have shown efficacy in the treatment of
autoimmune diseases. Our review aims to summarize the functions and targeted therapies (as well as clinical trials) of IFN-Is in
both adult and pediatric autoimmune diseases, such as SLE, pediatric SLE (pSLE), rheumatoid arthritis (RA), juvenile idiopathic
arthritis (JIA), juvenile dermatomyositis (JDM), Sjögren syndrome (SjS), and systemic sclerosis (SSc), discussing the potential
abnormal regulation of transcription factors and epigenetic modifications and providing a potential mechanism for pathogenesis
and therapeutic strategies for future clinical use.

Keywords Autoimmunedisease . TypeI interferonsignaling pathway . Epigenetic modifications . Systemiclupus erythematosus .

Juvenile idiopathic arthritis . Sjogren’s syndrome . Interferonopathies

Abbreviations IRF Interferon regulatory family

AGS Aicardi-Goutières syndrome ISG Interferon-stimulated gene
BTK Bruton’s tyrosine kinase JAK Janus kinase
cGAS Cyclic GMP-AMP synthase JDM Juvenile dermatomyositis
IFN-I Type I interferon JIA Juvenile idiopathic arthritis
IRAK Interleukin-1 receptor-associated kinase MAVS Mitochondrial antiviral signaling protein
MDA Melanoma differentiation-associated gene
MyD Myeloid differentiation primary response gene
pDC Plasmacytoid dendritic cell
* Haijing Wu
PRR Pattern recognition receptor
chriswu1010@csu.edu.cn
pSjS primary Sjögren syndrome
* Qianjin Lu
pSLE Pediatric systemic lupus erythematosus
qianlu5860@csu.edu.cn
RA Rheumatoid arthritis
1
Department of Dermatology, Second Xiangya Hospital, Central RIG-I Retinoic acid-inducible gene-I
South University, Changsha 410008, Hunan, People’s Republic of SSc Systemic sclerosis
China STAT Signal transducers and activators of transcription
2
Hunan Key Laboratory of Medical Epigenomics, Second Xiangya STING Stimulator of interferon
Hospital, Central South University, Changsha 410008, Hunan, Syk Spleen tyrosine kinase
People’s Republic of China
TBK TANK-binding kinase
3
Division of Pediatric Immunology and Allergy, Joe DiMaggio TLR Toll-like receptor
Children’s Hospital, Hollywood, FL 33021, USA
TRAF Tumor necrosis factor receptor-associated factor
4
Division of Rheumatology, Allergy and Clinical Immunology, TREX Three prime repair exonuclease
University of California, Davis, CA 95616, USA

TRIF Toll-IL-1 receptor domain-containing adaptor in-
ducing IFN-β
TYK Tyrosine kinase
Introduction
Autoimmune diseases include a wide range of diseases, in-
cluding systemic lupus erythematosus (SLE), rheumatoid ar-
thritis (RA), Sjögren syndrome (SjS), and systemic sclerosis
(SSc) [1]. They occur when the immune system loses the
ability to maintain self-tolerance and produces overactive
immunocytes and an abnormal balance of cytokines [3].
These lead to abnormally increased autoantibodies against
self-tissues, resulting in inflammation and damage to multiple
organs, such as the kidneys, joints, skin, and central nervous
system. The conventional treatments of autoimmune disorders
include anti-inflammatory and immunosuppressive agents,
which often provide only partial amelioration of symptoms
[4–8]. In addition, these agents possess numerous side effects,
including infection, obesity, abnormal glucose metabolism,
osteoporosis, and even avascular necrosis [4, 5]. Due to the
complex and unclear mechanisms of the pathogenesis of au-
toimmune diseases, the effective therapies are lacking [6–8].
In 1979, IFNs were found to be increased in autoimmune
disorders, and there is a positive correlation between the
amount of IFNs in the sera and disease activity as well as
the level of antibodies to DNA in patients with SLE [9]. In
addition, after IFN-α therapy, autoimmune disorders such as
autoimmune thyroid disease and SLE-like syndrome can oc-
cur in patients with hepatitis C virus or malignant carcinoid
tumors [10, 11]. Similarly, type I IFN signatures are also in-
creased in the patients with RA and dermatomyositis (DM),
demonstrating a role of IFNs in promoting the development of
autoimmune diseases [12, 13].
Type I IFNs are widely expressed cytokines that are in-
volved in innate immunity and adaptive immune system and
in particular play an important role in antiviral activity and
cancer immunosurveillance [14–16]. IFN-Is are mainly pro-
duced by innate immune cells in mammals, such as macro-
phages and dendritic cells (DCs) [17]. IFN-β can be induced
by most types of cells, whereas IFN-α is largely produced by
plasmacytoid DC (pDCs) [17]. Once produced, type I IFNs
interact with the interferon-α/β receptor (IFNAR, including
subunits IFNAR1 and IFNAR2) expressed in most nucleated
cells, and ultimately initiate the transcription of interferon-
stimulated genes (ISGs) to produce type I IFN gene signature
through JAK/signal transducers and activators of transcription
(STAT) pathway [14, 17, 18]. Many molecules encoded by
ISGs induce antiviral and antitumor activity but may also play
a role in autoimmunity [12].
With more attention on the significance of type I IFN sig-
naling pathway in autoimmune diseases, many monoclonal
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antibodies (mAbs) and small molecule inhibitors are designed
to target the type I IFN signaling pathway for the treatment of
autoimmune disorders, such as therapies targeting IFN-α or
IFNARs, pDCs, Toll-like receptors (TLRs), and their down-
stream pathways. Clinical trials using these treatments have
already produced positive results. The JAK inhibitors
tofacitinib and baricitinib have been approved by the United
States Food and Drug Administration (FDA) and the
European Medicines Agency (EMA) for the treatment of RA
[19]. A mAb against IFNAR, anifrolumab (formerly MEDI-
546), has just completed phase III clinical trials in patients
with SLE and has shown excellent efficacy and safety profiles
[20]. The JAK1/JAK2 inhibitor baricitinib has also entered
phase III trials for the treatment of SLE [21]. Furthermore,
there are also many ongoing clinical trials and experiments
about treatments blocking the type I IFN pathway in both
humans and animals with SLE, pediatric SLE (pSLE), RA,
JIA, SjS, and other autoimmune diseases. However, there are
also some challenges that will be discussed in more detail
below. We focus on type I IFNs (mainly IFN-α and IFN-β)
and summarize their roles in the pathogenesis and treatment of
autoimmune diseases. Our purpose is to find new potential
pathogenesis and therapeutic strategies for type I IFNs for
further studies.
The Family and Origin of Type I Interferons
The IFN family contains three groups: type I, type II, and type
III IFNs. IFN-Is include IFN-α (13 distinct subtypes of IFN-α
in humans and 14 in mice), IFN-β, IFN-δ, IFN-ε, IFN-κ,
IFN-ω, and IFN-ζ [22]. Humans can express IFN-α, IFN-β,
IFN-ε, IFN-κ, and IFN-ω [22]. The production of type I IFNs
is induced when different stimuli are detected by pattern rec-
ognition receptors (PRRs) on the plasma membrane in
endosomes and the cytoplasm of aforementioned type I IFN-
producing cells [17]. Different stimuli consist of exogenous
pathogens, apoptotic cells, apoptosis-derived membrane vesi-
cles (AdMVs), NETotic neutrophils, endogenous self-nucleic
acids, and related immune complexes (ICs) [23–26]. The
PRRs, such as TLRs, retinoic acid-inducible gene-I (RIG-I)-
like receptors (RLRs), and nod-like receptors (NLRs), can be
divided into DNA or RNA sensors during the productions of
type I IFNs [2].
TLR9 is an endosomal membrane sensor for DNA stimuli
and is mainly expressed in pDCs, macrophages, B cells [24,
25, 27, 28]. Extracellular stimuli containing nucleic acids can
be internalized by FcγRIIa on the surface of pDCs to form
endosomes [23–26]. TLR9 in the endoplasmic reticulum (ER)
can traffic into the endosome and deliver extracellular DNA
signals. Upon recognizing unmethylated CpG DNA released
by the above complexes, TLR9 interacts with myeloid differ-
entiation primary response gene 88 (MyD88). MyD88 then
Clinic Rev Allerg Immunol
recruits and activates interleukin-1 receptor-associated kinase
4 (IRAK4), triggering IRAK1, tumor necrosis factor receptor-
associated factor 6 (TRAF6), and TRAF3 pathway to activate
interferon regulatory family 7 (IRF7), which can translocate to
the nucleus and initiate transcription of IFN-Is [23–26].
Cyclic GMP-AMP synthase (cGAS) is expressed in most
cells and is the most important intracellular DNA sensor dur-
ing the production of IFN-Is [25, 29, 30]. When activated by
double-stranded (ds) DNA, cGAS initiates the synthesis of
cyclic dinucleotide second messenger (cGAMP) and then ac-
tivates stimulator of interferon genes (STING) in the ER [29].
STING then recruits TANK-binding kinase 1 (TBK1) to
phosphorylate IRF3, which can translocate to the nucleus to
promote IFN-β production [29]. Other intracellular receptors
for DNA stimuli include interferon-induced protein 16
(IFI16), Z-DNA-binding protein 1 (ZBP1, also known as
DAI), and DNA-dependent RNA polymerase III [25, 30, 31].
TLR3, TLR7, and TLR8 are endosomal membrane recep-
tors expressed in many innate immune cells, and TLR7 is
particularly highly expressed in pDCs [24, 27, 28, 32, 33].
TLR3 can detect dsRNA in endosomes internalized by
FcγRIIa, and TLR7 and TLR8 can detect single-stranded
(ss) RNA in endosomes [24, 33]. After activation, TLR3 can
bind to Toll-IL-1 receptor domain-containing adaptor induc-
ing IFN-β (TRIF) to activate TRAF3 and then recruit and
activate TBK1 to phosphorylate IRF3 for IFN-β production
[34]. Currently, cyclin-dependent kinases (CDKs) have been
found to be critical in the translation of IFN-β, and CDK
inhibition dramatically suppresses the transcription of ISGs
[35]. Activated TLR7 and TLR8 induce the transcription of
IFN-Is in the same manner as that of TLR9 [34].
RLRs include RIG-I, melanoma differentiation-associated
gene 5 (MDA5), and laboratory of genetics and physiology 2
(LGP2) [33]. RIG-I and MDA5 are expressed in cytoplasm of
fibroblasts, cDCs, macrophages [33, 35]. RIG-I detects short
ds-5′ tri-phosphorylated RNA and ss-5′ tri-phosphorylated
RNA, whereas MDA5 can recognize long dsRNA and
ssRNA [33, 35, 36]. After activation, RIG-I and MDA5 bind
to the adaptor mitochondrial antiviral signaling protein
(MAVS) on the outer membrane of mitochondria and then
activate IRF3 through TRAF3 and TBK1 [37]. TLR4 can
sense extracellular lipopolysaccharide (LPS) on the cell mem-
brane. Activated TLR4 recruits TRAM and then activates
TRIF, TBK1, and IRF3 to initiate the transcription of IFN-Is
[34].
Type I Interferon Signaling Pathway
IFN-α and IFN-β exert their immune functions by ligating
with their specific IFNARs that are expressed on the plasma
membrane of most nucleated cells [18]. The interactions be-
tween IFNAR and IFN-α/β drive the dimerization of
IFNARs, and its subunits IFNAR1 and IFNAR2 separately
bind to and activate different types of Janus kinase (JAK)
protein families: IFNAR1 activates tyrosine kinase 2
(TYK2) and IFNAR2 activates JAK1 [15]. Later, cytoplasmic
transcription factors STAT1 and STAT2 can be phosphory-
lated by JAKs, and interferon regulatory family 9 (IRF9) can
bind to STAT1/STAT2 heterodimers to form the
heterotrimeric complex IFN-stimulated gene factor 3
(ISGF3), which can initiate transcription of ISGs by combin-
ing with IFN-stimulated response elements (ISREs, consensus
sequence TTTCNNTTTC) [15, 17]. ISGs include a series of
genes encoding antiviral and antitumor molecules, and tran-
scription factors such as IRFs [12] (Fig. 1). Notably, IRF7
promotes the expression of ISGs that also include IRF7,
forming a positive feedback loop within the type I IFN signal-
ing pathway [38].
The Regulation of the Type I Interferon
Signaling Pathway
The Interferon Regulatory Family
Interferon regulatory family (IRF) family is the regulator of
IFN signaling pathways and includes 9 members in human:
IRF1, IRF2, IRF3, IRF4 (PIP/LSIRF/ICSAT), IRF5, IRF6,
IRF7, IRF8 (ICSBP), and IRF9 (ISGF3γ) [14]. IRF proteins
contain conserved amino-terminal DNA-binding domains
(DBDs), carboxy-terminal IRF-association domain 1 (IAD1)
and IAD2 [14]. The DBDs can detect and regulate ISRE, and
the IADs can mediate homodimers and heterodimers with
other IRFs and transcription factors [14].
The type I IFN signaling pathway begins with IRF3 being
phosphorylated via signaling from PRRs, which leads to ex-
pression of IFN-β and IFN-α4 through dimerization, nuclear
translocation, and formation of a multiprotein complex with
coactivators CREB binding protein (CBP) and p300 [39].
IRF7 is poorly expressed in multiple cells but can be strongly
induced by the type I IFN signaling pathway [38]. Type I IFNs
induced by IRF3 then initiate the transcription and expression
of ISGs that include IRF7, initiating a positive feedback loop
of IRF7 [12]. At the later phase, both IRF3 and IRF7 can
promote the expression of IFN-Is [39].
IRF1, IRF5, IRF8, and IRF9 also participate in the regula-
tion of type I IFN signaling pathways [38]. IRF9 is a part of
ISGF3 that is necessary for the transcription of ISGs [15, 17].
IRF8 has been proved to cooperatively promote the rapid pro-
duction of IFN-β induced by IRF3 in human monocytes [40].
IRF1 and MyD88 are required for the expression of IFN-β in
cDCs but not pDCs [41]. IRF5 promotes the transcriptions of
specific ISREs that are mainly for encoding proinflammatory
cytokines [38, 39]. Additionally, IRF4 and IRF8 are essential
for DC subset development [39].

