Future Perspectives on Pathogenesis of Lupus Nephritis

Rekvig, Ole Petter; Thiyagarajan, Dhivya; Pedersen, Hege Lynum; Horvei, Kjersti Daae; Seredkina, Natalya

doi:10.1016/j.ajpath.2016.06.026

Cited by 18 publications

(8 citation statements)

References 84 publications

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“…In a strict context, these facts involve recognition of DNA by antibodies linked to autoimmune inflammation in SLE, but do not necessarily provide information about which of the structures represent glomerular targets for the SLE-associated antibodies [chromatin or inherent glomerular structures, see e.g., the divergent interpretations by (130) and (40)]. The data only demonstrate that the pathogenic antibodies recognize at least dsDNA.…”

Section: Lupus Nephritis: Contexts and Pathogenesesmentioning

confidence: 94%

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

Rekvig

2019

Front. Immunol.

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This study aims to understand what lupus nephritis is, its origin, clinical context, and its pathogenesis. Truly, we encounter many conceptual and immanent tribulations in our attempts to search for the pathogenesis of this disease—and how to explain its assumed link to SLE. Central in the present landscape stay a short history of the early studies that substantiated the structures of isolated or chromatin-assembled mammalian dsDNA, and its assumed, highly controversial role in induction of anti-dsDNA antibodies. Arguments discussed here may provoke the view that anti-dsDNA antibodies are not what we think they are, as they may be antibodies operational in quite different biological contexts, although they bind dsDNA by chance. This may not mean that these antibodies are not pathogenic but they do not inform how they are so. This theoretical study centers the content around the origin and impact of extra-cellular DNA, and if dsDNA has an effect on the adaptive immune system. The pathogenic potential of chromatin-anti-dsDNA antibody interactions is limited to incite lupus nephritis and dermatitis which may be linked in a common pathogenic process. These are major criteria in SLE classification systems but are not shared with other defined manifestations in SLE, which may mean that they are their own disease entities, and not integrated in SLE. Today, the models thought to explain lupus nephritis are divergent and inconsistent. We miss a comprehensive perspective to try the different models against each other. To do this, we need to take all elements of the syndrome SLE into account. This can only be achieved by concentrating on the interactions between autoimmunity, immunopathology, deviant cell death and necrotic chromatin in context of elements of system science. System science provides a framework where data generated by experts can be compared, and tested against each other. This approach open for consensus on central elements making up “lupus nephritis” to separate what we agree on and how to understand the basis for conflicting models. This has not been done yet in a systematic context.

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Section: Lupus Nephritis: Contexts and Pathogenesesmentioning

confidence: 94%

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

Rekvig

2019

Front. Immunol.

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“…The anti-dsDNA autoantibody is the critical factor in the pathogenesis of SLE [15]. The level of anti-dsDNA antibodies in serum and anti-dsDNA antibodies deposition in the glomeruli absolutely correlate with lupus nephritis progress in SLE patients [16]. First, we investigated the effect of PD-L1-Ig on the production of anti-dsDNA autoantibodies in the serum with ELISA.…”

Section: Resultsmentioning

confidence: 99%

The Systemic Activation of Programmed Death 1-PD-L1 Axis Protects Systemic Lupus Erythematosus Model from Nephritis

Liao

Zheng²,

Wu³

et al. 2017

Am J Nephrol

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Background: Systemic lupus erythematosus (SLE) is characterized by abnormal activated T cells, autoreactive B cells, and massive cytokines. The CD4+ T cells determined B-cells differentiation and cytokines production. The programmed death 1 (PD-1) is the checkpoint immunoinhibitory receptor of activated T cells, and its engagement could exhaust T cells. In this study, we investigated the role of PD-1 systemic engagement with PD-L1-Ig in lupus-like nephritis in SLE mice. Methods: The murine PD-L1-Ig was injected into SLE-prone mice. The proteinuria and survival ratio were monitored. The production of anti-dsDNA autoantibodies and cytokines in serum were measured by enzyme-linked immunosorbent assay. The cytokine-producing T cells (interferon-γ, IFN-γ and IL-17α) in kidney and spleen were detected with flowcytometry. The pathological evaluation of the Ig deposition in the glomeruliand was determined with immunofluorescence. Lymphocytes in 24-h urine were detected with flowcytometry. Results: The systemic administration of PD-L1-Ig activated PD-1-PD-L1 axis of CD4+ T lymphocytes, suppressed Th17 formation in many organs, including the spleen and the kidney, demolished abnormal production of cytokines (IFN-γ, IL-17, and IL-10) and anti-dsDNA autoantibodies in serum, inhibited immunoglobulin G deposition in the glomeruli with the decrease of proteinuria, and activated T cells in urine. Accordingly, the systemic conjugation of PD-L1-PD-1 impaired renal autoimmune injure and prolonged survival time. Conclusion: Our research demonstrated that the protective function of systemic activation of PD-1-PD-L1 axis with PD-L1-Ig attenuates the nephritis in SLE-prone mice, which facilitates us to understand the suppressive function of PD-1-PD-L1 axis in the pathogenesis and progress of the lupus nephritis, and to explore a possible effective therapeutic strategy to SLE.

