scholarly journals Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus

2018 ◽  
Vol 77 (10) ◽  
pp. 1507-1515 ◽  
Author(s):  
Yasuhiro Kato ◽  
JeongHoon Park ◽  
Hyota Takamatsu ◽  
Hachirou Konaka ◽  
Wataru Aoki ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Membrane Vesicles ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Healthy Controls ◽  
Reporter System ◽  
Systemic Lupus ◽  
Sting Pathway

ObjectiveDespite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)–AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS–STING pathway in the IFN-I-producing cascade driven by SLE serum.MethodsWe collected sera from patients with SLE (n=64), patients with other autoimmune diseases (n=31) and healthy controls (n=35), and assayed them using a cell-based reporter system that enables highly sensitive detection of IFN-I and ISG-inducing activity. We used Toll-like receptor-specific reporter cells and reporter cells harbouring knockouts of cGAS, STING and IFNAR2 to evaluate signalling pathway-dependent ISG induction.ResultsIFN-I bioactivity and ISG-inducing activities of serum were higher in patients with SLE than in patients with other autoimmune diseases or healthy controls. ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Double-stranded DNA levels were elevated in SLE. Apoptosis-derived membrane vesicles (AdMVs) from SLE sera had high ISG-inducing activity, which was diminished in cGAS-knockout or STING-knockout reporter cells.ConclusionsAdMVs in SLE serum induce IFN-I production through activation of the cGAS–STING pathway. Thus, blockade of the cGAS–STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.

scholarly journals Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

2021 ◽  
Vol 2 (3) ◽  
pp. 173-184
Author(s):  
Audrey M. Hagiwara ◽  
Richard E. Moore ◽  
Daniel J. Wallace ◽  
Mariko Ishimori ◽  
Caroline A. Jefferies
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Systemic Lupus ◽  
Downstream Signaling ◽  
Potential Therapeutic Application ◽  
Sting Pathway

Abstract Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the “interferonopathies.” Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

scholarly journals Cytokines in Systemic lupus erythematosus.

2020 ◽  
Author(s):  
Angel Alberto Justiz-Vaillant
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Pearson Correlation ◽  
Caribbean Region ◽  
Type I ◽  
Healthy Controls ◽  
Childbearing Age ◽  
Systemic Lupus ◽  
Sledai Score ◽  
Significant Difference

The systemic lupus erythematosus (SLE) is the greatest manifestation of autoimmunity. It is characterized by the presence of cytokines, including type I and II interferons, interleukin-6 (IL-6), IL-1, and tumor necrosis factor-alpha (TNF-α), the immunomodulatory cytokines like IL-10 and TGF-β, be essential players in SLE. Additionally, T-cell-derived cytokines like IL-17A, IL-21, and IL-2 are dysregulated in SLE. In this paper, a prospective cross-sectional and observational study was done. It was measured the levels of 3 essential cytokines in SLE: IL-17A, IL-23, and IL-33 using three enzyme-linked immunosorbent assays (ELISA). Thirty (30) patients attending the rheumatoid clinic at one of the major regional hospitals in the Caribbean region were recruited. Mostly females above the childbearing age give their consent to be included in the study and other 30 healthy patients were used a control. Of all the SLE patients, 15 (50%) patients were of Afro-Caribbean descent, 12 (40%) of patients were of Indo-Caribbean descent, and 3 (10%) of patients were of mixed descent. Nineteen (63%) healthy controls were females, and 11 (37%) were males. The results showed that serum IL-17A and IL-23 were more significantly higher in SLE patients than controls (P<0.01); however, there was no statistically significant difference between IL-33 levels between SLE patients and healthy controls. The study showed no correlation between serum IL-17A and IL-23 in SLE patients as judged by the result of the Pearson correlation coefficient (r=0.308, p>0.05). It also showed that serum IL-17A and IL-23 levels positively correlate to the SLE disease activity index 2000 score (SLEDAI score). Nevertheless, IL-33 levels show no correlation with the SLEDAI score. In this study, higher cytokines were reported mostly in patients between the ages of 25 to 30-year-old and Afro-Caribbean descent.

scholarly journals AB0002 ASSOCIATION OF C1Q GENETIC POLYMORPHISMS WITH SUSCEPTIBILITY TO RHEUMATOID ARTHRITIS IN BULGARIAN COHORT

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1036.3-1036
Author(s):  
M. Kosturkova ◽  
G. Mihaylova ◽  
M. Radanova
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Gene Cluster ◽  
Lupus Erythematosus ◽  
Annual Review ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Allelic Discrimination Assay ◽  
Increased Risk

