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

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.

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Successful pregnancy and follow-up after in vitro fertilization of a kidney transplant patient with systemic lupus erythematosus, primary biliary cholangitis, and hypothyroidism

JBRA Assisted Reproduction ◽

10.5935/1518-0557.20210052 ◽

2021 ◽

Author(s):

Teresa Gastañaga-Holguera ◽

Marta Calvo ◽

Laura Gómez-Irwin ◽

Isabel Campo Gesto ◽

Virginia González- González ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Transplant Patient ◽

Primary Biliary Cholangitis ◽

Kidney Transplant Patient ◽

Systemic Lupus ◽

Successful Pregnancy ◽

Vitro Fertilization

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

Annals of the Rheumatic Diseases ◽

10.1136/ard.2007.075762 ◽

2007 ◽

Vol 67 (4) ◽

pp. 450-457 ◽

Cited By ~ 95

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.

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TIPE2 Alleviates Systemic Lupus Erythematosus Through Regulating Macrophage Polarization

Cellular Physiology and Biochemistry ◽

10.1159/000438633 ◽

2016 ◽

Vol 38 (1) ◽

pp. 330-339 ◽

Cited By ~ 26

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.

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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 ◽

10.3390/cells8080898 ◽

2019 ◽

Vol 8 (8) ◽

pp. 898 ◽

Cited By ~ 23

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.

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

Lupus ◽

10.1177/0961203321995576 ◽

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.

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Chloroquine Autophagic Inhibition Rebalances Th17/Treg-Mediated Immunity and Ameliorates Systemic Lupus Erythematosus

Cellular Physiology and Biochemistry ◽

10.1159/000484955 ◽

2017 ◽

Vol 44 (1) ◽

pp. 412-422 ◽

Cited By ~ 26

Author(s):

Ning An ◽

Yanwen Chen ◽

Chao Wang ◽

Chen Yang ◽

Zhi-hong Wu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune Response ◽

Lupus Erythematosus ◽

Treg Cells ◽

Healthy Controls ◽

Systemic Lupus ◽

Immune Imbalance ◽

The Impact

Background: Imbalanced cellular immunity is critical to the pathogenesis of systemic lupus erythematosus (SLE). Recently, autophagy has emerged as a key homeostatic mechanism in T lymphocytes. This study was conducted to explore the impact of autophagy on the Th17/ regulatory T (Treg) immune imbalance in SLE. Methods: Peripheral Th17 and Treg cells from newly diagnosed patients with SLE and healthy controls were detected by flow cytometry. Additionally, the effects of chloroquine (CQ) autophagic inhibition on the Th17/Treg immune response were investigated in vitro. In addition, hydroxychloroquine (HCQ) treatment of the Th17/Treg immune response and the disease progression of lupus MRL/lpr mice were studied in vivo. Results: Compared with healthy controls, both peripheral Th17 and Treg cells of patients with SLE exhibited activated autophagy, resulting in a heightened Th17 proinflammatory response and diminished Treg immunosuppression. Furthermore, in vitro experiments indicated that CQ autophagic inhibition effectively rebalanced the Th17/Treg immune responses in patients with SLE. In vivo studies of MRL/lpr mice similarly confirmed that HCQ treatment decisively inhibited the autophagy of Th17/Treg cellular subsets, restoring the immune balance, lowering the serum levels of inflammatory cytokines and autoantibodies, and improving renal histopathology. Conclusion: Activated autophagy contributed to the Th17/Treg immune imbalance in SLE, and chloroquine autophagic inhibition rebalanced Th17/ Treg-mediated immunity and ameliorated SLE.

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