Post-Translational Modifications of the Type I
Interferon Signaling Pathway
Post-translational modifications (PTMs), including phosphor-
ylation, polyubiquitylation, methylation, acetylation,
ISGylation, and SUMOylation, are emerging mechanisms
for regulating the type I IFN signaling pathway to maintain
the balance of the production of IFN-Is and transcription of
ISGs [17, 42]. PTMs of type I IFN signaling pathway are
summarized in Fig. 2 and Table 1.
Epigenetic Modifications in the Regulation of the
Type I Interferon Signaling Pathway
Epigenetic modifications generate hereditary alterations in
gene expression without changing the DNA coding sequence
[71]. Epigenetic modifications, including DNA methylation,
histone modifications, microRNAs (miRNAs), and long non-
coding RNAs (lncRNAs), are important in regulating the type
I IFN pathway [71].
DNA methylation is involved in heritable DNA modifica-
tion at the 5′-position of cytosine rings residing in the dinu-
cleotide sequence CpG [72]. Decreased DNA methylation in
IFN-induced genes have been found in patients with SLE,
compared to healthy controls [73]. Several different methyla-
tion positions and genes have been identified in patients with
RA, including MX dynamin-like GTPase 1 (MX1), IFN-
induced protein 44-like (IFI44L), Deltex E3 Ubiquitin
Ligase 3L (DTX3L), and polymerase family member 9
(PARP9), forming the IFN-inducible gene interaction network
[74]. In addition, hypomethylation of IFN-regulated genes,
including MX1, IFI44L, and PARP9, have also been identified
in patients with prim ary SjS (pSjS) [75]. Many
hypomethylations of type I IFN-associated genes have been
identified in CD4+ and CD8+ methylated regions in patients
with SSc [76]. Furthermore, inhibition of DNA methylation
can induce type I IFN responses in cancer, demonstrating
negative regulatory functions of DNA methylation in type I
IFN pathway [77].
Histone modifications include methylation, acetylation,
ubiquitination, and phosphorylation [78]. The dimethylation
of histone H3 at lysine 9 (H3K9me2) has an inhibitory effect
on IFN and ISG expression [79]. Methyltransferase SET
domain-containing protein 2 (SETD2) can catalyze the
trimethylation of H3K36 at certain ISG promoters, such as
ISG15, to activate them, and SETD2 can also amplify the
functions of IFN-Is by inducing STAT1 methylation [80].
Disruption of telomeric silencing-1 like (DOT1L) protein is
a methyltransferase that can mediate the modification of
H3K79me2/3 at Ifnb1 promoters, promoting the transcription
and expression of IFN-β [81]. The transcription of IFN-β can
also be regulated by the histone acetyltransferase proteins
CBP and p300/CBP-associated factors (PCAF)/general
Clinic Rev Allerg Immunol
control non-derepressible 5 (GCN5) [82]. The GCN5/PCAF
complex is recruited to acetylate nucleosomes to accelerate the
transcription of IFN-β through recruiting SWItch/sucrose
non-fermentable (SWI/SNF) to bind to transcription initiation
factor IID (TFIID) [83].
Histone deacetylase 1 (HDAC1) and HDAC8 can in-
hibit the production of IFN-β by inducing histone H3/H4
deacetylation of the Ifnb1 promoter [84]. However,
HDAC has also been shown to promote the initiation of
transcription or transcription elongation of ISGs by
recruiting P-TEFb to ISG promoters through Brd4 [85].
Furthermore, small ubiquitin-like modifier (SUMO) can
silence Ifnb1 at its promoter through sumoylation [86].
In addition, PARP9-DTX3L is also an E3 ubiquitin ligase
and can bind to STAT1 to act on host histone H2BJ to
promote the expression of ISGs [42, 87]. The human
Bre1/RNF20 complex is necessary to promote global in-
creased monoubiquitination of histone 2B at lysine 120 to
activate the expression of ISGs [88].
miRNA and lncRNAs are also important in regulating
type I IFN signaling pathways. miR-466l can directly sup-
press multiple IFN-α species via their 3′ untranslated re-
gion (3′UTR) [89]. miR-130b negatively regulates IFN-α
in renal cells in a mouse model of lupus nephritis, whereas
miR-618 can increase IFN-α production in patients with
SSc [90, 91]. miR-146a can suppress IFN-β production
and miRNA-302d can suppress ISG expression by
targeting IRF9 [92, 93]. miR-279 can inhibit type I IFN
signaling directly via inhibiting STAT [94]. miR-155 can
inhibit suppressors of cytokine signaling 1 (SOCS1) and
promote the phosphorylation of STAT1 and STAT3 in
hepatocarcinoma cells [95]. Controversially, type I IFN
signaling was found to be enhanced in miR-155-deficient
CD8+ T cells [96]. In addition, miR-221 and miR-203 can
activate JAK–STAT pathway by inhibiting SOCS1 and
SOCS3 [97]. The miR-21 negatively regulates IFN-α sig-
naling through targeting MyD88 and IRAK1 in patients
with HCV infection [98]. Furthermore, lncRNA#32 has
been shown to upregulate ISG expression and the antiviral
functions of type I IFN [99]. lncLrrc55-AS can promote
the production of IRF3 and IFN-I [100]. However,
lncRNA-CMPK2 has been identified as a negative regula-
tor of the type I IFN signaling pathway [101].
Susceptibility Genes in the Type I Interferon
Signaling Pathway in Autoimmune Diseases
Several susceptibility genes have been found to be related to
the production of type I IFN or type I IFN signaling pathway
in autoimmune diseases. Susceptibility genes of SLE associ-
ated with type I IFNs include IRF5, IRF7, IRF8, IRAK1, tu-
mor necrosis factor, alpha-induced protein 3 (TNFAIP3),
Clinic Rev Allerg Immunol