Background:Complement is strongly implicated in the pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Its component C1q plays a dualistic role, triggering the inflammatory cascade on one hand and directing the clearance of immune complexes on the other. Homozygous genetic deficiency of C1q is strongly associated with SLE and SLE-like phenotype as almost 90% of C1q deficient individuals develop SLE or similar disease. Nevertheless, there are few and inconsistent studies exploring the single nucleotide polymorphisms (SNPs) of the C1q gene cluster in relation to the pathogenesis of SLE and RA.Objectives:The aim of the study was to evaluate the possible association of five SNPs – rs292001, rs172378, rs294179, rs665691 and rs682658 in complement C1q gene cluster with susceptibility to SLE and RA in Bulgarian cohort.Methods:Fifty patients with SLE, sixty-one patients with RA and sixty-seven healthy controls were genotyped for the five SNPs by TaqMan allelic discrimination assay.Results:Frequency of genotypes and alleles of rs294179, rs665691 and rs682658 SNPs was similar between patients with SLE, RA and healthy controls. For rs172378 SNP, the minor G allele (OR = 2.73; 95% CI, 1.59-4.67, p=0.0003) and GG genotype (OR = 5.12; 95% CI, 1.60-16.49, p=0.006) were associated with susceptibility to RA. In our cohort in accordance with others, AA rs292001 SNP genotype was associated with increased risk for RA (OR = 3.32; 95% CI, 1.19-9.20, p=0.021). For SLE patients, AA rs292001 SNP genotype was low presented and did not associate with disease.Conclusion:GG genotype of rs172378 SNP in C1q gene cluster could be considered as a new risk factor for RA.References:[1]Diane Scott et al (2016). The paradoxical roles of C1q and C3 in autoimmunity. Immunobiology, 719-25. doi:10.1016/j.imbio.2015.05.001.[2]Giles JL et al (2015). Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis. J Immunol., 3029-34. doi:10.4049/jimmunol.1402956.[3]Holers, V. M. (2018). Complement in the Initiation and Evolution of Rheumatoid Arthritis. Frontiers in immunology, 1057. doi:10.3389/fimmu.2018.01057.[4]Lintner, K. E. (2016). Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Frontiers in immunology, 36. doi:10.3389/fimmu.2016.00036.[5]Lu, J. &. (2017). C1 Complex: An Adaptable Proteolytic Module for Complement and Non-Complement Functions. Frontiers in immunology, 592. doi:10.3389/fimmu.2017.00592.[6]Manderson, A. P. (2004). The role of complement in the development of systemic lupus erythematosus. Annual review of immunology, 431-456. doi:10.1146/annurev.immunol.22.012703.104549.[7]Martens, H. A. (2009). Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity. Annals of the rheumatic diseases, 715–720. doi:10.1136/ard.2007.085688.[8]Namjou B, G.-M. C. (2009). Evaluation of C1q genomic region in minority racial groups of lupus. Genes Immun., 517-24. doi:10.1038/gene.2009.33.[9]Radanova M et al(2015). Association of rs172378 C1q gene cluster polymorphism with lupus nephritis in Bulgarian patients. Lupus, 280-9. doi:10.1177/0961203314555173.[10]Rafiq S et al (2010). Assessing association of common variation in the C1Q gene cluster with systemic lupus erythematosus. Clin Exp Immunol., 284-9. doi:10.1111/j.1365-2249.2010.04185.x.[11]Schejbel L et al (2011). Molecular basis of hereditary C1q deficiency-revisited: identification of several novel disease-causing mutations. Genes Immun., 626-634.[12]Trouw LA et al (2013). Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis. Clin Exp Immunol., 76-83. doi:10.1111/cei.12097.[13]Trouw L. A. (2017). The complement system as a potential therapeutic target in rheumatic disease. Nature reviews. Rheumatology, 538–547. doi:10.1038/nrrheum.2017.125.[14]Walport M. J. (2002). Complement and systemic lupus erythematosus. Arthritis research, S279–S293. doi:10.1186/ar586.Disclosure of Interests:None declared

scholarly journals Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 963 ◽  
Author(s):  
I-Tsu Chyuan ◽  
Hong-Tai Tzeng ◽  
Ji-Yih Chen
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Signaling Pathways ◽  
Lupus Erythematosus ◽  
Janus Kinase ◽  
Type I ◽  
Systemic Lupus ◽  
Type Iii ◽  
Signature Genes

Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.

scholarly journals Extracellular Vesicles in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Functions and Applications

2021 ◽  
Vol 11 ◽  
Author(s):  
Bo Zhang ◽  
Ming Zhao ◽  
Qianjin Lu
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Clinical Research ◽  
Extracellular Vesicles ◽  
Lupus Erythematosus ◽  
Membrane Vesicles ◽  
Systemic Lupus ◽  
Almost All ◽  
Extracellular Environment

In the last two decades, extracellular vesicles (EVs) have aroused wide interest among researchers in basic and clinical research. EVs, small membrane vesicles are released by almost all kinds of cells into the extracellular environment. According to many recent studies, EVs participate in immunomodulation and play an important role in the pathogenesis of autoimmune diseases. In addition, EVs have great potential in the diagnosis and therapy of autoimmune diseases. Here, we reviewed the latest research advances on the functions and mechanisms of EVs and their roles in the pathogenesis, diagnosis, and treatment of rheumatoid arthritis and systemic lupus erythematosus.

