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The Molecular and Cellular Basis for Lupus
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The Molecular and Cellular Basis for Lupus

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 102905

Special Issue Editor

Dr. Anselm Mak

E-Mail Website
Guest Editor
Division of Rheumatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
Interests: systemic lupus erythematosus; inflammation; autoimmunity; T cells; neurocognition; functional MRI; meta-analyses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Systemic lupus erythematosus (SLE) is an autoimmune condition with a complicated pathophysiology that is not completely understood. While many molecular pathways and cellular alterations have been postulated and published in the literature, a number of clinical trials addressing these potentially pathological mechanisms have disappointingly failed to reach their respective primary endpoints, leading to the current paucity of targeted therapeutic agents that are capable of decelerating and even terminating the disease process and damage.

Nevertheless, some early and promising signals such as the success of the manipulation of the BAFF/ARPIL system, antagonization of IL-12/23 and the use of IL-2 in the management of SLE are currently in the pipeline for further evaluation for the clinical management of SLE. Obviously, these potential successes will not materialize if the basic molecular and cellular mechanisms of these new targets that are involved in the pathophysiology of SLE are not fully explored, vigorously tested and meticulously monitored.

This Special Issue of Cells aims to summarize the cutting-edge knowledge on the molecular and cellular basis of the pathogenesis and pathophysiology of SLE, in the hope of expanding the treatment armamentarium and ultimately, personalized treatment for patients with SLE.

We are looking forward to your significant contributions.

Dr. Anselm Mak
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Signaling pathways related to SLE
  • Molecular alterations related to SLE
  • Cell-surface, cytosolic and nuclear-membrane receptors related to SLE
  • SLE-related cytokines and chemokines in SLE
  • Cell–cell interactions in SLE
  • Mechanisms of organ involvement and damage in SLE

Published Papers (16 papers)

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Research

Jump to: Review

16 pages, 1657 KiB  
Article
IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis
by Angelika Rose, Caroline von Spee-Mayer, Lutz Kloke, Kaiyin Wu, Anja Kühl, Philipp Enghard, Gerd-Rüdiger Burmester, Gabriela Riemekasten and Jens Y. Humrich
Cells 2019, 8(10), 1234; https://doi.org/10.3390/cells8101234 - 11 Oct 2019
Cited by 27 | Viewed by 4239
Abstract
An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its [...] Read more.
An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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17 pages, 4774 KiB  
Article
Lipocalin-2 (Lcn-2) Attenuates Polymicrobial Sepsis with LPS Preconditioning (LPS Tolerance) in FcGRIIb Deficient Lupus Mice
by Thunnicha Ondee, Joseph Gillen, Peerapat Visitchanakun, Poorichaya Somparn, Jiraphorn Issara-Amphorn, Cong Dang Phi, Wiwat Chancharoenthana, Devikala Gurusamy, Aleksandra Nita-Lazar and Asada Leelahavanichkul
Cells 2019, 8(9), 1064; https://doi.org/10.3390/cells8091064 - 11 Sep 2019
Cited by 35 | Viewed by 4261
Abstract
In patients with active lupus, spontaneous endotoxemia and possibly tolerance to lipopolysaccharide (LPS) is a potentially adverse complication. Similarly, previous reports have demonstrated that FcGRIIb deficient mice (FcGRIIb-/-; a lupus mouse model) are susceptible to LPS tolerance-induced decreased cytokine responses that inadequate for [...] Read more.
In patients with active lupus, spontaneous endotoxemia and possibly tolerance to lipopolysaccharide (LPS) is a potentially adverse complication. Similarly, previous reports have demonstrated that FcGRIIb deficient mice (FcGRIIb-/-; a lupus mouse model) are susceptible to LPS tolerance-induced decreased cytokine responses that inadequate for the organismal control. Thus, understanding the relationship between FcGRIIb and LPS tolerance could improve the therapeutic strategy for lupus. LPS tolerance can be induced through sequential LPS stimulations in either cells or a model organism. In RAW264.7 (a mouse macrophage cell-line), sequential LPS stimulation induced the secretion of Lipocalin-2 (Lcn-2) despite reduced cytokine secretion and severe energy depletion, as measured by the extracellular flux analysis, typical of LPS tolerance. In contrast, treatment with recombinant Lcn-2 (rLcn-2) attenuated LPS tolerance, as shown by an increase in secreted cytokines and altered macrophage polarization toward M1 (increased iNOS and TNF-α) in RAW264.7 cells. These results suggest a role of Lcn-2 in LPS tolerance attenuation. In bone marrow derived macrophages, Lcn-2 level was similar in LPS tolerant FcGRIIb-/- and wild-type (WT) cells despite the increased LPS tolerance of FcGRIIb-/- cells, suggesting relatively low basal levels of Lcn-2 produced in FcGRIIb-/- cells. In addition, attenuation of LPS tolerance effectuated by granulocyte-monocyte colony stimulating factor (GM-CSF) reduced Lcn-2 in both cell types, implying an inverse correlation between Lcn-2 and the severity of LPS tolerance. Consequently, rLcn-2 improved LPS tolerance only in FcGRIIb-/- macrophages and attenuated disease severity of cecal ligation and puncture (CLP) sepsis pre-conditioning with sequential LPS injection (LPS-CLP model) only in FcGRIIb-/- mice, but not in WT mice. To summarize, inadequate Lcn-2 production in FcGRIIb-/- macrophage might, at least in part, be responsible for the inordinate LPS tolerance compared with WT cells. Additionally, supplementation of rLcn-2 attenuates LPS tolerance in FcGRIIb-/- macrophages in vitro, and in FcGRIIb-/- mice with LPS-CLP sepsis in vivo. In conclusion, Lcn-2 secreted by macrophages is possibly an autocrine signal to counter the reduced cytokine secretion in LPS tolerance. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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19 pages, 2997 KiB  
Article
Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Faslpr Mice
by Akiko Nagasu, Tomoyuki Mukai, Masanori Iseki, Kyoko Kawahara, Shoko Tsuji, Hajime Nagasu, Yasuyoshi Ueki, Katsuhiko Ishihara, Naoki Kashihara and Yoshitaka Morita
Cells 2019, 8(5), 402; https://doi.org/10.3390/cells8050402 - 30 Apr 2019
Cited by 9 | Viewed by 4662
Abstract
SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored [...] Read more.
SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4−CD8− T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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Review

