scholarly journals Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Xiaofeng Liao ◽  
Alec M. Reihl ◽  
Xin M. Luo
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Immune Tolerance ◽  
Lupus Erythematosus ◽  
Treatment Strategies ◽  
Systemic Lupus ◽  
Lupus Pathogenesis ◽  
Self Potential

Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensivein vitroandin vivostudies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.

scholarly journals Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1291 ◽  
Author(s):  
Ritprajak ◽  
Kaewraemruaen ◽  
Hirankarn
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Ex Vivo ◽  
Immunosuppressive Drugs ◽  
Clinical Implications ◽  
Systemic Lupus ◽  
Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

scholarly journals Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon.

1983 ◽  
Vol 157 (6) ◽  
pp. 2140-2146 ◽  
Author(s):  
O T Preble ◽  
K Rothko ◽  
J H Klippel ◽  
R M Friedman ◽  
M I Johnston
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Interferon Production ◽  
Systemic Lupus ◽  
Endogenous Production ◽  
Acid Labile

The interferon (IFN)-induced enzyme 2-5A synthetase was elevated in mononuclear cells from both serum IFN-positive and -negative systemic lupus erythematosus (SLE) patients. This suggests that a much higher percentage of patients than previously thought produce endogenous IFN. These results may partly explain findings that mononuclear cells from SLE patients are deficient in IFN production in vitro in response to certain IFN inducers. Although normal lymphocytes can produce an acid-labile alpha IFN after stimulation with C. parvum in vitro, the reason for endogenous production of this unusual alpha IFN by SLE patients remains unknown.

scholarly journals In vivo and in vitro use of plasma membrane DNA in the detection and follow-up of systemic lupus erythematosus

2011 ◽  
Vol 3 (3) ◽  
pp. 200-201 ◽  
Author(s):  
Jacqueline Keyhani ◽  
Ezzatollah Keyhani ◽  
Genevieve Servais ◽  
Jean Duchateau
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Plasma Membrane ◽  
Lupus Erythematosus ◽  
Systemic Lupus

Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls

2007 ◽  
Vol 67 (4) ◽  
pp. 450-457 ◽  
Author(s):  
A M Jacobi ◽  
D M Goldenberg ◽  
F Hiepe ◽  
A Radbruch ◽  
G R Burmester ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Therapeutic Option ◽  
Normal Subjects ◽  
Systemic Lupus

Objective:B lymphocytes have been implicated in the pathogenesis of lupus and other autoimmune diseases, resulting in the introduction of B cell-directed therapies. Epratuzumab, a humanised anti-CD22 monoclonal antibody, is currently in clinical trials, although its effects on patients’ B cells are not completely understood.Methods:This study analysed the in vivo effect of epratuzumab on peripheral B cell subsets in 12 patients with systemic lupus erythematosus, and also addressed the in vitro effects of the drug by analysing anti-immunoglobulin-induced proliferation of isolated B cells obtained from the peripheral blood of 11 additional patients with lupus and seven normal subjects.Results:Upon treatment, a pronounced reduction of CD27– B cells and CD22 surface expression on CD27– B cells was observed, suggesting that these cells, which mainly comprise naïve and transitional B cells, are preferentially targeted by epratuzumab in vivo. The results of in vitro studies indicate additional regulatory effects of the drug by reducing the enhanced activation and proliferation of anti-immunoglobulin-stimulated lupus B cells after co-incubation with CD40L or CpG. Epratuzumab inhibited the proliferation of B cells from patients with systemic lupus erythematosus but not normal B cells under all culture conditions.Conclusions:Epratuzumab preferentially modulates the exaggerated activation and proliferation of B cells from patients with lupus in contrast to normal subjects, thus suggesting that epratuzumab might offer a new therapeutic option for patients with systemic lupus erythematosus, as enhanced B cell activation is a hallmark of this disease.

scholarly journals TIPE2 Alleviates Systemic Lupus Erythematosus Through Regulating Macrophage Polarization

2016 ◽  
Vol 38 (1) ◽  
pp. 330-339 ◽  
Author(s):  
Feng Li ◽  
Xiaohua Zhu ◽  
Yongsheng Yang ◽  
Lan Huang ◽  
Jinhua Xu
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Macrophage Polarization ◽  
Pathological Changes ◽  
Systemic Lupus ◽  
Urine Protein ◽  
Protein Levels ◽  
M2 Phenotype

