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Special Issue "Systemic Lupus Erythematosus: Research Updates in Immunopathogenesis, Biomarkers and Therapeutics"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editors

Guest Editor
Prof. Dr. Chak-Sing Lau Website E-Mail
Division of Rheumatology and Clinical Immunology, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Fax: (852) 2818 6474
Interests: role of dendritic cells in SLE pathogenesis; molecular regulatory mechanisms of dendritic cell functions; mechanistic studies of cellular immuno-dysregulation in SLE; evaluation of the clinical outcome of SLE
Guest Editor
Dr. Vera Sau-Fong Chan Website E-Mail
Division of Rheumatology and Clinical Immunology, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Fax: (852) 2818 6474
Interests: C-type lectin receptors immunobiology and its role in autoimmune diseases and infection; cellular and molecular dysregulation in SLE; immuno-therapeutics development

Special Issue Information

Dear Colleagues,

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse clinical manifestations involving multiple organ systems. Clinically, SLE is still mainly managed by the use of conventional immunosuppressants and steroids with undesirable side-effects; the efficacies of new biologics are yet to be substantiated. Thus, understanding SLE pathogenic mechanisms is of imminent importance to advancing the management of this condition. SLE pathogenesis is highly intricate and etiologically contributed by a combination of multiple genetic and environmental elements. SLE is characterized by the loss of tolerance to self-antigens, dysregulated autoreactive T- and B-cell activation, the production of autoantibodies, and perturbed cytokine activities. In the past decade, advances in next-generation genomics technology have revealed many molecular targets that, as substantiated by many cellular and in vivo animal studies, can be further explored as potential therapeutics. In addition, new cellular players that contribute to disease progression and perpetuation have also been unveiled. This Special Issue aims to provide recent research highlights that focus on understanding the immuno-pathogenesis mechanisms, biomarkers, and novel therapeutics development in SLE. Topics include, but are not limited to, the following:

  • The genetics of lupus
  • The epigenetic regulation of lupus
  • Cellular and molecular dysregulation in SLE
  • Cytokine perturbation and contribution to lupus progression
  • Innate and adaptive immunity in SLE
  • Immuno-regulatory cells in lupus
  • Biomarker development for prognosis and monitoring lupus disease
  • Novel therapeutics and new treatment strategies for lupus

Prof. Dr. Chak-Sing Lau
Dr. Vera Sau-Fong Chan
Guest Editors

Manuscript Submission Information

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Keywords

  • Lupus
  • Autoimmunity
  • Cytokines
  • Epigenetics
  • Innate immunity
  • Genetics
  • Immunoregulation
  • Biomarkers
  • Therapeutics

Published Papers (5 papers)

