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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) | Viewed by 64595

Special Issue Editors


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Guest Editor
Division of Rheumatology and Clinical Immunology, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
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
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Division of Rheumatology and Clinical Immunology, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Interests: C-type lectin receptors immunobiology and its role in autoimmune diseases and infection; cellular and molecular dysregulation in SLE; immuno-therapeutics development
Special Issues, Collections and Topics in MDPI journals

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

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Keywords

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

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Published Papers (10 papers)

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Research

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16 pages, 3977 KiB  
Article
Immune Complexes Impaired Glomerular Endothelial Cell Functions in Lupus Nephritis
by Linlin Wang and Helen Ka Wai Law
Int. J. Mol. Sci. 2019, 20(21), 5281; https://doi.org/10.3390/ijms20215281 - 24 Oct 2019
Cited by 10 | Viewed by 2721
Abstract
Lupus nephritis (LN) is one of the most common and severe complications of lupus. However, the mechanisms for renal damage have not been well elucidated. There are evidences show that glomerular endothelial cells (GECs) are damaged in LN. Immune complexes can deposit in [...] Read more.
Lupus nephritis (LN) is one of the most common and severe complications of lupus. However, the mechanisms for renal damage have not been well elucidated. There are evidences show that glomerular endothelial cells (GECs) are damaged in LN. Immune complexes can deposit in subendothelial area and could affect GEC functions. In the present study, we used heat-aggregated gamma globulin (HAGG) to simulate immune complexes and investigated their effects on GEC functions. Our results revealed that HAGG impaired different aspect of the GEC functions. HAGG changed cell morphology, upregulated the expression of active caspase-3, inhibited angiogenesis, and increased NO production in GECs. These results provide new clues for the mechanisms of renal damage and the pathology of LN. Full article
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18 pages, 2180 KiB  
Article
Heightened TLR7/9-Induced IL-10 and CXCL13 Production with Dysregulated NF-ҝB Activation in CD11chiCD11b+ Dendritic Cells in NZB/W F1 Mice
by Lok Yan Yim, Chak Sing Lau and Vera Sau-Fong Chan
Int. J. Mol. Sci. 2019, 20(18), 4639; https://doi.org/10.3390/ijms20184639 - 19 Sep 2019
Cited by 7 | Viewed by 4427
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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19 pages, 2675 KiB  
Article
Urinary Neuropilin-1: A Predictive Biomarker for Renal Outcome in Lupus Nephritis
by Maria Teresa Torres-Salido, Mireia Sanchis, Cristina Solé, Teresa Moliné, Marta Vidal, Xavier Vidal, Anna Solà, Georgina Hotter, Josep Ordi-Ros and Josefina Cortés-Hernández
Int. J. Mol. Sci. 2019, 20(18), 4601; https://doi.org/10.3390/ijms20184601 - 17 Sep 2019
Cited by 22 | Viewed by 3970
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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12 pages, 5487 KiB  
Article
BTLA Expression on Th1, Th2 and Th17 Effector T-Cells of Patients with Systemic Lupus Erythematosus Is Associated with Active Disease
by Christoph Oster, Benjamin Wilde, Christof Specker, Ming Sun, Andreas Kribben, Oliver Witzke and Sebastian Dolff
Int. J. Mol. Sci. 2019, 20(18), 4505; https://doi.org/10.3390/ijms20184505 - 11 Sep 2019
Cited by 30 | Viewed by 4585
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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16 pages, 2865 KiB  
Article
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
by Thunnicha Ondee, Thiranut Jaroonwitchawan, Trairak Pisitkun, Joseph Gillen, Aleksandra Nita-Lazar, Asada Leelahavanichkul and Poorichaya Somparn
Int. J. Mol. Sci. 2019, 20(6), 1354; https://doi.org/10.3390/ijms20061354 - 18 Mar 2019
Cited by 25 | Viewed by 4356
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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18 pages, 867 KiB  
Review
B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments
by Desmond Y. H. Yap and Tak Mao Chan
Int. J. Mol. Sci. 2019, 20(24), 6231; https://doi.org/10.3390/ijms20246231 - 10 Dec 2019
Cited by 111 | Viewed by 9898
Abstract
Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell [...] Read more.
Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell–T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell–T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients. Full article
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19 pages, 1837 KiB  
Review
Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus
by Kongyang Ma, Wenhan Du, Xiaohui Wang, Shiwen Yuan, Xiaoyan Cai, Dongzhou Liu, Jingyi Li and Liwei Lu
Int. J. Mol. Sci. 2019, 20(23), 6021; https://doi.org/10.3390/ijms20236021 - 29 Nov 2019