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“…In contrast to this hypothetical model, lines 5 and 6 summarize progressive lupus nephritis according to the chromatin model. These principally conflicting models are summarized in (A) , lines 2 and 3 for the chromatin model, and in (B) , line 2 for the cross-reactive model [This figure is a revised and extended version of Figure 4 in Rekvig et al ( 182 ) with permission from Elsevier (License number 4832930988362)].…”

Section: Anti-dsdna Antibodies and Lupus Nephritismentioning

confidence: 99%

“…These EDS were TUNEL positive, and bound antibodies against histones, transcription factors and dsDNA added to sections in vitro . Because of the problematization of how “The anti-dsDNA antibody” promotes lupus nephritis, questions that are illustrated in Figure 4 , should be considered and focused on in future studies on the distinct autoimmune pathogenesis of nephritis [ A in this figure is a truncated reprint of Figure 4 in Rekvig et al ( 182 ) with permission from Elsevier (License number 4832930988362)].…”

Section: Anti-dsdna Antibodies and Lupus Nephritismentioning

confidence: 99%

Autoimmunity and SLE: Factual and Semantic Evidence-Based Critical Analyses of Definitions, Etiology, and Pathogenesis

Rekvig

2020

Front. Immunol.

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One cannot discuss anti-dsDNA antibodies and lupus nephritis without discussing the nature of Systemic lupus erythematosus (SLE). SLE is insistently described as a prototype autoimmune syndrome, with anti-dsDNA antibodies as a central biomarker and a pathogenic factor. The two entities, “SLE” and “The Anti-dsDNA Antibody,” have been linked in previous and contemporary studies although serious criticism to this mutual linkage have been raised: Anti-dsDNA antibodies were first described in bacterial infections and not in SLE; later in SLE, viral and parasitic infections and in malignancies. An increasing number of studies on classification criteria for SLE have been published in the aftermath of the canonical 1982 American College of Rheumatology SLE classification sets of criteria. Considering these studies, it is surprising to observe a nearby complete absence of fundamental critical/theoretical discussions aimed to explain how and why the classification criteria are linked in context of etiology, pathogenicity, or biology. This study is an attempt to prioritize critical comments on the contemporary definition and classification of SLE and of anti-dsDNA antibodies in context of lupus nephritis. Epidemiology, etiology, pathogenesis, and measures of therapy efficacy are implemented as problems in the present discussion. In order to understand whether or not disparate clinical SLE phenotypes are useful to determine its basic biological processes accounting for the syndrome is problematic. A central problem is discussed on whether the clinical role of anti-dsDNA antibodies from principal reasons can be accepted as a biomarker for SLE without clarifying what we define as an anti-dsDNA antibody, and in which biologic contexts the antibodies appear. In sum, this study is an attempt to bring to the forum critical comments on the contemporary definition and classification of SLE, lupus nephritis and anti-dsDNA antibodies. Four concise hypotheses are suggested for future science at the end of this analytical study.

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Future Perspectives on Pathogenesis of Lupus Nephritis

Cited by 18 publications

References 84 publications

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

The Systemic Activation of Programmed Death 1-PD-L1 Axis Protects Systemic Lupus Erythematosus Model from Nephritis

Autoimmunity and SLE: Factual and Semantic Evidence-Based Critical Analyses of Definitions, Etiology, and Pathogenesis

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