Deregulated NLRP3 and NLRP1 Inflammasomes and Their Correlations with Disease Activity in Systemic Lupus Erythematosus

2013 ◽  
Vol 41 (3) ◽  
pp. 444-452 ◽  
Author(s):  
Qingrui Yang ◽  
Chengcheng Yu ◽  
Zhaowen Yang ◽  
Qing Wei ◽  
Kun Mu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Activity Index ◽  
Type I ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Glucocorticoid Treatment ◽  
Peripheral Blood Mononuclear

Objective.NOD-like receptor family, pyrin domain containing 3 and 1 (NLRP3 and NLRP1) inflammasomes are molecular platforms that sense the damage or danger signals of cells. We investigated whether NLRP3/NLRP1 inflammasomes are involved in the pathogenesis and progression of systemic lupus erythematosus (SLE).Methods.Expressions of inflammasome components at the mRNA and protein levels in the peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy controls were investigated by quantitative real-time transcription PCR and Western blot, respectively. Correlations between NLRP3/NLRP1 inflammasome components’ expression and clinical disease progression were investigated. Expressions of NLRP3/NLRP1 inflammasomes before and after treatment in the patients with SLE were also analyzed and compared.Results.Our data showed that expressions of NLRP3/NLRP1 inflammasomes were significantly downregulated in PBMC from patients with SLE compared with PBMC from healthy controls. Further, expressions of NLRP3/NLRP1 inflammasomes were negatively correlated with the SLE Disease Activity Index, and regular glucocorticoid treatment significantly corrected this deregulation of these inflammasomes. Further analysis showed that type I interferon (IFN) level was significantly negatively correlated with expression of NLRP3/NLRP1 inflammasomes, which indicated that enhanced IFN-I level in patients with SLE was responsible, at least to a great degree, for the deregulation of inflammasomes.Conclusion.These results indicated deregulation of NLRP3/NLRP1 inflammasomes in patients with SLE, and suggested an important role for inflammasomes in the pathogenesis and progression of SLE.

scholarly journals Coordination of retrotransposons and type I interferon with distinct interferon pathways in dermatomyositis, systemic lupus erythematosus and autoimmune blistering disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuko Kuriyama ◽  
Akira Shimizu ◽  
Saki Kanai ◽  
Daisuke Oikawa ◽  
Sei-ichiro Motegi ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Quantitative Polymerase Chain Reaction ◽  
Type I ◽  
Systemic Lupus ◽  
Autoimmune Blistering Disease ◽  
Type I Ifns ◽  
Blistering Disease

AbstractType I interferon (IFN) plays a crucial role in innate and adaptive immunity, and aberrant IFN responses are involved in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). Type I IFNs can be induced by transcribed retrotransposons. The regulation of retrotransposons and type I IFN and the downstream IFN pathways in SLE, DM, and autoimmune blistering disease (AIBD) were investigated. The gene expression levels of retrotransposons, including LINE-1, type I-III IFNs, and IFN-stimulated genes (ISGs) in peripheral blood cells from patients with DM (n = 24), SLE (n = 19), AIBD (n = 14) and healthy controls (HCs, n = 10) were assessed by quantitative polymerase chain reaction. Upregulation of retrotransposons and IFNs was detected in DM patient samples, as is characteristic, compared to HCs; however, ISGs were not uniformly upregulated. In contrast, retrotransposons and IFNs, except for type II IFN, such as IFN-γ, were not upregulated in SLE. In AIBD, only some retrotransposons and type I interferons were upregulated. The DM, SLE, and AIBD samples showed coordinated expression of retrotransposons and type I IFNs and distinct spectra of IFN signaling. A positive correlation between LINE-1 and IFN-β1 was also detected in human cell lines. These factors may participate in the development of these autoimmune diseases.

scholarly journals The Pathogenesis, Molecular Mechanisms and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

2021 ◽  
Vol 22 (20) ◽  
pp. 11286
Author(s):  
Madhu Ramaswamy ◽  
Raj Tummala ◽  
Katie Streicher ◽  
Andre Nogueira da Costa ◽  
Philip. Z. Brohawn
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Disease Etiology ◽  
Interferon Pathway

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

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