Cited by 66 | Viewed by 10484
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of [...] Read more.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE. Full article
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14 pages, 802 KiB  
Review
Interferon-Inducible Protein 10 and Disease Activity in Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-Analysis
by Pongpratch Puapatanakul, Sonchai Chansritrakul, Paweena Susantitaphong, Thornthun Ueaphongsukkit, Somchai Eiam-Ong, Kearkiat Praditpornsilpa, Wonngarm Kittanamongkolchai and Yingyos Avihingsanon
Int. J. Mol. Sci. 2019, 20(19), 4954; https://doi.org/10.3390/ijms20194954 - 8 Oct 2019
Cited by 29 | Viewed by 7863
Abstract
There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the [...] Read more.
There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the end of December 2017. All studies that compared serum and/or urine IP-10 between active SLE/LN patients and any control groups were identified and included in this systematic review and meta-analysis. The mean difference (MD) of IP-10 level among active SLE and LN patients, as well as the correlation of IP-10 with disease activity, were meta-analyzed using a random-effects model. From 23 eligible studies, 15 provided adequate data for meta-analysis. Serum IP-10 was significantly elevated in patients with active SLE compared to non-active SLE patients (MD 356.5 pg/mL, 95% CI 59.6 to 653.4, p = 0.019). On the other hand, the levels of serum IP-10 was not different between active LN and non-active LN. However, serum IP-10 was positively correlated with disease activity like SLE disease activity index (SLEDAI) (pooled r = 0.29, 95% CI 0.22 to 0.35, p < 0.001). Furthermore, urine IP-10 tended to be higher in patients with active LN compared to non-active LN patients but this did not reach statistical significance (MD 3.47 pg/mgCr × 100, 95% CI −0.18 to 7.12, p = 0.06). Nevertheless, urine IP-10 was positively correlated with renal SLEDAI (pooled r = 0.29, 95% CI 0.05 to 0.50, p = 0.019). In conclusion, serum and urine IP-10 levels may be useful in monitoring the disease activity of SLE and LN. Serum IP-10 was correlated with systemic disease whereas urine IP-10 was a useful biomarker for detecting active LN. Full article
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13 pages, 510 KiB  
Review
Recent Advances in Our Understanding of the Link between the Intestinal Microbiota and Systemic Lupus Erythematosus
by Ji-Won Kim, Seung-Ki Kwok, Jung-Yoon Choe and Sung-Hwan Park
Int. J. Mol. Sci. 2019, 20(19), 4871; https://doi.org/10.3390/ijms20194871 - 30 Sep 2019
Cited by 75 | Viewed by 9277
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease featuring enhanced expression of type I interferon (IFN) and autoantibody production triggering inflammation of, and damage to, multiple organs. Continuing research efforts focus on how gut microbes trigger systemic autoimmunity and SLE. The gut microbial [...] Read more.
Systemic lupus erythematosus (SLE) is an autoimmune disease featuring enhanced expression of type I interferon (IFN) and autoantibody production triggering inflammation of, and damage to, multiple organs. Continuing research efforts focus on how gut microbes trigger systemic autoimmunity and SLE. The gut microbial communities of mice and humans with lupus have been investigated via high-throughput sequencing. The Firmicutes-to-Bacteroidetes ratio is consistently reduced in SLE patients, regardless of ethnicity. The relative abundance of Lactobacillus differs from the animal model used (MRL/lpr mice or NZB/W F1 mice). This may indicate that interactions between gut microbes and the host, rather than the enrichment of certain gut microbes, are especially significant in terms of SLE development. Enterococcus gallinarum and Lactobacillus reuteri, both of which are possible gut pathobionts, become translocated into systemic tissue if the gut epithelial barrier is impaired. The microbes then interact with the host immune systems, activating the type I IFN pathway and inducing autoantibody production. In addition, molecular mimicry may critically link the gut microbiome to SLE. Gut commensals of SLE patients share protein epitopes with the Ro60 autoantigen. Ruminococcus gnavus strain cross-reacted with native DNA, triggering an anti-double-stranded DNA antibody response. Expansion of R. gnavus in SLE patients paralleled an increase in disease activity and lupus nephritis. Such insights into the link between the gut microbiota and SLE enhance our understanding of SLE pathogenesis and will identify biomarkers predicting active disease. Full article
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20 pages, 1924 KiB  
Review
Molecular and Cellular Bases of Immunosenescence, Inflammation, and Cardiovascular Complications Mimicking “Inflammaging” in Patients with Systemic Lupus Erythematosus
by Chang-Youh Tsai, Chieh-Yu Shen, Hsien-Tzung Liao, Ko-Jen Li, Hui-Ting Lee, Cheng-Shiun Lu, Cheng-Han Wu, Yu-Min Kuo, Song-Chou Hsieh and Chia-Li Yu
Int. J. Mol. Sci. 2019, 20(16), 3878; https://doi.org/10.3390/ijms20163878 - 9 Aug 2019
Cited by 32 | Viewed by 5898
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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