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      Towards Precision Medicine in Systemic Lupus Erythematosus

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          Abstract

          Systemic lupus erythematosus (SLE) is a remarkable condition characterised by diversity amongst its clinical features and immunological abnormalities. In this review, we attempt to capture the major immunological changes linked to the pathophysiology of lupus and discuss the challenge it presents in moving towards the concept of precision medicine. Currently broadly similar types of drugs, e.g., steroids, immunosuppressives, hydroxychloroquine are used to treat many of the diverse clinical features of SLE. We suspect that, as the precise immunopathological abnormalities differ between the various organs/systems in lupus patients, it will be some time before precision medicine can be fully applied to SLE.

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          Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview

          Vidal Delgado-Rizo, Marco Martínez-Guzmán, Liliana Iñiguez-Gutierrez … (2017)
          In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6–8 h, and in tissue, where they can last up to 7 days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy three to five times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL37, peptidoglycan-binding proteins, and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2–4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5–60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory, and metabolic diseases.
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            Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

            Maria K. Smatti, Farhan Cyprian, Gheyath K. Nasrallah … (2019)
            For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.
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              Control of lupus nephritis by changes of gut microbiota

              Qinghui Mu, Husen Zhang, Xiaofeng Liao … (2017)
              Background Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether. Results Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner. Conclusions This work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupus-associated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects. Electronic supplementary material The online version of this article (doi:10.1186/s40168-017-0300-8) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmgenomics Pers Med
                Journal ID (iso-abbrev): Pharmgenomics Pers Med
                Journal ID (publisher-id): PGPM
                Journal ID (pmc): ppm
                Title: Pharmacogenomics and Personalized Medicine
                Publisher: Dove
                ISSN (Electronic): 1178-7066
                Publication date (Electronic): 04 February 2020
                Publication date Collection: 2020
                Volume: 13
                Pages: 39-49
                Affiliations
                [1 ]Centre for Rheumatology, Division of Medicine, University College Hospital London , London, UK
                [2 ]Internal Medicine, Department of Medicine, Centro Hospitalar do Porto , Porto, Portugal
                Author notes
                Correspondence: David A Isenberg Centre for Rheumatology, Division of Medicine, University College Hospital London , Room 424, the Rayne Building, 5 University Street, LondonWC1E 6JF, UK Email d.isenberg@ucl.ac.uk
                Author information
                http://orcid.org/0000-0002-5483-6933
                Article
                Publisher ID: 205079
                DOI: 10.2147/PGPM.S205079
                PMC ID: 7007776
                PubMed ID: 32099443
                SO-VID: e341e7a0-5774-481d-804a-f9e7381486c7
                Copyright © © 2020 Lever et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 29 October 2019
                Date accepted : 14 January 2020
                Page count
                Tables: 2, References: 92, Pages: 11
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: systemic lupus erythematosus,anti-dna antibodies,lupus nephritis,lupus genetics,immunosuppression
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: systemic lupus erythematosus, anti-dna antibodies, lupus nephritis, lupus genetics, immunosuppression

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