LPS
AdMV TLR4
Apoptotic cell
FcγRIIa
Virus TRAM TRIF

IFN-α
dsDNA
Endosome
cGAS IFN-β

RIG-1

ssRNA P STAT2
TLR3
STAT1 P
cGAMP ISGF3
TRIF TLR7 TLR8 TLR9 IRF9
MAVS STING

TRAF3 Endoplasmic TRAF3 MyD88

reticulum
IRAK4 IRAK1 TRAF6

TBK1 TRAF3

IRF7 ISGs
Ribosome
CDK transcription
IRF3

IRF7
IRF3
IFN-Is
transcription

Fig. 1 The production of type I interferons and type I interferon
signaling pathway. Extracellular stimuli containing DNA can be
internalized to form endosomes by FcγRIIa on the surface of pDCs,
and then recognized by TLR9 to activate MyD88. MyD88 recruits
IRAK4 and leads, through a pathway involving IRAK1, TRAF6, and
TRAF3, to activation of IRF7, which can translocate into the nucleus
and initiate transcription of IFN-Is. cGAS can be activated by
intracellular dsDNA. cGAS phosphorylates IRF3 to translocate into the
nucleus and induce IFN-β production through the cGAMP/STING/
TBK1 pathway. CDKs are very critical in the translation of IFN-β.
TLR3 can detect dsRNA and then activate IRF3 to induce IFN-β produc-
tion by activating TRIF, TRAF3, and TBK1. TLR7 and 8 can recognize
ssRNA in endosomes and then bind to MyD88 and interact with IRAK4,
IRAK1, TRAF6, and TRAF3 to activate IRF7 to induce the transcription
of IFN-Is. RIG-I and MDA5 mainly recognize dsRNA and then bind to
the adaptor MAVS on the outer membrane of mitochondria, and MAVS
then activates IRF3 through TRAF3 and TBK1. TLR4 can sense LPS on
the cell membrane. Activated TLR4 recruits TRAM and then activates
TRIF, TBK1, and IRF3 to initiate the transcription of IFN-Is. The inter-
action between IFN-α/β and IFNARs drives the dimerization of IFNARs,
leading to the autophosphorylation and transphosphorylation of JAKs.
TYK2 and JAK1 bind to IFNAR1 and IFNAR2, respectively. Type I
IFN signals then pass to the inner side of cells via the JAK–STAT sig-
naling pathway. Later, IFNAR1 can be phosphorylated by JAKs, leading
to repositioning and binding of STAT2. Phosphorylated STAT2 can re-
cruit and phosphorylate STAT1 to form STAT1/STAT2 heterodimers
and separate from IFNAR. The heterotrimeric complex ISGF3 comprises
IRF9 and STAT1/STAT2 heterodimers to initiate transcription of ISGs
by combining with ISREs. AdMV: apoptosis-derived membrane vesicle;
RIG-I: retinoic acid-inducible gene-I; MAVS: mitochondrial antiviral
signaling protein; MDA5: melanoma differentiation-associated gene 5;
TRAF3: tumor necrosis factor receptor-associated factor 3; TBK1:
TANK-binding kinase 1; IRF3: interferon regulatory family 3; cGAS:
cyclic GMP-AMP synthase; cGAMP: cyclic dinucleotide second mes-
senger; STING: stimulator of IFN genes; LPS: lipopolysaccharide; TLR:
Toll-like receptor; TRAM: TRIF-related adaptor molecule; TRIF: TIR-
domain-containing adaptor protein-inducing IFN-β; MyD88: myeloid
differentiation primary response gene 88; IRAK1: Interleukin-1 recep-
tor-associated kinase 1; IFN: interferon; CDK: cyclin-dependent kinase;
IFNAR1: interferon-α/β receptor 1; JAK: Janus kinase 1; TYK2: tyro-
sine kinase 2; STAT1: signal transducers and activators of transcription 1;
ISGF3: IFN-stimulated gene factor 3; ISG: interferon-stimulated gene

TNFAIP3 interacting protein 1 (TNIP1), interferon induced
with helicase C domain 1 (IFIH1), TYK2, STAT4, protein
tyrosine phosphatase non-receptor type 22 (PTPN22), three
prime repair exonuclease 1(TREX1), E26 transformation-
specific 1 (ETS1), and ubiquitin-conjugating enzyme E2 L3
(UBE2L3) [102–107].
Large-scale association studies have shown a relationship
between polymorphisms of IRF5, IRF7, IRF8, and SLE risk
[102]. Several variants of IRF5, IRF7, and IRF8 can induce
transcription and expression of proteins in regulating the type
I IFN signaling pathway [102]. Notably, IRF5 and STAT4 are
considered the most strongly SLE-associated loci except for
the MHC region [103, 104]. A variant of STAT4 (rs7574865)
is related to elevated sensitivity to IFN-α signaling [103].
STAT4 protein can be phosphorylated and activated by
interacting with IFNAR2 cytoplasmic domain, and then trans-
locate into nucleus to initiate the expression of IFN-γ and
other proinflammatory molecules [108–110]. PTPN22 is the
susceptibility gene for both SLE and RA in the European
population [103, 105]. High IFN-α and low TNF-α in serum
occur in patients with SLE with the rs2476601 risk allele of
PTPN22 [103, 105]. PTPN22 protein can directly interact
with and promote the ubiquitination of TRAF3 [111].
TNFAIP3 and TNIP1, which are proven to be susceptibility

Fig. 2 The post-translational modifications (PTMs) of type I interferon
pathway. The gray boxes represent the negative regulators of type I IFN
signaling pathway, and the orange arrows shows the path of type I IFN
pathway and the blue one represents the negative webs. IFI35, RNF125,
NLRC5, PCBP2, CYLD, TRIM13, and TRIM40 can negatively regulate
the type I IFN pathway through sensing of RNA via RIG-I or MDA5 and
signaling MAVS. A20, TRIP, TRIM8, TRIM11, TRIM26, TRIM27,
TRIM56, and SHP-2 can suppress TBK1, and NLRC5, TRIM26,
TRIM27, TRIM56, PLASy, ISG56, ASCC3, RAUL, SMAD2, and
SMAD3 can inhibit IRF3. TRIM38 can induce SUMOylation of cGAS
and STING to inhibit type I IFN response, and TRIM32 and TRIM56 can
induce polyubiquitination of STING. The TRIF can be negatively regu-
lated by TRIM32, TRIM38, SHP-2, and TRAF3 and TRAF6 through
TLRs signaling can be inhibited by TRIM38, OTUB1, OTUB2, and
DUBA. GBP4 can disrupt the interactions between TRAF6 and IRF7,
and IRF7 can be directly suppressed by PLASy, ISG56, Nmi, OASL1,
DDX24, ASCC3, and RAUL. The production of IFN-β can be directly
inhibited via TRIP, ISG56, SMAD2, and SMAD3. PKD2 can regulate
ubiquitination and degradation of IFNAR1, and USP18 can compete with
JAK1 for IFNAR2. SHP-1, SHP-2, PTPN1, TC-PTP, SOCS1, SOCS3,
PLAS1, PLASy, C1S, and DCST1 can suppress the JAK–STAT pathway
by inhibiting JAKs or STATs. RIG-I: retinoic acid-inducible gene-I;
MAVS: mitochondrial antiviral signaling protein; MDA5: melanoma
differentiation-associated gene 5; TRAF3: tumor necrosis factor
receptor–associated factor 3; TBK1: TANK-binding kinase 1; IRF3: in-
terferon regulatory family 3; cGAS: cyclic GMP-AMP synthase;
cGAMP: cyclic dinucleotide second messenger; STING: stimulator of
Clinic Rev Allerg Immunol
IFN genes; TLR: Toll-like receptor; TRAM: TRIF-related adaptor mole-
cule; TRIF: TIR-domain-containing adaptor protein-inducing IFN-β;
MyD88: myeloid differentiation primary response gene 88; IRAK1:
Interleukin-1 receptor-associated kinase 1; IFNAR1: interact with inter-
feron-α/β receptor 1; JAK: Janus kinase 1; TYK2: tyrosine kinase 2;
STAT1: signal transducers and activators of transcription 1; ISGF3:
IFN-stimulated gene factor 3; ISG: interferon-stimulated gene; IFI35:
interferon-induced protein 35; RNF125: ring-finger protein 125;
NLRC5: NLR family CARD domain-containing 5; PCBP2: poly(rC)-
binding protein 2; CYLD: cylindromatosis lysine 63 deubiquitinase;
TRIP: TNF receptor-associated factor (TRAF)–interacting protein;
TRIM: tripartite motif-containing; GBP4: guanylate binding protein 4;
OTUB1: OTU domain-containing ubiquitin aldehyde binding protein 1;
DUBA: deubiquitinating enzyme A; PLAS: protein inhibitor of activated
STAT; ISG56: IFN-stimulated gene 56; IFIT1: interferon-induced protein
with tetratricopeptide repeats 1; Nmi: N-Myc and STATs interactor;
OASL1: oligoadenylate synthetase-like 1; DDX24: DEAD-box helicase
24; ASCC3: activating signal cointegrator complex 3; RAUL: RTA-
associated ubiquitin ligase; SMAD2: SMAD family member 2; PKD2:
protein kinase D2; USP18: ubiquitin-specific peptidase 18; SHP-1: SH2-
containing protein tyrosine phosphatase 1; PTPN1: protein tyrosine phos-
phatase, non-receptor type 1; PTP1B: protein tyrosine phosphatase 1B;
TC-PTP: T cell-protein tyrosine phosphatase; PTPN2: protein tyrosine
phosphatase, non-receptor type 2; SOCS: suppressors of cytokine signal-
ing; CIS: cytokine-induced SRC-homology 2 (SH2) protein; DCST1:
DC-STAMP domain-containing 1
Clinic Rev Allerg Immunol

