scholarly journals Cytokines and Their Roles in the Pathogenesis of Systemic Lupus Erythematosus: From Basics to Recent Advances

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Desmond Yat Hin Yap ◽  
Kar Neng Lai
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Immune Disorder ◽  
Autoantibody Production ◽  
Inflammatory Processes ◽  
Complex Deposition

Systemic lupus erythematosus (SLE) is a complex auto-immune disorder which involves various facets of the immune system. In addition to autoantibody production and immune complex deposition, emerging evidences suggest that cytokines may act as key players in the immunopathogenesis of SLE. These cytokines assume a critical role in the differentiation, maturation and activation of cells and also participate in the local inflammatory processes that mediate tissue insults in SLE. Certain cytokines such as the IL-6, IL-10, IL-17, BLys, type I interferons (IFN) and tumor necrosis factor-α(TNF-α) are closely linked to pathogenesis of SLE. The delineation of the role played by these cytokines not only fosters our understanding of this disease but also provides a sound rationale for various therapeutic approaches. In this context, this review focuses on selected cytokines which exert significant effect in the pathogenesis of SLE and their possible clinical applications.

scholarly journals Regulatory T-Cell-Associated Cytokines in Systemic Lupus Erythematosus

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Akiko Okamoto ◽  
Keishi Fujio ◽  
Tomohisa Okamura ◽  
Kazuhiko Yamamoto
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Organ Damage ◽  
Interleukin 10 ◽  
Peripheral Tolerance ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Inflammatory Processes ◽  
Complex Deposition

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition, resulting in tissue and organ damage. An understanding of the mechanisms responsible for homeostatic control of inflammation, which involve both innate and adoptive immune responses, will enable the development of novel therapies for SLE. Regulatory T cells (Treg) play critical roles in the induction of peripheral tolerance to self- and foreign antigens. Naturally occurring CD4+CD25+Treg, which characteristically express the transcription factor forkhead box protein P3 (Foxp3), have been intensively studied because their deficiency abrogates self-tolerance and causes autoimmune disease. Moreover, regulatory cytokines such as interleukin-10 (IL-10) also play a central role in controlling inflammatory processes. This paper focuses on Tregs and Treg-associated cytokines which might regulate the pathogenesis of SLE and, hence, have clinical applications.

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

2021 ◽  
Vol 12 (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.

Type I Interferons in Autoimmune Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 369-393 ◽  
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.

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

2019 ◽  
Vol 21 (1) ◽  
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.

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

2020 ◽  
Vol 18 (6) ◽  
pp. 549-565 ◽  
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.

scholarly journals Recent Advances in Our Understanding of the Link between the Intestinal Microbiota and Systemic Lupus Erythematosus

2019 ◽  
Vol 20 (19) ◽  
pp. 4871 ◽  
Author(s):  
Ji-Won Kim ◽  
Seung-Ki Kwok ◽  
Jung-Yoon Choe ◽  
Sung-Hwan Park
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
High Throughput Sequencing ◽  
Lactobacillus Reuteri ◽  
Molecular Mimicry ◽  
Type I ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Gut Microbes ◽  
Multiple Organs

Systemic lupus erythematosus (SLE) is an autoimmune disease featuring enhanced expression of type I interferon (IFN) and autoantibody production triggering inflammation of, and damage to, multiple organs. Continuing research efforts focus on how gut microbes trigger systemic autoimmunity and SLE. The gut microbial communities of mice and humans with lupus have been investigated via high-throughput sequencing. The Firmicutes-to-Bacteroidetes ratio is consistently reduced in SLE patients, regardless of ethnicity. The relative abundance of Lactobacillus differs from the animal model used (MRL/lpr mice or NZB/W F1 mice). This may indicate that interactions between gut microbes and the host, rather than the enrichment of certain gut microbes, are especially significant in terms of SLE development. Enterococcus gallinarum and Lactobacillus reuteri, both of which are possible gut pathobionts, become translocated into systemic tissue if the gut epithelial barrier is impaired. The microbes then interact with the host immune systems, activating the type I IFN pathway and inducing autoantibody production. In addition, molecular mimicry may critically link the gut microbiome to SLE. Gut commensals of SLE patients share protein epitopes with the Ro60 autoantigen. Ruminococcus gnavus strain cross-reacted with native DNA, triggering an anti-double-stranded DNA antibody response. Expansion of R. gnavus in SLE patients paralleled an increase in disease activity and lupus nephritis. Such insights into the link between the gut microbiota and SLE enhance our understanding of SLE pathogenesis and will identify biomarkers predicting active disease.

scholarly journals Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37000 ◽  
Author(s):  
Emily C. Somers ◽  
Wenpu Zhao ◽  
Emily E. Lewis ◽  
Lu Wang ◽  
Jeffrey J. Wing ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus

scholarly journals TANK prevents IFN-dependent fatal diffuse alveolar hemorrhage by suppressing DNA-cGAS aggregation

2021 ◽  
Vol 5 (2) ◽  
pp. e202101067
Author(s):  
Atsuko Wakabayashi ◽  
Masanori Yoshinaga ◽  
Osamu Takeuchi
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Vascular Endothelial Cell ◽  
Diffuse Alveolar Hemorrhage ◽  
Negative Regulator ◽  
Alveolar Hemorrhage ◽  
Type I ◽  
Systemic Lupus ◽  
Cytoplasmic Dna

Diffuse alveolar hemorrhage (DAH) is one of the serious complications associated with systemic lupus erythematosus, an autoimmune disease whose pathogenesis involves type I IFNs and cytokines. Here, we show that TANK, a negative regulator of the NF-κB signaling via suppression of TRAF6 ubiquitination, is critical for the amelioration of fatal DAH caused by lung vascular endothelial cell death in a mouse model of systemic lupus erythematosus. The development of fatal DAH in the absence of TANK is mediated by type I IFN signaling, but not IL-6. We further uncover that STING, an adaptor essential for the signaling of cytoplasmic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), plays a critical role in DAH under Tank deficiency. TANK controls cGAS-mediated cGAMP production and suppresses DNA-mediated induction of IFN-stimulated genes in macrophages by inhibiting the formation of DNA-cGAS aggregates containing ubiquitin. Collectively, TANK inhibits the cGAS-dependent recognition of cytoplasmic DNA to prevent fatal DAH in the murine lupus model.

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