An update on the role of type I interferons in systemic lupus erythematosus and Sjögrenʼs syndrome

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated theIFNKlocus in SLE susceptibility. We studiedIFNKsingle nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93,P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific.IFNKSNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association betweenIFNKSNPs and SLE and skin phenotypes. The serum IFN association suggests thatIFNKvariants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

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Advances in understanding the role of type I interferons in systemic lupus erythematosus

Current Opinion in Rheumatology ◽

10.1097/bor.0000000000000087 ◽

2014 ◽

Vol 26 (5) ◽

pp. 467-474 ◽

Cited By ~ 63

Author(s):

Mary K. Crow

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Type I ◽

Systemic Lupus

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

Nature Communications ◽

10.1038/s41467-021-22312-y ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Norzawani Buang ◽

Lunnathaya Tapeng ◽

Victor Gray ◽

Alessandro Sardini ◽

Chad Whilding ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Lupus Erythematosus ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

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Type I Interferons in Autoimmune Disease

Annual Review of Pathology Mechanisms of Disease ◽

10.1146/annurev-pathol-020117-043952 ◽

2019 ◽

Vol 14 (1) ◽

pp. 369-393 ◽

Cited By ~ 46

Author(s):

Mary K. Crow ◽

Mikhail Olferiev ◽

Kyriakos A. Kirou

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune System ◽

Lupus Erythematosus ◽

Type I Interferon ◽

Type I Interferons ◽

Type I ◽

Systemic Lupus ◽

Pathway Activation ◽

Interferon Pathway ◽

Chronic Activation

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

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The innate immune system in human systemic lupus erythematosus

Clinical Science ◽

10.1042/cs20160415 ◽

2017 ◽

Vol 131 (8) ◽

pp. 625-634 ◽

Cited By ~ 19

Author(s):

Marc Weidenbusch ◽

Onkar P. Kulkarni ◽

Hans-Joachim Anders

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune System ◽

Lupus Erythematosus ◽

Innate Immune System ◽

Innate Immune ◽

Type I ◽

Human Systemic Lupus Erythematosus ◽

Systemic Lupus ◽

Adaptive Immune

Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

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Interferon score is increased in incomplete systemic lupus erythematosus and correlates with myxovirus-resistance protein A in blood and skin

Arthritis Research & Therapy ◽

10.1186/s13075-019-2034-4 ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 3

Author(s):

Wietske M. Lambers ◽

Karina de Leeuw ◽

Berber Doornbos-van der Meer ◽

Gilles F.H. Diercks ◽

Hendrika Bootsma ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Protein A ◽

Type I Interferons ◽

Type I ◽

Systemic Lupus ◽

Skin Symptoms ◽

Skin Biopsies ◽

Resistance Protein ◽

Unaffected Skin

Abstract Objectives Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Methods Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. Results IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). Conclusions IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.

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Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on Epidemiology, Risk Factors and Prevention

Current Vascular Pharmacology ◽

10.2174/1570161118666191227101636 ◽

2020 ◽

Vol 18 (6) ◽

pp. 549-565 ◽

Cited By ~ 6

Author(s):

Myrto Kostopoulou ◽

Dionysis Nikolopoulos ◽

Ioannis Parodis ◽

George Bertsias

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Statin Treatment ◽

Type I Interferons ◽

Type I ◽

Lifestyle Modifications ◽

Systemic Lupus ◽

Increased Risk ◽

Atherogenic Dyslipidaemia

Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.

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

Cells ◽

10.3390/cells8090963 ◽

2019 ◽

Vol 8 (9) ◽

pp. 963 ◽

Cited By ~ 10

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.

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