Table 1 Negative regulators in the type I IFN signaling pathway

Negative regulator Mechanism Ref

IFI35 (also called IFP35) Inhibiting dephosphorylation, promoting K48-linked ubiquitination and [43]
proteasomal degradation of RIG-I
RNF125 Conjugating ubiquitin to and suppressing MDA5/MAVS/RIG-I [44]
NLRC5 Blocking the interactions between MAVS and RIG-I and IRF3 phosphorylation [45]
A20 Blocking IRF signaling induced by RIG-I and the IFN response by removing [46]
K63-linked ubiquitin chains from TBK1/IKKi
PCBP2 Interacting with and promoting the proteasomal degradation of MAVS to inhibit [47]
the RIG-I/MAVS pathway
CYLD Removing K63-linked polyubiquitin chains from RIG-I [48]
TRIP Promoting K48-linked polyubiquitination and proteasomal degradation of [49]
TBK1;
Inhibiting IFN-β production promoted by TLR3, TLR4 and RIG-I
TRIM family TRIM 8 Disrupting the TRIF-TBK1 interaction [50]
TRIM 11 Interacting with TBK1 to inhibit the functions of IRF3 and IFN-β production [50]
TRIM 13 Suppressing MDA5-induced IFN-Is; upregulating RIG-I [50]
TRIM 26 Inhibiting RNA virus infection by TBK1; [50]
Promoting K48-linked polyubiquitination and proteasome-mediated degradation
of phosphorylated IRF3
TRIM 27 Targeting TBK1 and inhibiting the expression of IRF3 [50, 51]
TRIM 32 Inducing K63-linked polyubiquitination of STING; [50]
Synthesizing unanchored polyubiquitin chains to activate NEMO, IKKβ, and
TBK1 to induce IRF3 and NF-κB activation;
Promoting the degradation of TRIF to suppress TLR3/4 responses
TRIM 38 Inducing SUMOylation of cGAS and STING to prevent K48-linked [50]
polyubiquitination and proteasomal degradation;
Negatively affecting TLR signaling by destabilizing TRAF6, TRIF, TAB2/3 and
NAP1
TRIM 40 Promoting K27- and K48-linked polyubiquitin to RIG-I and MDA5 and [50]
proteasomal degradation
TRIM 56 Inducing K63-linked polyubiquitination of STING; [50]
Synthesizing unanchored polyubiquitin chains to activate NEMO, IKKβ and
TBK1 to induce IRF3 and NF-κB activation
GBP4 Disrupting the interaction between TRAF6 and IRF7 [52]
OTUB1 and OTUB2 Deubiquitinating TRAF3 and TRAF6 [48]
DUBA (also called OTUD5) Suppressing K63-specific autoubiquitination of TRAF3 [48]
PIAS PIASy targets IRF3 and IRF7 to negatively regulate IFN-Is expression; [53, 54]
PIAS1 and PIASy inhibit STAT1
ISG56 (also called IFIT1) Inhibiting Sendai virus (SeV)-activated IRF3, IFN-β promoter; [55, 56]
Facilitating interaction of SAP25-HDAC2-Sin3A at LPS-induced gene loci, to
inhibit activation at promoters of IFNB1, IRF7, IRF8
Nmi Promoting the K48-linked ubiquitination and proteasomal degradation of IRF7 [57]
OASL1 Inhibiting translation of IRF7 mRNA [58]
DDX24 Disrupting the IRF7/RIP1 interaction to suppress RLR activity; [59]
possibly competing with RIG-I for binding of RNA
ASCC3 Dampening ISG expression by interacting with IRF-3 and IRF-7 [60]
RAUL Ubiquitinating IRF7 and IRF3 to suppress the type I IFNs signature [61]
SMAD2 and SMAD3 Inhibiting IRF3 phosphorylation and transcription by directly interacting to [62]
reduce IFN-β expression
PKD2 Regulating ubiquitination and degradation of IFNAR1 [63]
USP18 Competing with JAK1 for binding IFNAR2 [64]
SHP-1 Dephosphorylating JAKs; [65, 66]
Inhibiting activation of the kinase IRAK1 to promote type I IFN signatures
SHP-2 Inhibiting signal transduction of TBK1 and TRIF to suppress TLR4- and [67]
TLR3-activated IFN-β;
Inhibiting JAK–STAT signaling
PTPN1 (also called PTP1B) Dephosphorylating JAK2 and TYK2 [68]
TC-PTP (also called PTPN2) Modulating JAK1 and JAK3 [68]
 Clinic Rev Allerg Immunol

Table 1 (continued)

Negative regulator Mechanism Ref

SOCS SOCS1 Inhibiting the catalytic activity of JAKs by interacting with the JAK activation [69]
loop
SOCS3 Inhibiting JAKs through receptor binding and JAK activation loop; Competing
for receptor phosphotyrosine-docking sites
CIS Blocking the recruitment and activation of STATs
DCST1 Promoting ubiquitination-mediated degradation of STAT2 [70]

IFI35 interferon-induced protein 35, RNF125 ring-finger protein 125, NLRC5 NLR family CARD domain-containing 5, PCBP2 poly(rC)-binding
protein 2, CYLD cylindromatosis lysine 63 deubiquitinase, TRIP TNF receptor-associated factor (TRAF)–interacting protein, TRIM tripartite motif-
containing, GBP4 guanylate binding protein 4, OTUB1 OTU domain-containing ubiquitin aldehyde binding protein 1, DUBA deubiquitinating enzyme
A, PLAS protein inhibitor of activated STAT, ISG56 IFN-stimulated gene 56, IFIT1 interferon-induced protein with tetratricopeptide repeats 1, Nmi N-
Myc and STATs interactor, OASL1 oligoadenylate synthetase-like 1, DDX24 DEAD-box helicase 24, ASCC3 activating signal cointegrator complex 3,
RAUL RTA-associated ubiquitin ligase, SMAD2 SMAD family member 2, PKD2 protein kinase D2, USP18 ubiquitin-specific peptidase 18, SHP-1
SH2-containing protein tyrosine phosphatase 1, PTPN1 protein tyrosine phosphatase, non-receptor type 1, PTP1B protein tyrosine phosphatase 1B, TC-
PTP T cell-protein tyrosine phosphatase, PTPN2 protein tyrosine phosphatase, non-receptor type 2, SOCS suppressors of cytokine signaling, CIS
cytokine-induced SRC-homology 2 (SH2) protein, DCST1 DC-STAMP domain-containing 1