Background/Aims: We have recently shown that macrophage polarization may alter the pathogenesis and severity of systemic lupus erythematosus (SLE). However, a practical approach to modulate macrophage polarization in vivo is so far not available. In the current study, we aimed to use tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) to regulate macrophage polarization in vitro and in vivo, and to study the effects on experimental SLE. Methods: We prepared adeno-associated virus carrying TIPE2 (AAV-TIPE2). We induced experimental SLE in mice with an activated lymphocyte-derived DNA (ALD-DNA) method. We examined the effects of TIPE2 overexpression on macrophage polarization in vitro, and in vivo in the SLE model. We also examined the effects of TIPE2 overexpression on the severity of SLE, by serum anti-dsDNA autoantibody, renal pathological changes, and urine protein levels. Results: ALD-DNA induced SLE-like features in mice, manifested by induction of serum anti-dsDNA autoantibody, renal pathological changes, and increases in urine protein levels. TIPE2 overexpression by AAV-TIPE2 induced macrophage polarization to a M2 phenotype, in vitro and in vivo in the SLE mouse model. TIPE2 overexpression significantly decreased SLE severity. Conclusion: TIPE2 alleviates experimental SLE through induction of macrophage polarization to a M2 phenotype, which may be used as a promising therapeutic strategy for treating SLE.

scholarly journals Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 898 ◽  
Author(s):  
Alessia Alunno ◽  
Ivan Padjen ◽  
Antonis Fanouriakis ◽  
Dimitrios T. Boumpas
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Signal Transduction ◽  
Lupus Erythematosus ◽  
Immune Surveillance ◽  
Systemic Lupus ◽  
Therapeutic Implications ◽  
Therapeutic Relevance ◽  
Stat Pathway

Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.

Novel signatures associated with systemic lupus erythematosus clinical response to IFN-α/-ω inhibition

Lupus ◽  
2021 ◽  
pp. 096120332199557
Author(s):  
Loqmane Seridi ◽  
Matteo Cesaroni ◽  
Ashley Orillion ◽  
Jessica Schreiter ◽  
Marc Chevrier ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Clinical Response ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Systemic Lupus ◽  
Point Change ◽  
Blood Samples ◽  
Gene Signatures

Objectives We aimed to identify transcriptional gene signatures predictive of clinical response, for pharmacodynamic evaluation, and to provide mechanistic insight into JNJ-55920839, a human IgG1κ neutralizing mAb targeting IFN-α/IFN-ω, in participants with systemic lupus erythematosus (SLE). Methods Blood samples were obtained from SLE participants at baseline and up to Day 130, who received six 10 mg/kg IV doses of JNJ-55920839/placebo every 2 weeks. Participants with mild-to-moderate SLE who achieved clinical responses using SLE Disease Activity Index 2000 Responder Index 4-point change were considered responders. Transcriptional signatures from longitudinally collected blood were generated by RNA-Seq; signatures were generated by microarray from baseline blood samples exposed in vitro to JNJ-55920839 versus untreated. Results Two gene signatures (IFN-I Signaling and Immunoglobulin Immune Response) exhibited pharmacodynamic changes among JNJ-55920839 responders. The Immunoglobulin signature, but not the IFN-I signature, was elevated at baseline in JNJ-55920839 responders. A gene cluster associated with neutrophil-mediated immunity was reduced at baseline in JNJ-55920839 responders, substantiated by lower neutrophil counts in responders. An IFN-I signature was suppressed by JNJ-55920839 in vitro treatment versus untreated blood to a greater extent in responders before in vivo dosing. Conclusions These signatures may enable enrichment for treatment responders when using IFN-I-suppressing treatments in SLE.

The high expression of miR-564 in patients with systemic lupus erythematosus promotes differentiation and maturation of DC cells by negatively regulating TP53 expression in vitro

Lupus ◽  
2021 ◽  
pp. 096120332110203
Author(s):  
Ziyue Teng ◽  
Xiaoying Lin ◽  
Chunyan Luan ◽  
Yixuan Sun ◽  
Xiaolan Li
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Target Genes ◽  
Differentially Expressed ◽  
Systemic Lupus ◽  
Differentially Expressed Mirnas ◽  
And Migration ◽  
Si Rna

Background miRNA is involved in the occurrence and progression of systemic lupus erythematosus (SLE), but the regulatory effect of miRNA on dendritic cells in SLE patients is still unclear. Material and methods Bioinformatics methods were used to analyze the differentially expressed miRNA and its target genes in SLE patients. In vitro experiments were conducted to explore the effects and mechanisms of differentially expressed miRNAs in SLE patients on the differentiation and maturation of monocyte-derived dendritic cells. Results Bioinformatics analysis showed that miR-564 was up-regulated in SLE patients, and TP53 was the core target gene of miR-564. The expression level of miR-564 showed a rising trend during the differentiation and maturation of monocytes into Mo-DC cells. The differentiation, maturation and proliferation of Mo-DC cells were significantly inhibited by transfection with miR-564 antagomir. The expression of TP53 is negatively regulated by miR-564. In rescue experiments, the proliferation and migration of DC cells were significantly restored by co-transfection of miR-564 antagomir and TP53 si-RNA. Conclusion Highly expressed miR-564 promotes the maturation, proliferation of Mo-DC cells by negatively regulating the expression of TP53.

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