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13 pages, 2494 KiB  
Review
Mechanistic Paradigms of Natural Plant Metabolites as Remedial Candidates for Systemic Lupus Erythromatosus
by Acharya Balkrishna, Pallavi Thakur, Shivam Singh, Swami Narsingh Chandra Dev and Anurag Varshney
Cells 2020, 9(4), 1049; https://doi.org/10.3390/cells9041049 - 22 Apr 2020
Cited by 7 | Viewed by 8556
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving a dysregulated immune response which ultimately leads to multiple organ failure. Several immunological and cellular checkpoints are available as drug targets. However, the available chemosynthetic drugs such as non-steroidal anti-inflammatory drugs and corticosteroids [...] Read more.
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving a dysregulated immune response which ultimately leads to multiple organ failure. Several immunological and cellular checkpoints are available as drug targets. However, the available chemosynthetic drugs such as non-steroidal anti-inflammatory drugs and corticosteroids provide limited therapy with extreme toxicities. Moreover, the disease heterogeneity in SLE is very difficult to manage by a single drug component. Hence, it is imperative to utilize the holistic capabilities of natural plant products as immunomodulators and intracellular signaling regulators, thereby providing an auxiliary option of treatment. Additionally, the herbal drugs also serve as symptomatic relief providers, thereby serving as a prophylactic remedy in case of cerebrovascular, hepatic, nephropathological, hematological, cardiopulmonary, mucocutaneous and musculoskeletal manifestations of SLE. The present review attempts to showcase the current state of knowledge regarding the utility of plant-derived phyto-metabolites with their probable mechanistic roles in treating SLE, by means of targeting the signaling cascade, proinflammatory cytokine production and B–T cell co-stimulation. It is hoped that further preclinical and clinical studies will be embarked upon in order to understand the underlying therapeutic and mechanistic aspects of these medicinal herbs. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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13 pages, 255 KiB  
Review
Anti-Cytokine Autoantibodies in Systemic Lupus Erythematosus
by Hwee Siew Howe and Bernard Pui Lam Leung
Cells 2020, 9(1), 72; https://doi.org/10.3390/cells9010072 - 27 Dec 2019
Cited by 25 | Viewed by 4932
Abstract
Cytokine dysregulation is characteristic of systemic lupus erythematosus (SLE), a systemic autoimmune disease of considerable heterogeneity. Insights gained about the cytokine dysregulation in SLE have the potential for identifying patient subsets before the onset of clinical disease and during established disease. Clustering patients [...] Read more.
Cytokine dysregulation is characteristic of systemic lupus erythematosus (SLE), a systemic autoimmune disease of considerable heterogeneity. Insights gained about the cytokine dysregulation in SLE have the potential for identifying patient subsets before the onset of clinical disease and during established disease. Clustering patients by cytokine and disease activity subsets is more informative than isolated cytokine studies, as both pro inflammatory and immunoregulatory cytokines contribute to the cytokine dysregulated state in SLE. Endogenous anti-cytokine autoantibodies (ACAAs) may be involved in the regulation of cytokine biology by reducing excessive production or by prolonging their half-life in the circulation through the formation of cytokine-antibody immune complexes. Although endogenous ACAAs may have deleterious effects such as contributing to immunodeficiency states, their role in the pathophysiology of autoimmune conditions such as SLE has yet to be clearly elucidated. The aim of the present article is to provide a focused review of the current knowledge of ACAAs in SLE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
13 pages, 1344 KiB  
Review
MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus
by Huai-Chia Chuang and Tse-Hua Tan
Cells 2019, 8(11), 1433; https://doi.org/10.3390/cells8111433 - 13 Nov 2019
Cited by 55 | Viewed by 9300
Abstract
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of [...] Read more.
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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25 pages, 1143 KiB  
Review
Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus
by Patcharee Ritprajak, Chamraj Kaewraemruaen and Nattiya Hirankarn
Cells 2019, 8(10), 1291; https://doi.org/10.3390/cells8101291 - 21 Oct 2019
Cited by 24 | Viewed by 5125
Abstract
Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of [...] Read more.
Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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28 pages, 1063 KiB  
Review
The Role of Immune Checkpoint Receptors in Regulating Immune Reactivity in Lupus