genes of SLE through GWAS, encode A20 and A20-binding
protein, respectively, and are regulators in type I IFN pathway,
NF-κB activation, and TNF-mediated apoptosis [102–104].
TREX1 encodes 3′-5′ DNA exonuclease TREX1 to clear
aberrant DNA and is a susceptibility gene of SLE [103, 105].
IFIH1 encodes the dsRNA sensor MDA5 [102]. A missense
allele of IFIH1 (rs1990760) is identified to be related to in-
creased transcription and expression of IFIH1 and is involved
in elevated expression of IFN-induced genes in anti-dsDNA-
positive patients with SLE [102, 104]. TYK2 encodes TYK2, a
member of the JAK–STAT pathway [105]. UBE2L3 has
genome-wide significance in relation to SLE in Asian but
not European populations [103]. UBE2L3 encodes an E2
ubiquitin-conjugating enzyme that can interact with Triad3A
(also called RNF216) to regulate the degradation of TLR4 and
TLR9 [112]. IRAK1 acts on the delivery of TLR signaling,
and IRAK1 gene polymorphisms were identified to be related
to the pathogenesis of SLE [106, 107]. ETS1 is a negative
regulator in expression of IFN-induced genes by interacting
with ISGs [102]. ETS1 is an SLE susceptibility locus in Asia,
and the SNP rs6590330 is related to decreased expression of
ETS1 [102, 105].
Many SLE risk susceptibility genes involved in the type I
IFN pathway also participate in the pathogenesis of other au-
toimmune diseases, such as RA, JIA, SSc, and SjS.
Susceptibility genes in RA related to the type I IFN pathway
include PTPN22, STAT4, TNFAIP3, IRF5, UBE2L3, ETS1,
IRF8, TYK2, IRAK1, and TRAF6 [105, 113]. IRF5,
PTPN22, STAT4, TYK2, and UBE2L3 are associated with an
increased risk of JIA [114, 115]. Susceptibility genes in SSc
include IRF5, IRF7, IRF8, PTPN22, STAT4, TNFAIP3,
TNIP1, and TYK2, while IRF5, STAT4 TNFAIP3, and
TNIP1 are involved in SjS [116, 117]. The association be-
tween susceptibility genes and type I IFN signaling pathway
is described in Fig. 3.
Type I Interferon Signaling Pathway
and Autoimmune Diseases
Type I Interferonopathies
Type I interferonopathy is a type of Mendelian genetic disor-
der with diverse molecular defects and clinical features but
with the same overproduction of type I IFNs [118, 119].
Type I interferonopathies include a wide range of genetic dis-
eases, such as Aicardi-Goutières syndrome (AGS), Sting-
associated vasculopathy with onset in infancy (SAVI),
spondyloenchrondro-dysplasia (SPENCD), Singleton-
Merten syndrome, and ISG15 deficiency [118, 119]. Type I
interferonopathies usually occur in childhood and some of
them possess lupus-like features, supporting the association
between lupus and high level of IFN-Is [108]. Type I
interferonopathies can be caused by mutations in multiple
genes associated with type I IFN signaling pathway, such as
TREX1, ribonuclease H2 subunit A (RNASEH2A),
RNASEH2B, RNASEH2C, SAM, and HD domain-
containing deoxynucleoside triphosphate
triphosphohydrolase 1 (SAMHD1), adenosine deaminase
RNA specific (ADAR1), and IFIH1 [119]. Type I
interferonopathies are summarized in Table 2.
Due to the poor response of biologic disease–modifying
antirheumatic drugs (DMARDs) in type I interferonopathies,
there is increasing interest in targeted therapies related to the
type I IFN signaling pathway [137]. JAK inhibition has shown
promising results in type I interferonopathies [137–140]. Case
reports of JAK inhibitors, such as baricitinib, ruxolitinib to
treat ubiquitin-specific peptidase 18 (USP18) deficiency,
SAVI, AGS, and TREX1 chilblain lupus, have been published
[136–142]. Cases of chilblain lupus have also shown a good
response to tofacitinib therapy [127]. Furthermore, in the
NCT01724580 and NCT02974595 programs, 18 patients
Clinic Rev Allerg Immunol
with CANDLE or SAVI treated with baricitinib also had good
results [137]. The side effects of JAK inhibition seem to be
mild and acceptable, with slight and reversible decreases in
lymphocytes and platelets, elevated transaminases and serum
creatinine, and herpes zoster infection [143, 144]. However,
due to the extremely low incidence of type I
interferonopathies, conducting clinical trials is difficult.
In vitro experiments or the use of animal models may help
identify additional JAK–STAT candidates.
Systemic Lupus Erythematosus and Pediatric
Systemic Lupus Erythematosus
In 1999, genes induced by IFN-Is were found to be upregu-
lated in peripheral blood mononuclear cells (PBMCs) of ap-
proximately two-thirds of adult patients with SLE through
microarray gene expression analysis [145]. The level of type
I IFNs is also positively related to the disease activities and
severity of symptoms (such as skin rash, fever, and leucope-
nia) in patients with SLE [146]. In addition, ANA and anti-
dsDNA antibodies appear in patients after treatment with IFN-
Is in patients with malignant carcinoid tumors [11]. Moreover,
TLRs have been identified to be crucial in the maintaining
SLE [147].
IFN-α is a powerful inducer for the differentiation or acti-
vation of DCs [148]. The activation of T cells and the sup-
pression of Treg cells can be induced by IFN-Is in lupus-prone
mice after UVB exposure [149]. IFN-Is participate in early
transitional B cells and promote the expansion of
autoantibody-secreting cells [150]. In patients with SLE,
IFN-Is can lead to a strong inflammatory response by sup-
pressing the maturation of miR-146a [151]. IFN-β is in-
creased in circulating B cells in SLE patients, especially those
with nephritis and autoantibodies [152]. Moreover, increased
IFN-κ promotes the development of CLE after ultraviolet light
exposure [146, 153, 154].
pSLE or childhood-onset SLE (cSLE) occurs during child-
hood with more severe damage to internal organs (especially
to kidney) than adult SLE, revealing its stronger association
with genetics [155]. The lupus-like phenotypes in children,
also called “monogenic lupus,” is one of type I
interferonopathies and can be caused by mutation of genes
involved in type I IFN signaling pathway, such as
DNase1L3, TREX1, SAMHD1, RNASEH2ABC, ADAR1,
IFIH1, ISG15 [130, 155]. In a study assessing type I IFN
signaling in pediatric autoimmune diseases, 82% (64 of 78)
of samples from patients with juvenile SLE (JSLE) and 75%
(76 of 101) of samples from children with juvenile DM (JDM)
had positive IFN scores [156]. Upregulated expression of
ISGs was also observed in cSLE, and it can be suppressed
with TBK1 inhibitors BX795 [157]. The expression of
TLRs in JSLE is also increased [158]. TLRs can be activated
by apoptotic neutrophils and the IFN-α expression can be
suppressed after MyD88 and TRIF inhibitors in PBMC of
JSLE patients [158]. However, more clinical research on in-
hibitors involved in type I IFN pathway is urgently needed
[157, 158].
With better understanding of the role of IFN-I, many prom-
ising treatments targeting type I IFN signaling pathway are
undergoing clinical studies in SLE [159]. Rontalizumab, a
humanized IgG1 anti-IFN-α mAb, has an acceptable safety
profile and induces decreased expression of IRGs in phase I
studies of patients with SLE [160, 161]. However, due to the
unmet endpoints in phase II trials, the development of
rontalizumab was terminated [160]. Sifalimumab (formerly
MEDI-545) is a fully humanized IgG1 anti-IFN-α mAb
[162]. In a phase IIb trial in 2016, SLE patients treated with
sifalimumab met the primary endpoint and their other ob-
served indexes and symptoms were also significantly im-
proved [162]. AGS-009 is a humanized IgG4 anti-IFN-α
mAb that was shown to be generally tolerated by patients with
SLE [163]. However, there were no subsequent trials.
Interferon-α-kinoid (IFN-K) is a therapeutic vaccine targeting
IFN-α [164, 165]. In a phase IIb trial, IFN-K significantly
decreased IFN gene signatures and achieved the biological
coprimary endpoint but not the clinical coprimary endpoint,
revealing a need for further evaluation [165].
An anti-IFNAR1 mAb, anifrolumab, showed significant
effects in decreasing the disease activity of SLE in phase II
trials, and another phase IIb study in patients with moderate to
severe SLE was considered very successful [166, 167]. Two
phase III trials (known as TULIP–1 and TULIP–2) in patients
with SLE were completed in 2019. One of the endpoints,
British Isles Lupus Disease Activity Group (BILAG)–based
Composite Lupus Assessment (BICLA), but not SLE re-
sponse index (SRI), was met in the first phase III trial,
TULIP-1, and both were achieved in TULIP-2 [20, 168].
Regardless of the seemingly conflicting results, anifrolumab
is the most successful and promising IFN pathway-targeted
therapy for SLE and awaits use in clinical practice [20, 168].
BIIB059 is a mAb that binds to blood DC antigen 2
(BDCA2), an inhibitory receptor on pDCs, and induces its
rapid internalization to inhibit the production of IFN-Is
[169]. BIIB059 was seemingly beneficial to patients with
SLE with cutaneous manifestations [169]. Venetoclax (also
called ABT-199) is a Bcl-2 antagonist that can kill pDCs in
lupus-prone mice and has shown a good clinical response in
patients with SLE in a phase I trial [170–172].
Hydroxychloroquine, a TLR9, TLR7, and TLR8 antago-
nist, is a conventional antimalarial drug for SLE [6]. The pre-
clinical data of CPG-52364, an inhibitor of TLR7, TLR8, and
TLR9, showed that it can enhance the effectiveness of
hydroxychloroquine [173]. Dynavax posted a news article
about a phase 1b/2a trial of DV1179, a TLR7 and TLR9
inhibitor, in patients with SLE, but it did not meet the phar-
macodynamic endpoints. A small molecular TLR9 inhibitor

