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 Decreased miR-4512 Levels in Monocytes and Macrophages of Individuals With Systemic Lupus Erythematosus Contribute to Innate Immune Activation and Neutrsophil NETosis by Targeting TLR4 and CXCL2

2021 ◽  
Vol 12 ◽  
Author(s):  
Binbin Yang ◽  
Xinwei Huang ◽  
Shuangyan Xu ◽  
Li Li ◽  
Wei Wu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Luciferase Reporter ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Monocytes And Macrophages

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology that is not yet entirely understood. We aimed to elucidate the mechanisms and therapeutic potential of microRNAs (miRNAs) in SLE in a Tibetan population.MethodsPeripheral blood mononuclear cells from SLE patients (n = 5) and healthy controls (n = 5) were used for miRNA–mRNA co-sequencing to detect miRNAs related to immune abnormalities associated with SLE. Luciferase reporter assay was used to identify potential targets of candidate miRNA. The target genes were verified in miRNA-agomir/antagomir transfection assays with multiple cells lines and by expression analysis. The effects of candidate miRNA on monocyte and macrophage activation were evaluated by multiple cytokine profiling. Neutrophil extracellular traps (NETs) formation was analyzed in vitro by cell stimulation with supernatants of monocytes and macrophages transfected with candidate miRNA. The rodent MRL/lpr lupus model was used to evaluate the therapeutic effect of CXCL2Ab on SLE and the regulation effect of immune disorders.ResultsIntegrated miRNA and mRNA expression profiling identified miRNA-4512 as a candidate miRNA involved in the regulation of neutrophil activation and chemokine-related pathways. MiR-4512 expression was significantly reduced in monocytes and macrophages from SLE patients. MiR-4512 suppressed the TLR4 pathway by targeting TLR4 and CXCL2. Decreased monocyte and macrophage miR-4512 levels led to the expression of multiple proinflammatory cytokines in vitro. Supernatants of miR-4512 antagomir-transfected monocytes and macrophages significantly promoted NETs formation (P < 0.05). Blocking of CXCL2 alleviated various pathogenic manifestations in MRL/lpr mice, including kidney damage and expression of immunological markers of SLE.ConclusionsWe here demonstrated the role of miR-4512 in innate immunity regulation in SLE. The effect of miR-4512 involves the regulation of monocytes, macrophages, and NETs formation by direct targeting of TLR4 and CXCL2, indicating the miR-4512-TLR4-CXCL2 axis as a potential novel therapeutic target in SLE.

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 presence of IFL3/4 rs12979860 C allele influences the in vitro IP-10 production by mononuclear cells from patients with systemic lupus erythematosus

Lupus ◽  
2020 ◽  
Vol 29 (5) ◽  
pp. 482-489
Author(s):  
Y Juárez-Vicuña ◽  
J Pérez-Ramos ◽  
L Adalid-Peralta ◽  
F Sánchez ◽  
R Springall ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Peripheral Blood Mononuclear Cells ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Objective To explore whether the IFNL3/4 rs12979860 genotype may influence serum levels or production of interferon-inducible protein-10 (IP-10) by peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). Methods Sixty-six patients with SLE and 22 healthy blood donors (controls) were included. The IFNL3/4 rs12979860 polymorphism was genotyped by real-time polymerase chain reaction. IP-10 levels in sera supernatants of IFNα stimulated peripheral blood mononuclear cells were measured by enzime-linked immunosorbent assay. Results Allelic frequencies were CC (29%), CT (52%) and TT (20%) in SLE, and CC (32%), CT (41%) and TT (27%) in healthy controls. Median serum IP-10 levels were higher in SLE patients than in controls (190.8 versus 118.1 pg/ml; p < 0.001), particularly in those with high disease activity (278.5 versus 177.2 pg/ml; p = 0.037). However, serum IP-10 levels were not influenced by IFNL3/4 genotypes. Higher IP-10 production by peripheral blood mononuclear cells was found in both SLE patients (median 519.3 versus 207.6 pg/ml; p = 0.012) and controls (median 454.0 versus 201.7 pg/ml; p = 0.034) carrying the IFNL3/4 C allele compared with carriers of the T allele. Conclusions Although IFNL3/4 rs12979860 allele C does not appear to influence serum IP-10 levels in SLE, it plays an important role in the production of IP-10 by peripheral blood mononuclear cells after IFNα stimulation.

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