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Research

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Open AccessArticle
Heightened TLR7/9-Induced IL-10 and CXCL13 Production with Dysregulated NF-ҝB Activation in CD11chiCD11b+ Dendritic Cells in NZB/W F1 Mice
Int. J. Mol. Sci. 2019, 20(18), 4639; https://doi.org/10.3390/ijms20184639 - 19 Sep 2019
Abstract
Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease that predominantly affects young females. Dysregulation of different immune cell populations leads to self-tolerance breakdown and subsequent multiple organ damage as the disease develops. Plasmacytoid dendritic cells (pDCs) are potent producers of type [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease that predominantly affects young females. Dysregulation of different immune cell populations leads to self-tolerance breakdown and subsequent multiple organ damage as the disease develops. Plasmacytoid dendritic cells (pDCs) are potent producers of type I interferon (IFN), while myeloid dendritic cells (mDCs) are more specialized in antigen presentations. We have previously reported that bone-marrow (BM)-derived pDCs from the murine lupus model New Zealand black/white F1 (BWF1) possess abnormalities. Therefore, this study continues to investigate what aberrant properties peripheral pDCs and mDCs possess in BWF1 and how they mediate SLE progression, by comparing their properties in pre-symptomatic and symptomatic mice. Results showed that CD11chiCD11b+ myeloid DCs expanded during the disease state with down-regulation of co-stimulatory molecules and major histocompatibility complex class II molecules (MHC II), but their capacity to stimulate T cells was not hampered. During the disease state, this subset of mDCs displayed heightened toll-like receptors 7 and 9 (TLR 7/9) responses with increased interleukin 10 (IL-10) and C-X-C motif chemokine ligand 13 (CXCL13) expressions. Moreover, the expressions of myeloid differentiation primary response 88 (Myd88) and nuclear factor kappa B subunit 1 (Nfkb1) were higher in CD11chiCD11b+ DCs at the disease stage, leading to higher nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 phosphorylation activity. In summary, we reported aberrant phenotypic properties with enhanced TLR7/9 responses of CD11chiCD11b+ DCs in SLE mediated by aberrant NF-κB signaling pathway. Our findings add additional and novel information to our current understanding of the role of DCs in lupus immunopathogenesis. Lastly, molecular candidates in the NF-κB pathway should be exploited for developing therapeutic targets for SLE. Full article
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Open AccessArticle
Urinary Neuropilin-1: A Predictive Biomarker for Renal Outcome in Lupus Nephritis
Int. J. Mol. Sci. 2019, 20(18), 4601; https://doi.org/10.3390/ijms20184601 - 17 Sep 2019
Abstract
At present, Lupus Nephritis (LN) is still awaiting a biomarker to better monitor disease activity, guide clinical treatment, and predict a patient’s long-term outcome. In the last decade, novel biomarkers have been identified to monitor the disease, but none have been incorporated into [...] Read more.
At present, Lupus Nephritis (LN) is still awaiting a biomarker to better monitor disease activity, guide clinical treatment, and predict a patient’s long-term outcome. In the last decade, novel biomarkers have been identified to monitor the disease, but none have been incorporated into clinical practice. The transmembrane receptor neuropilin-1 (NRP-1) is highly expressed by mesangial cells and its genetic deletion results in proteinuric disease and glomerulosclerosis. NRP-1 is increased in kidney biopsies of LN. In this work we were interested in determining whether urinary NRP-1 levels could be a biomarker of clinical response in LN. Our results show that patients with active LN have increased levels of urinary NRP-1. When patients were divided according to clinical response, responders displayed higher urinary and tissue NRP-1 levels at the time of renal biopsy. Areas under the receiver operating characteristic curve, comparing baseline creatinine, proteinuria, urinary NRP-1, and VEGFA protein levels, showed NRP-1 to be an independent predictor for clinical response. In addition, in vitro studies suggest that NRP-1could promote renal recovery through endothelial proliferation and migration, mesangial migration and local T cell cytotoxicity. Based on these results, NRP-1 may be used as an early prognostic biomarker in LN. Full article
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Open AccessArticle
BTLA Expression on Th1, Th2 and Th17 Effector T-Cells of Patients with Systemic Lupus Erythematosus Is Associated with Active Disease
Int. J. Mol. Sci. 2019, 20(18), 4505; https://doi.org/10.3390/ijms20184505 - 11 Sep 2019
Abstract
An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim [...] Read more.
An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127 regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity. Full article
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Open AccessArticle
Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb−/− Lupus Prone Mice is Revealed by Phosphoproteomic Analysis
Int. J. Mol. Sci. 2019, 20(6), 1354; https://doi.org/10.3390/ijms20061354 - 18 Mar 2019
Cited by 1
Abstract
Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb−/− mice were explored on [...] Read more.
Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb−/− mice were explored on bone marrow-derived macrophages using phosphoproteomic analysis. As such, LPS tolerance decreased several phosphoproteins in the FcGRIIb−/− macrophage, including protein kinase C-β type II (PRKCB), which was associated with phagocytosis function. Overexpression of PRKCB attenuated LPS tolerance in RAW264.7 cells, supporting the role of this gene in LPS tolerance. In parallel, LPS tolerance in macrophages and in mice was attenuated by phorbol 12-myristate 13-acetate (PMA) administration. This treatment induced several protein kinase C families, including PRKCB. However, PMA attenuated the severity of mice with cecal ligation and puncture on LPS tolerance preconditioning in FcGRIIb−/− but not in wild-type cells. The significant reduction of PRKCB in the FcGRIIb−/− macrophage over wild-type cell possibly induced the more severe LPS-exhaustion and increased the infection susceptibility in FcGRIIb−/− mice. PMA induced PRKCB, improved LPS-tolerance, and attenuated sepsis severity, predominantly in FcGRIIb−/− mice. PRKCB enhancement might be a promising strategy to improve macrophage functions in lupus patients with LPS-tolerance from chronic infection. Full article
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Review

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Open AccessReview
Molecular and Cellular Bases of Immunosenescence, Inflammation, and Cardiovascular Complications Mimicking “Inflammaging” in Patients with Systemic Lupus Erythematosus
Int. J. Mol. Sci. 2019, 20(16), 3878; https://doi.org/10.3390/ijms20163878 - 09 Aug 2019
Abstract
Systemic lupus erythematosus (SLE) is an archetype of systemic autoimmune disease, characterized by the presence of diverse autoantibodies and chronic inflammation. There are multiple factors involved in lupus pathogenesis, including genetic/epigenetic predisposition, sexual hormone imbalance, environmental stimulants, mental/psychological stresses, and undefined events. Recently, [...] Read more.
Systemic lupus erythematosus (SLE) is an archetype of systemic autoimmune disease, characterized by the presence of diverse autoantibodies and chronic inflammation. There are multiple factors involved in lupus pathogenesis, including genetic/epigenetic predisposition, sexual hormone imbalance, environmental stimulants, mental/psychological stresses, and undefined events. Recently, many authors noted that “inflammaging”, consisting of immunosenescence and inflammation, is a common feature in aging people and patients with SLE. It is conceivable that chronic oxidative stresses originating from mitochondrial dysfunction, defective bioenergetics, abnormal immunometabolism, and premature telomere erosion may accelerate immune cell senescence in patients with SLE. The mitochondrial dysfunctions in SLE have been extensively investigated in recent years. The molecular basis of normoglycemic metabolic syndrome has been found to be relevant to the production of advanced glycosylated and nitrosative end products. Besides, immunosenescence, autoimmunity, endothelial cell damage, and decreased tissue regeneration could be the results of premature telomere erosion in patients with SLE. Herein, the molecular and cellular bases of inflammaging and cardiovascular complications in SLE patients will be extensively reviewed from the aspects of mitochondrial dysfunctions, abnormal bioenergetics/immunometabolism, and telomere/telomerase disequilibrium. Full article
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