Fig. 3 The susceptibility genes involved in type I interferon pathway in
autoimmune diseases. The red words represent the susceptibility genes
involved in type I IFN pathway and some of them also represent their
encoded proteins. TREX1 encodes 3′-5’ DNA exonuclease TREX1, and
TREX1 is related to the susceptibility of SLE by impacting the
degradations and increasing the expression of IFN-Is. IFIH1 encodes
dsRNA sensor MDA5 and is involved in increased transcription of
IFIH1 and elevated expression of IFN-induced genes. UBE2L3 encodes
an E2 ubiquitin-conjugating enzyme that involves in the degradation of
TLR4 and TLR9. IRAK1 and TRAF6 are related to the production of
IFN-Is and NF-κB, and the multiple SNPs with IRAK1 and TRAF6 are
associated with onset and development of autoimmune diseases. PTPN22
can regulate type I IFN signatures by interacting with TRAF3, and the
polymorphism in PTPN22 (rs2476601) is related to high serum IFN-α
activity. IRF5, IRF7, and IRF8 play an important role in upregulating the
type I IFN responses. Several polymorphisms of IRF5, IRF7, and IRF8
are related to their expression of proteins and increased IFN-Is. TYK2
encodes TYK2 in JAK–STAT pathway, and a variant (rs280519) of
TYK2 is related to increased production of IFN-I. STAT4 encodes
STAT4 protein that is associated with increased sensitivity to IFN-α
ST2825 has demonstrated great potential, with promising
safety and efficacy profiles in patients with SLE [173].
The IRAK4 inhibitor BMS-986126, and Bruton’s tyrosine
kinase (BTK) inhibitor evobrutinib (also called M2591,
MSC2364447C) have been shown to suppress the type 1
IFN signaling pathway in preclinical experiments of SLE,
but the results of clinical trials are either lacking or unpub-
lished [174, 175]. Baricitinib (also called LY3009104) is a
selective inhibitor of JAK1/JAK2 and has shown significant
efficacy in patients with SLE in phase trials [21]. Tofacitinib,
an inhibitor of JAK1/JAK3, is approved by the FDA for the
treatment of RA, psoriatic arthritis, and ulcerative colitis
[176]. However, clinical trials of tofacitinib for SLE and
CLE are still in progress [176]. Filgotinib, a highly selective
JAK1 inhibitor, has just finished phase II clinical trials. R333,
a topical JAK/SYK inhibitor for DLE treatment, failed to
Clinic Rev Allerg Immunol
signaling and elevated expression of IFN-γ. TNFAIP3 and TNIP1 encode
A20 and A20-binding protein separately that are regulatory factors in type
I IFN pathway, NF-κB activation. ETS1 can negatively regulate the ex-
pression of IFN-induced genes by interacting with ISGs. The SNP
rs6590330 of ETS1 is related to the decreased expression of ETS1.
MDA5: melanoma differentiation-associated gene 5; MAVS: mitochon-
drial antiviral signaling protein; TRAF3: tumor necrosis factor receptor–
associated factor 3; TBK1: TANK-binding kinase 1; IRF3: interferon
regulatory family 3; TLR: Toll-like receptor; TRAM: TRIF-related adap-
tor molecule; TRIF: TIR-domain-containing adaptor protein-inducing
IFN-β; MyD88: myeloid differentiation primary response gene 88;
IRAK1: Interleukin-1 receptor-associated kinase 1; IFNAR1: interact
with interferon-α/β receptor 1; JAK: Janus kinase 1; TYK2: tyrosine
kinase 2; STAT1: signal transducers and activators of transcription 1;
ISGF3: IFN-stimulated gene factor 3; ISG: interferon-stimulated gene;
TREX1: three prime repair exonuclease 1; IFIH1: interferon induced with
helicase C domain 1; UBE2L3: ubiquitin-conjugating enzyme E2 L3;
PTPN22: protein tyrosine phosphatase non-receptor type 22; TNFAIP3:
tumor necrosis factor, alpha-induced protein 3; TNIP1: TNFAIP3
interacting protein 1
significantly improve lesion activity in Phase II trials [177].
For nucleic acid-targeted therapies, rhDNase seemed to be
unsuccessful, whereas RSLV-132 showed good results in a
phase I trial and has entered a phase II trial for SLE (Table 3)
[176].
Rheumatoid Arthritis
Case reports show that IFN-β1, a therapy used in multiple
sclerosis (MS), can lead to the development of RA [179].
Type I IFN signatures can be detected in the peripheral blood
of patients with RA, even in the preclinical phase [12]. Data
from clinical trials show that high IFN-I signatures can predict
RA as a biomarker in at-risk individuals [180]. In addition,
synovial DCs have been shown to promote the inflammatory
response and differentiation of Th1 and Th17 cells [7].
Table 2 Introduction of type I interferonopathies

Disease Clinical feature Gene involved Function of involved gene Ref

AGS · Autosomal recessive disorder TREX1 (OMIM 225750) Encoding 3′-5′ DNA exonuclease TREX1 [120, 121]
· Systemic inflammation occurs in infancy to clear aberrant DNA
· Leukoencephalopathy RNASEH2A (OMIM 610333) Encoding RNASEH2 subunits A, B and C, [120, 121]
· Basal ganglia calcifications RNASEH2B (OMIM 610181) respectively;
Clinic Rev Allerg Immunol

· Cerebral atrophy RNASEH2C (OMIM 610329) Complex formed by RNASEH2A, B and C

· Developmental retardation and functions as RNase H2 and can degrade
microcephaly RNA/DNA hybrids
· Lymphocytosis SAMHD1 (OMIM 612952) SAMHD1 encodes SAMHD1 protein: [120–123]
· Dystonia, seizures, and fever preventing the synthesis of cDNA by
depleting the dNTPs pool;
repairing DNA damage;
possessing nuclease activity to ssRNA
ADAR1 (OMIM 615010) Encoding ADAR (adenosine deaminase [120, 121, 124]
acting on RNA), which can edit long
dsRNA
IFIH1 (OMIM 615846) Encoding MDA5, a RNA sensor in the [120, 121, 125]
type I IFN pathway
RVCL · Autosomal dominant disorder occurring TREX1 (OMIM 192315) Encoding 3′-5′ DNA exonuclease TREX1 [120, 126]
in early adulthood to clear aberrant DNA
· Retinal vasculopathy
· Cerebral leukoencephalopathy
· Dementia
Familial chilblain lupus · Autosomal dominant disorder occurring TREX1 (OMIM 610448) Encoding 3′-5′ DNA exonuclease TREX1 [120, 127]
in early adulthood to clear aberrant DNA
· Cold-induced painful erythematous infil- SAMHD1 (OMIM 614415) Preventing the synthesis of cDNA by [123, 127]
trates in acral locations depleting the dNTPs pool;
· Similar histological findings to cutaneous Repairing DNA damage and DSB;
lupus erythematosus Possessing nuclease activity to ssRNA
SAVI · Autoinflammatory vasculopathy in lung TMEM173 (OMIM 615934) Encoding STING, the adaptor of type I IFN [128]
and skin signaling
· Necrotizing lesions on face, ears, nose,
digits
· Interstitial lung disease
SPENCD · Specific metaphyseal and vertebral ACP5 (OMIM 271550) Encoding TRAP: [129, 130]
lesions in radiology negative regulator of osteopontin and IRF7
· Immune disorders like thrombocytopenia,
thyroiditis
· Neurological symptoms like
baryencephalia, spasticity
Singleton-Merten syndrome · Early and extreme major vessels and IFIH1 (OMIM 182250) Encoding MDA5, an RNA sensor in the [125, 131]
valvular calcification type I IFN pathway
· Dental anomalies (early-onset DDX58 (OMIM 616298) Encoding RIG-I, an RNA sensor in the [131, 132]
periodontitis and root resorption) type I IFN pathway
· Osteopenia
· Acro-osteolysis
ISG15 deficiency · Basal ganglia calcification and seizures ISG15 (OMIM 61626) [133]
 Clinic Rev Allerg Immunol

AGS Aicardi-Goutières syndrome, SAMHD1 SAM And HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1, DBS dried blood spots, ADAR adenosine deaminase RNA specific,

family 7, RIG-I retinoic acid-inducible gene-I, ISG15 interferon-stimulated gene 15, CANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, PSMB8 proteasome
infancy, TMEM173 transmembrane protein 173, STING stimulator of interferon genes, SPENCD spondyloenchrondro-dysplasia, TRAP tartrate-resistant acid phosphatase, IRF7 interferon regulatory
TREX1 three prime repair exonuclease 1, MDA5 melanoma differentiation-associated gene 5, RVCL retinal vasculopathy with cerebral leukodystrophy, SAVI Sting-associated vasculopathy with onset in
Furthermore, some susceptibility genes in RA are related to
the type I IFN signaling pathway, such as IRF5, STAT4, and

[134, 135]
PTPN22 [105, 113].

[136]
Ref

Due to the unsatisfactory response to DMARDs, inhibitors

targeting the type I IFN pathway have entered clinical trials of
patients with RA. The selective JAK1/JAK3 inhibitor
tofacitinib and the selective JAK1/JAK2 inhibitor baricitinib

and IFNAR2, then downregulating type

are effective and are approved by the FDA and EMA for the
Encoding ISG15, a negative regulator of

blocking the interactions between JAK1 treatment of RA, especially for those intolerant or unrespon-
Encoding PSMB8 involved in the

sive to DMARDs [19]. Upadacitinib and filgotinib are selec-

tive JAK1 inhibitors, and both have shown good results in
Function of involved gene

the type I IFN response

patients with RA in phase II and III studies [19, 181, 182].

I interferon signatures
induction of IFN-Is

The JAK1/JAK3 inhibitor, peficitinib, has also been shown to

Encoding USP18:

be effective in patients with RA, but the data from phase III
trials are still pending [183, 184]. On the other hand,
decernotinib, a JAK3 inhibitor, did not show clear dose–
response curves and had a higher risk of toxic effects at higher
doses [185]. The JAK1/JAK2 inhibitor ruxolitinib is also a
promising candidate and is entering clinical trials [178]. JAK
inhibitors are generally tolerated in patients with RA, with a
risk of herpes zoster but not serious infections or malignancies
[186]. Currently, Syk and BTK inhibitors have also entered
PSMB8 (OMIM 256040)

clinical trials for RA [187, 188].

