Introduction

Autoimmune diseases include a wide range of diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (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 [4,5,6,7,8]. 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 autoimmune diseases, the effective therapies are lacking [6,7,8].

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 occur in patients with hepatitis C virus or malignant carcinoid tumors [10, 11]. Similarly, type I IFN signatures are also increased 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 involved in innate immunity and adaptive immune system and in particular play an important role in antiviral activity and cancer immunosurveillance [14,15,16]. IFN-Is are mainly produced by innate immune cells in mammals, such as macrophages 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 signaling pathway in autoimmune diseases, many monoclonal 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 downstream 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 recognition 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 vesicles (AdMVs), NETotic neutrophils, endogenous self-nucleic acids, and related immune complexes (ICs) [23,24,25,26]. 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 [23,24,25,26]. 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 differentiation primary response gene 88 (MyD88). MyD88 then 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 [23,24,25,26].

Cyclic GMP-AMP synthase (cGAS) is expressed in most cells and is the most important intracellular DNA sensor during 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 activates 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 receptors 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 inducing 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 membrane. 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 between 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 phosphorylated 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 combining with IFN-stimulated response elements (ISREs, consensus sequence TTTCNNTTTC) [15, 17]. ISGs include a series of genes encoding antiviral and antitumor molecules, and transcription 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 signaling pathway [38].

Fig. 1
figure 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 production 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 interaction 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 signaling pathway. Later, IFNAR1 can be phosphorylated by JAKs, leading to repositioning and binding of STAT2. Phosphorylated STAT2 can recruit 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 messenger; 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 receptor-associated kinase 1; IFN: interferon; CDK: cyclin-dependent kinase; IFNAR1: 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

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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 expression 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 regulation 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 production 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 phosphorylation, 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.

Fig. 2
figure 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 regulated 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: interferon regulatory family 3; cGAS: cyclic GMP-AMP synthase; cGAMP: cyclic dinucleotide second messenger; STING: stimulator of IFN genes; 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 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; 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

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Table 1 Negative regulators in the type I IFN signaling pathway
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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 modification at the 5′-position of cytosine rings residing in the dinucleotide sequence CpG [72]. Decreased DNA methylation in IFN-induced genes have been found in patients with SLE, compared to healthy controls [73]. Several different methylation 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 primary 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 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 inhibit 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 increased 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 suppress multiple IFN-α species via their 3′ untranslated region (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 signaling 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 regulator 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 associated with type I IFNs include IRF5, IRF7, IRF8, IRAK1, tumor necrosis factor, alpha-induced protein 3 (TNFAIP3), 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) [102,103,104,105,106,107].

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 translocate into nucleus to initiate the expression of IFN-γ and other proinflammatory molecules [108,109,110]. 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 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 [102,103,104].

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 increased 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 autoimmune 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 between susceptibility genes and type I IFN signaling pathway is described in Fig. 3.

Fig. 3
figure 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 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 expression 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: mitochondrial 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 adaptor 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

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Type I Interferon Signaling Pathway and Autoimmune Diseases

Type I Interferonopathies

Type I interferonopathy is a type of Mendelian genetic disorder 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 diseases, 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.

Table 2 Introduction of type I interferonopathies
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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 [137,138,139,140]. 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 [136,137,138,139,140,141,142]. Cases of chilblain lupus have also shown a good response to tofacitinib therapy [127]. Furthermore, in the NCT01724580 and NCT02974595 programs, 18 patients 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 upregulated in peripheral blood mononuclear cells (PBMCs) of approximately 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 leucopenia) 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 activation of DCs [148]. The activation of T cells and the suppression 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 suppressing the maturation of miR-146a [151]. IFN-β is increased 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 childhood 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 inhibitors involved in type I IFN pathway is urgently needed [157, 158].

With better understanding of the role of IFN-I, many promising 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 observed indexes and symptoms were also significantly improved [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 response 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 [170,171,172].

Hydroxychloroquine, a TLR9, TLR7, and TLR8 antagonist, is a conventional antimalarial drug for SLE [6]. The preclinical 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 pharmacodynamic endpoints. A small molecular TLR9 inhibitor 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 unpublished [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 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].

Table 3 Clinical trials of molecules targeting the type I interferon pathway in patients with SLE
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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]. Furthermore, some susceptibility genes in RA are related to the type I IFN signaling pathway, such as IRF5, STAT4, and PTPN22 [105, 113].

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 are effective and are approved by the FDA and EMA for the treatment of RA, especially for those intolerant or unresponsive to DMARDs [19]. Upadacitinib and filgotinib are selective JAK1 inhibitors, and both have shown good results in patients with RA in phase II and III studies [19, 181, 182]. The JAK1/JAK3 inhibitor, peficitinib, has also been shown to 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 clinical trials for RA [187, 188].

Although INF-Is have been implicated in the pathogenesis of RA, intra-articular injections with IFN-α and intraperitoneal injection with IFN-β can prevent the occurrence or development 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 improvement in active patients in a phase II clinical trial (Table 4) [190].

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

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease with persistent arthritis in children or teenagers under 16 years of age [191]. Both IFN-γ and IFN-Is contribute to the pathogenesis of JIA [192, 193]. Type I 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 monocytes [194]. IRF5 (rs2004640) and PTPN22 1858C > T have been reported to be involved in an increased risk of JIA [113, 195].

More and more clinical studies involving inhibitors suppressing the type I IFN pathway have been conducted in patients with JIA. Selective JAK inhibitors, such as tofacitinib, have shown promising results in the treatment of JIA. In a phase I, open-label, and multicenter study (NCT01513902) in 2017, tofacitinib was well tolerated in patients with JIA [196]. Tofacitinib has been shown to be effective in the treatment 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 autoimmune disease with an average age at disease onset of 7.5 years. JDM is characterized by proximal muscle weakness and pathognomonic 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 patients 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 [200,201,202]. 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 autoimmune 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 correlation 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 decreased in the peripheral blood [210, 212,213,214]. This phenomenon 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 remarkable 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 pathogenesis and treatment of SjS.

Systemic Sclerosis

Systemic sclerosis (SSc), also called scleroderma, is characterized 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 myelogenous leukemia or IFN-β to treat hepatitis C [220]. IFN signatures 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 correlated with anti-topoisomerase antibodies or anti-U1-RNP antibodies 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 pathogenesis of SSc [224].

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 [4,5,6,7]. The type I IFN signaling pathway is of great significance in antiviral and antitumor immunity [15, 17]. In addition, as mentioned above, the type I IFN signaling pathway is essential for the initiation and development of autoimmune diseases [15, 17]. Several inhibitors blocking specific molecules 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 undergoing 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 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 diseases is still unclear. Under most circumstances, IFN-Is are proinflammatory, but type I IFNs also seem to have a protective 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 functions 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 establishment of subtypes and personalized approaches based on immune genotypes is needed for solving disease heterogeneity 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 significance 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 important to further explore the role of the type I IFN signaling pathway in autoimmune diseases to develop more effective and safe therapies.