by Kun-Lin Lu, Ming-Ying Wu, Chi-Hui Wang, Chuang-Wei Wang, Shuen-Iu Hung, Wen-Hung Chung and Chun-Bing Chen
Cells 2019, 8(10), 1213; https://doi.org/10.3390/cells8101213 - 08 Oct 2019
Cited by 14 | Viewed by 6078
Abstract
Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune [...] Read more.
Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune responses interacting with genetics and the environment. The close connections between co-signaling pathways and SLE have gradually been established in past research. Also, the recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the co-inhibitory receptors in cancer immunotherapy. Moreover, immune checkpoint blockade could result in substantial immune-related adverse events that mimic autoimmune diseases, including lupus. Together, immune checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. Therefore, it appears reasonable to treat SLE by restoring the out-of-order co-signaling axis or by manipulating collateral pathways to control the pathogenic immune responses. Here, we review the current state of knowledge regarding the relationships between SLE and the co-signaling pathways of T cells, B cells, dendritic cells, and neutrophils, and highlight their potential clinical implications. Current clinical trials targeting the specific co-signaling axes involved in SLE help to advance such knowledge, but further in-depth exploration is still warranted. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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17 pages, 1649 KiB  
Review
Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond
by Young-Chang Kwon, Sehwan Chun, Kwangwoo Kim and Anselm Mak
Cells 2019, 8(10), 1180; https://doi.org/10.3390/cells8101180 - 30 Sep 2019
Cited by 81 | Viewed by 9152
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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16 pages, 2077 KiB  
Review
New Frontiers: ARID3a in SLE
by Joshua Garton, M. David Barron, Michelle L. Ratliff and Carol F. Webb
Cells 2019, 8(10), 1136; https://doi.org/10.3390/cells8101136 - 24 Sep 2019
Cited by 9 | Viewed by 4087
Abstract
Systemic lupus erythematosus (SLE) is a devastating and heterogeneous autoimmune disease that affects multiple organs, and for which the underlying causes are unknown. The majority of SLE patients produce autoantibodies, have increased levels of type-I inflammatory cytokines, and can develop glomerulonephritis. Recent studies [...] Read more.
Systemic lupus erythematosus (SLE) is a devastating and heterogeneous autoimmune disease that affects multiple organs, and for which the underlying causes are unknown. The majority of SLE patients produce autoantibodies, have increased levels of type-I inflammatory cytokines, and can develop glomerulonephritis. Recent studies indicate an unexpected but strong association between increased disease activity in SLE patients and the expression of the DNA-binding protein ARID3a (A + T rich interaction domain protein 3a) in a number of peripheral blood cell types. ARID3a expression was first associated with autoantibody production in B cells; however, more recent findings also indicate associations with expression of the inflammatory cytokine interferon alpha in SLE plasmacytoid dendritic cells and low-density neutrophils. In addition, ARID3a is expressed in hematopoietic stem cells and some adult kidney progenitor cells. SLE cells expressing enhanced ARID3a levels show differential gene expression patterns compared with homologous healthy control cells, identifying new pathways potentially regulated by ARID3a. The associations of ARID3a expression with increased disease severity in SLE, suggest that it, or its downstream targets, may provide new therapeutic targets for SLE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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11 pages, 1073 KiB  
Review
The Progress of Investigating the CD137-CD137L Axis as a Potential Target for Systemic Lupus Erythematosus
by Anselm Mak and Herbert Schwarz
Cells 2019, 8(9), 1044; https://doi.org/10.3390/cells8091044 - 06 Sep 2019
Cited by 7 | Viewed by 5207
Abstract
Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory [...] Read more.
Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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19 pages, 1551 KiB  
Review
Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus
by I-Tsu Chyuan, Hong-Tai Tzeng and Ji-Yih Chen
Cells 2019, 8(9), 963; https://doi.org/10.3390/cells8090963 - 23 Aug 2019
Cited by 48 | Viewed by 9630
Abstract
Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity [...] Read more.
Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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13 pages, 262 KiB  
Review
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
by Alessia Alunno, Ivan Padjen, Antonis Fanouriakis and Dimitrios T. Boumpas
Cells 2019, 8(8), 898; https://doi.org/10.3390/cells8080898 - 15 Aug 2019