USP18 (OMIM 607057)

subunit β type 8, USP18 ubiquitin-specific peptidase 18, JAK1 janus kinase 1, IFNAR2 interferon-α/β receptor 2

Although INF-Is have been implicated in the pathogenesis

of RA, intra-articular injections with IFN-α and intraperitone-
Gene involved

al injection with IFN-β can prevent the occurrence or devel-

opment of RA in wild-type mice or RA mouse models [189].
IFN-β injected daily can also relieve the symptoms of RA in
rhesus monkeys [189]. However, in clinical trials, treatment
with subcutaneous recombinant IFN-β showed no improve-
ment in active patients in a phase II clinical trial (Table 4)
[190].
· Perinatal-onset intracranial Hemorrhage;

Juvenile Idiopathic Arthritis

· Atypical neutrophilic dermatosis

· Septic-shock–like presentation;
· Occurrence in early childhood

Juvenile idiopathic arthritis (JIA) is the most common pediat-

ric rheumatic disease with persistent arthritis in children or
· Mycobacterial disease

· Brain malformations;

teenagers under 16 years of age [191]. Both IFN-γ and IFN-

· Thrombocytopenia
· Liver dysfunction;

Is contribute to the pathogenesis of JIA [192, 193]. Type I

Clinical feature

· Lipodystrophy

· Calcifications;
· Hyperthermia

IFN-producing cells were identified to be enriched in synovial

fluid and the IFN-α producing cells were found in the lymph-
follicular-like structures, but the expression of IFN-α was not
upregulated in the serum and synovial fluid [193]. In
enthesitis-associated JIA, the expression of TLR2 and TLR4
was elevated in the peripheral blood and synovial fluid mono-
cytes [194]. IRF5 (rs2004640) and PTPN22 1858C > T have
been reported to be involved in an increased risk of JIA [113,
Table 2 (continued)

195].
Deficiency of USP18
CANDLE syndrome

More and more clinical studies involving inhibitors sup-

pressing the type I IFN pathway have been conducted in pa-
tients with JIA. Selective JAK inhibitors, such as tofacitinib,
Disease

have shown promising results in the treatment of JIA. In a

phase I, open-label, and multicenter study (NCT01513902)
Clinic Rev Allerg Immunol
in 2017, tofacitinib was well tolerated in patients with JIA
[196]. Tofacitinib has been shown to be effective in the treat-
ment of refractory JIA in case reports [197]. Pfizer posted that
the phase III clinical trial (NCT02592434) for tofacitinib was
completed in 2019 with good results, supporting the use of
tofacitinib in patients with JIA. Clinical studies involving
baricitinib (NCT4088396; NCT03773965; NCT03773978)
and upadacitinib (NCT03725007) in patients with JIA are still
in the recruiting stage, and there are no results yet.
Juvenile Dermatomyositis
Juvenile dermatomyositis (JDM) is a rare pediatric autoim-
mune disease with an average age at disease onset of 7.5 years.
JDM is characterized by proximal muscle weakness and pa-
thognomonic skin rashes [198]. Overexpressed type I IFN-
inducible transcripts and activated type I IFN signatures are
observed in patients with DM [13]. Similarly, serum IFN-α
activity is increased for a short time in newly diagnosed pa-
tients with JDM and is associated with high serum muscle–
derived enzymes [199]. The expression of IFN-α/β-inducible
genes in muscle biopsy and proteins induced by type I IFNs
such as myxovirus resistance protein A (MxA) in PBMC,
affected muscle and skin, are elevated in patients with JDM
[200–202]. TLR3 was also found to be elevated in vascular
endothelial cells, myeloid DCs (mDCs), and regenerating
myofibers in patients with JDM [203]. Type I IFN signatures
are increased in B cells of JDM, and the activation of TLR7
and IFN-α may lead to the expanded immature transitional B
cell population [204]. In addition, in vivo and in vitro studies
have shown that myogenic precursor cells are also a source of
IFN-Is [205].
The JAK inhibitors, ruxolitinib and tofacitinib, have been
reported to be effective in the treatment of adult DM [206,
207]. In addition, a case report showed that refractory patients
with JDM responded to the JAK1/JAK2 inhibitor, baricitinib
[208]. A phase 1b clinical study (NCT00533091) observed
that the anti-IFN-α mAb, sifalimumab inhibited type I IFN
signatures in patients with DM, but there is as yet no pediatric
data [209]. A clinical trial (NCT02612857) of the TLR 7, 8, 9
inhibitor, IMO-8400, has been completed in patients with
DM, but again, no pediatric data is available. Clinical trials
on the treatment of JDM by inhibiting type I IFN signatures
are sorely needed.
Sjögren Syndrome
Primary Sjögren syndrome (pSjS) is an inflammatory autoim-
mune disorder with the loss of secretory function in exocrine
glands, causing dryness of the mucosal surfaces, especially in
the mouth (salivary) and eyes (lacrimal glands) [210]. IFN-α
expression levels at the transcript or protein levels have been
found to be increased in the labial salivary glands and blood of
patients with pSjS [210, 211]. In addition, a positive correla-
tion has been identified between genes induced by IFN-Is and
titers of anti-Ro/SSA, anti-La/SSB autoantibodies, EULAR
SjS disease activity index (ESSDAI), biological markers of
activity, and BAFF mRNA in monocytes of patients with
SjS, demonstrating a key role of IFN-Is in pSjS [210, 212].
pDCs, the main source of IFN-Is, have been found in the
salivary gland of patients with pSjS, whereas they are de-
creased in the peripheral blood [210, 212–214]. This phenom-
enon also exists in SLE, and both may be caused by the re-
translocation of pDCs from peripheral blood to diseased tissue
[210, 212].
A study (NCT03100942) involving the JAK1 inhibitor
filgotinib, Syk inhibitor lanraplenib, and BTK inhibitor
tirabrutinib has been completed, but results are pending [8].
The JAK inhibitor filgotinib-treated mouse models with SjS
showed significantly increased salivary flow rates and remark-
able reductions in lymphocytic infiltration of the salivary
gland and IFN-I signatures [215]. The JAK1/2 inhibitor
AG490 and ruxolitinib and the TBK1 inhibitor BX795 also
exhibited good responses in animal models with SjS [216,
217]. On the other hand, hydroxychloroquine, an inhibitor of
TLRs, decreased IFN-I signatures but did not improve the
symptoms of SjS in a clinical trial (NCT00632866) [218].
Moreover, IFN-α administered via the oromucosal route in
patients with pSjS was demonstrated to be effective and safe
in the improvement of salivary output in a phase II clinical
trial [219]. However, another trial of 497 patients with pSjS
with the treatment of either IFN-α or placebo failed to meet
the primary endpoints [219]. Therefore, more evidence is
needed to further understand the role of IFN-Is in the patho-
genesis and treatment of SjS.
Systemic Sclerosis
Systemic sclerosis (SSc), also called scleroderma, is charac-
terized by fibrosis and dysfunction of the skin, internal organs,
and a vasculopathy [8]. Case reports have shown that SSc
occurs in patients after using IFN-α to treat chronic myelog-
enous leukemia or IFN-β to treat hepatitis C [220]. IFN sig-
natures can also be found in peripheral blood and affected skin
of patients with SSc, even during the early phase of disease
[221]. In addition, higher IFN signatures are positively corre-
lated with anti-topoisomerase antibodies or anti-U1-RNP an-
tibodies but negatively correlated with anti-RNA polymerase
III antibodies in patients with SSc [220, 222]. The level of
type I IFNs is also related to severe symptoms in the skin,
lung, and skeletal muscle of patients with SSc [223].
Moreover, disease activity can be suppressed after treatment
with the anti-IFNAR mAb anifrolumab in patients with SSc,
demonstrating an important role of type I IFNs in the patho-
genesis of SSc [224].
Table 3 Clinical trials of molecules targeting the type I interferon pathway in patients with SLE

Mechanism Type of inhibitor Molecule Current developmental phase Ref

IFN-α Anti-IFN-α mAb Rontalizumab Phase II (completed) NCT00962832 [160]

Development terminated
Sifalimumab (formerly MEDI-545) Phase IIb (completed) NCT01283139 [162]
AGS-009 (NNC-0152-0000-0001) Phase I (completed) NCT00960362 [163]
No following trials yet
Therapeutic vaccine: IFN-α Interferon-α-kinoid (IFN-K) Phase I/II (completed) NCT01058343 [164]
Phase II (active, not recruiting) NCT02665364a
IFN-I Inhibitor of IFN-Is JNJ-55920839 Phase I (completed but no results) NCT02609789a
IFNAR1 Anti-IFNAR1 mAb Anifrolumab (formerly MEDI-546) Phase III (completed) NCT02446912 [20, 168]
Phase III (completed) NCT02446899
pDC Anti-BDCA2 mAb BIIB059 Phase II (completed) NCT02847598 [169]
Anti-CD123 Talacotuzumab (JNJ-56022473) Phase I (withdrawn, based on benefit risk assessment) NCT02920424 [176]
Bcl-2 inhibitor Venetoclax (ABT-199) Phase I (completed) NCT01686555 [171, 172]
TLRs Inhibitor of TLR7, 8, 9 CpG-52,364 Phase I (completed) NCT00547014 [173]
Oligonucleotide inhibitor of TLR7, 9 DV1179 Phase Ib/IIa (completed)b
MyD88 Inhibitor of MyD88 ST2825 Preclinical [173]
Syk Syk kinase inhibitors Lanraplenib (GS 9876) Phase II (completed, for CLE) NCT03134222a
GSK 2646264 Phase I (completed, for CLE) NCT02927457 [173]
Fostamatinib (R935788, R788) Phase II (withdrawn for business reasons) NCT00752999 [173]
IRAK4 IRAK4 inhibitor BMS-986126 Preclinical [174]
BTK BTK inhibitor Evobrutinib (M2591, MSC2364447C) Phase II (active, not recruiting) NCT02975336 [175]
ABBV-105 phase II (recruiting) NCT03978520a
GDC-0853 phase II (active, not recruiting) NCT03407482a
JAK JAK1/JAK2 inhibitor Baricitinib (LY3009104) Phase III (recruiting) NCT03843125a [21]
Phase III (recruiting) NCT03616912a
Phase III (recruiting) NCT03616964
Ruxolitinib (INCB018424) Preclinical in cutaneous lupus [178]
JAK1/JAK3 inhibitor Tofacitinib (CP-690550) Phase I (completed) NCT02535689a
Phase I (recruiting for CLE) NCT03159936a
Phase I/II (recruiting for CLE) NCT03288324a
JAK1/JAK2/JAK3 inhibitor Tanzisertib (CC-930) Phase II (terminated for benefit/risk profile) NCT01466725a
JAK1 selective inhibitor Solcitinib (GSK2586184) Phase II (terminated for meeting futility criterion) NCT01777256a
Filgotinib (GLPG0634) Phase II (completed, for CLE) NCT03134222a
topical JAK/SYK inhibitor R333 Phase II (completed) NCT01597050 [177]
Tyk2 Tyk2 inhibitor BMS-986165 Phase II (recruiting) NCT03920267a
Phase II (recruiting) NCT03252587a
Nucleic acid human RNase RSLV-132 Phase II (active, not recruiting) NCT02660944 [176]
Recombinant human Dnase I rhDNase Development terminated

IFN interferon, mAB monoclonal antibody, IFNAR1 interferon-α/β receptor 1, pDCs plasmacytoid dendritic cells, TLR Toll-like receptor, MyD88 myeloid differentiation primary response gene 88, Syk
spleen tyrosine kinase, IRAK4 interleukin-1 receptor-associated kinase 4, BTK Bruton’s tyrosine kinase, JAK Janus kinase, TYK2 tyrosine kinase 2
a
Deriving from the ClinicalTrials.gov website
b
Deriving from http://investors.dynavax.com
Clinic Rev Allerg Immunol
Clinic Rev Allerg Immunol

A phase 1, multicenter, open-label study (NCT00930683)
in which patients with SSc were treated with the anti-IFN-α
mAb anifrolumab has shown good results and supported its
further clinical development [225]. pDCs can directly promote
the development of skin fibrosis, and depleting pDCs can
prevent the progression of the fibrotic process in mouse
models of SSc [226]. Clinical trials (NCT03817424) of
VIB7734, an inhibitor of pDCs, in patients with SSc are still
recruiting, and another clinical study (NCT04206644) of JAK
inhibitors is also ongoing.
Perspectives
Autoimmune diseases consist of a wide range of systemic
diseases that affect up to 10% of the world’s population
[227]. Not only are the symptoms potentially disabling,
but the treatments are often not much better, with many
associated with significant side effects [4–7]. The type I
IFN signaling pathway is of great significance in antiviral
and antitumor immunity [15, 17]. In addition, as men-
tioned above, the type I IFN signaling pathway is essen-
tial for the initiation and development of autoimmune dis-
eases [15, 17]. Several inhibitors blocking specific mole-
cules in the type I IFN signaling pathway, such as
tofacitinib and baricitinib for the treatment of RA, are
licensed by the FDA/EMA, and more are currently under-
going clinical trials [19]. There are encouraging signs that
many targeted inhibitors have completed or entered phase
III clinical trials and seem to be very promising, including
the anti-IFNAR1 mAb anifrolumab for SLE [20, 168];
JAK1/JAK2 inhibitor baricitinib for SLE [21]; and the
JAK1 inhibitors upadacitinib and filgotinib for RA [181,
182]. Tofacitinib has completed a phase III clinical trial in

Table 4 Clinical trials of molecules targeting the type I interferon pathway in patients with RA

Mechanism Type of inhibitor Inhibitor Phase Ref

JAKs JAK1/JAK3 inhibitor Tofacitinib (Xeljanz; tasocitinib; CP-690550) FDA and EMA approved [19]
JAK1/JAK2 inhibitor Baricitinib (LY 3009104; INCB28050) FDA and EMA approved [19]
JAK1 inhibitor Upadacitinib (ABT-494) Phase III (active, not recruiting) NCT02675426a
Phase II/III (active, not recruiting) NCT02720523a
Phase III (active, not recruiting) NCT02706847a
Phase III (active, not recruiting) NCT02706951a
Phase III (active, not recruiting) NCT02706873a
Phase III (active, not recruiting) NCT02629159a
Phase III (active, not recruiting) NCT02955212a
Phase III (active, not recruiting) NCT03086343a
Filgotinib (GLPG0634) Phase III (active, not recruiting) NCT03025308a [182]
Phase III (completed) NCT02873936
Phase III (completed) NCT02886728a
Phase III (completed) NCT02886728a
Itacitinib (INCB039110) Phase II (completed) NCT01626573a
JAK1/JAK3 inhibitor Peficitinib (ASP015K) Phase III (completed) NCT02305849a
Phase III (completed) NCT02308163a
Phase III (recruiting) NCT03660059a
JAK1/JAK2 inhibitor Ruxolitinib (INCB18424) Phase II (completed) NCT00550043a
JAK3 inhibitor Decernotinib (VX-509) Phase II (completed) NCT01052194a
Phase II/III (completed) NCT01830985a
Development terminated
PF-06651600 Phase II (completed) NCT02969044a
Syk Syk inhibitor Fostamatinib Phase III (terminated) NCT01242514a [188]
Phase III (completed) NCT01197521
Phase III (completed) NCT01197534a
Development terminated
Lanraplenib (GS-9876) Phase II (completed) NCT02885181a
BTK BTK inhibitor Spebrutinib (CC-292) Phase II (completed) NCT01975610 [188]
ABBV-105 Phase II (active, not recruiting) NCT03823378a
Phase II (active, not recruiting) NCT03682705a
HM71224 Phase I (completed) NCT01765478a
TK-020 Phase I (completed) NCT02413255a

IFN interferon, JAK Janus kinase, TYK2 tyrosine kinase 2, Syk spleen tyrosine kinase, BTK Bruton’s tyrosine kinase
a
Deriving from the ClinicalTrials.gov website

patients with JIA and shown positive results [198]. Other
studies are still not completed so results are unavailable.
More data and evidence are needed to support targeted
inhibitors that have not entered phase III clinical trials
but which have shown good responses in case reports or
animal models.
The role of IFN-Is in the pathogenesis of autoimmune dis-
eases is still unclear. Under most circumstances, IFN-Is are
proinflammatory, but type I IFNs also seem to have a protec-
tive function in RA and MS based on some studies [189, 228].
Some have proposed that conflicting results may be a result of
the varying immunomodulatory and proinflammatory func-
tions of interacting cytokines in autoimmune disorders that
are predominately driven by Th1 cells or Th17 cells [229].
Furthermore, the results of anifrolumab in the phase III
TULIP-1 and TULIP-2 trials are partially inconsistent [20,
168]. The end point BICLA, but not SRI, was met in
TULIP-1, but both endpoints were met in TULIP-2 [20,
168]. Heterogeneity of the disease state and genetics may be
one of the reasons that different types of patients with SLE
may have varying responses to specific therapies. The estab-
lishment of subtypes and personalized approaches based on
immune genotypes is needed for solving disease heterogene-
ity and efficiently achieving better targeted therapies [6]. In
addition, the anti-IFN-α mAbs rontalizumab and AGS-009
did not achieve the expected results as anti-IFNAR mAbs,
which may be caused by the 13 different subtypes of IFN-α
in humans, making it difficult to block all types of IFN-α
[160]. Besides, IFN-β may continue to play a role in disease
progression even in the presence of anti-IFN-α therapies.
Overall, type I IFN signaling pathway is of great signifi-
cance in the pathogenesis and treatment of both adult and
pediatric autoimmune diseases. Many inhibitors targeting the
type I IFN signaling pathway have shown positive results in
clinical trials of autoimmune diseases. Thus, it is very impor-
tant to further explore the role of the type I IFN signaling
pathway in autoimmune diseases to develop more effective
and safe therapies.
Acknowledgments We thank Xing Wang, Meixi Liu, Zhenwei Tang,
and Bowen Li for their guidance in revising the manuscript.
Author Contributions Concept and design: Qianjin Lu, Haijing Wu,
Ming Zhao, Jiao Jiang; Drafting of the manuscript: Jiao Jiang; Revising
of the manuscript: Qianjin Lu, Haijing Wu, Christopher Chang, Ming
Zhao, Jiao Jiang.
Funding information
This work was supported by the National Natural Science Foundation
of China (No. 81972943 and No. 81830097) and the Hunan Talent
Young Investigator (No. 2019RS2012).
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts of
interest.
Clinic Rev Allerg Immunol
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