Cited by 98 | Viewed by 7732
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
18 pages, 13832 KiB  
Review
The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus
by Marcus Kai Xuan Tan, Thurston Yan Jia Heng and Anselm Mak
Cells 2019, 8(4), 323; https://doi.org/10.3390/cells8040323 - 06 Apr 2019
Cited by 27 | Viewed by 7066
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, therapeutic agents such as glucocorticoids, mycophenolate, azathioprine, cyclosporine, cyclophosphamide and various biologics are the mainstay of treatment based on their immunomodulatory and immunosuppressive properties. As a result of global immunosuppression, the side-effect profile of the current therapeutic approach is unfavourable, with adverse effects including myelosuppression, infection and malignancies. Hydroxychloroquine, one of the very few Food and Drug Administration (FDA)-approved medications for the treatment of SLE, has been shown to offer a number of therapeutic benefits to SLE patients independent of its immunomodulatory effect. As such, it is worth exploring drugs similar to hydroxychloroquine that confer additional clinical benefits unrelated to immunosuppressive mechanisms. Indeed, apart from hydroxychloroquine, a number of studies have explored the use of a few conventionally non-immunosuppressive drugs that are potentially useful in the management of SLE. In this review, non-immunosuppressive therapeutic agents, namely metformin, dipyridamole, N-acetylcysteine and statins, will be critically discussed with regard to their mechanisms of action and efficacy pertaining to their potential therapeutic role in SLE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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15 pages, 674 KiB  
Review
Immune Profiling and Precision Medicine in Systemic Lupus Erythematosus
by Yasuo Nagafuchi, Hirofumi Shoda and Keishi Fujio
Cells 2019, 8(2), 140; https://doi.org/10.3390/cells8020140 - 10 Feb 2019
Cited by 32 | Viewed by 8047
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of clinical symptoms. Enormous progress has been made in the immunological and genetic understanding of SLE. However, the biology of disease heterogeneity in SLE has remained largely unexplored. Human immune profiling [...] Read more.
Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of clinical symptoms. Enormous progress has been made in the immunological and genetic understanding of SLE. However, the biology of disease heterogeneity in SLE has remained largely unexplored. Human immune profiling studies, helped by recent technological advances especially in single-cell and “omics” analyses, are now shedding light on the cellular and molecular basis of clinical symptoms and disease flares in individual patients. Peripheral blood immunophenotyping analysis with flow cytometry or mass cytometry are identifying responsible cell subsets and markers characteristic of disease heterogeneity. Transcriptome analysis is discovering molecular networks responsible for disease activity, disease subtype and future relapse. In this review, we summarize recent advances in the immune profiling analysis of SLE patients and discuss how they will be used for future precision medicine. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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7 pages, 1147 KiB  
Review
Epigenetically Altered T Cells Contribute to Lupus Flares
by Bruce Richardson
Cells 2019, 8(2), 127; https://doi.org/10.3390/cells8020127 - 05 Feb 2019
Cited by 13 | Viewed by 3256
Abstract
Lupus flares when genetically predisposed people encounter exogenous agents such as infections and sun exposure and drugs such as procainamide and hydralazine, but the mechanisms by which these agents trigger the flares has been unclear. Current evidence indicates that procainamide and hydralazine, as [...] Read more.
Lupus flares when genetically predisposed people encounter exogenous agents such as infections and sun exposure and drugs such as procainamide and hydralazine, but the mechanisms by which these agents trigger the flares has been unclear. Current evidence indicates that procainamide and hydralazine, as well as inflammation caused by the environmental agents, can cause overexpression of genes normally silenced by DNA methylation in CD4+ T cells, converting them into autoreactive, proinflammatory cytotoxic cells that are sufficient to cause lupus in mice, and similar cells are found in patients with active lupus. More recent studies demonstrate that these cells comprise a distinct CD4+ T cell subset, making it a therapeutic target for the treatment of lupus flares. Transcriptional analyses of this subset reveal proteins uniquely expressed by this subset, which may serve as therapeutic to deplete these cells, treating lupus flares. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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