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Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0
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Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 16889

Special Issue Editors

Prof. Dr. Marzena Olesińska

E-Mail Website
Guest Editor
Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland
Interests: rheumatology; internal diseases; systemic lupus erythematosus; arthritis; systemic sclerosis; dermatomyositis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Przemysław Kotyla

E-Mail Website
Guest Editor
Department of Internal Medicine, Rheumatology and Clinical Immunology, Faculty in Katowice, Medical University of Silesia, Katowice, Poland
Interests: systemic lupus erythematosus; rheumatic diseases; autoimmunity; clinical rheumatology; autoimmune disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Systemic lupus erythematosus (SLE) is a connective tissue disease that may serve as a prototype for almost all autoimmune diseases. Its diversity of clinical presentations and involvement in all vitally important internal organs is challenging for treating physicians. Moreover, despite the enormous progress in rheumatology and clinical immunology, the pathophysiological background of the disease is still not understood completely. From a clinical point of view, corticosteroids and immunosuppressants are still the gold standard for the treatment of SLE. The main reason for this is still the lack of new treatment strategies that are safe and efficacious for SLE. Therefore, understanding the SLE pathogenic background and disease-driving mechanisms will contribute to the development of novel therapeutic strategies.

SLE pathogenesis is complex and, obviously, none of the single pathological mechanisms might be responsible for all SLE presentations. Moreover, the existence of many pathological theories suggests quite convincingly that none of them are universal or explain the disease satisfactorily. In the course of SLE, several immunological phenomena may be observed, such as the loss of tolerance to self-antigens, autoreactive T- and B-cell activation, the synthesis of autoantibodies, and the activation of interferon. In recent years, advances in immunology have translated to the identification of several molecular and cellular targets, the modulation of which may exert therapeutic potential in the disease.

This Special Issue is designed as a platform to provide recent research advantages that focus on understanding the immuno-pathological mechanisms, biomarkers, and novel therapeutic strategies in SLE. Both review and research papers are welcomed. Please note that pure clinical or model studies are unsuitable for this journal, but clinical submissions with biomolecular studies are welcome. Topics include, but are not limited to, the following:

  • The genetic background of SLE;
  • The epigenetic regulation of lupus;
  • Cellular and molecular mechanisms in lupus;
  • The role of cytokine networks in lupus progression;
  • Innate and adaptive immunity in SLE;
  • The role of immunocompetent cells in lupus pathogenesis and disease mechanisms;
  • The role of interferon and interferon signature in lupus pathogenesis;
  • Novel lupus biomarkers in SLE diagnosis and monitoring disease activity;
  • Novel therapeutics and new treatment strategies for lupus.

Prof. Dr. Marzena Olesińska
Prof. Dr. Przemysław Kotyla
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • systemic lupus erythematosus
  • SLE pathogenesis
  • the epigenetic regulation of lupus
  • the genetic background of SLE
  • interferon
  • cytokine networks
  • innate immunity
  • adaptive immunity

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Published Papers (7 papers)

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Research

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14 pages, 1495 KiB  
Article
B-Cell Maturation Antigen (BCMA) as a Biomarker and Potential Treatment Target in Systemic Lupus Erythematosus
by Jonas Martin, Qingyu Cheng, Sarah A. Laurent, Franziska S. Thaler, Anne Elisabeth Beenken, Edgar Meinl, Gerhard Krönke, Falk Hiepe and Tobias Alexander
Int. J. Mol. Sci. 2024, 25(19), 10845; https://doi.org/10.3390/ijms251910845 - 9 Oct 2024
Viewed by 1274
Abstract
The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, [...] Read more.
The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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18 pages, 2896 KiB  
Article
Dynamics of CD4+ and CD8+ Lymphocytic Inflammatory Infiltrates in Lupus Nephritis
by Tudor Azoicăi, Elena-Roxana Avădănei, Simona-Eliza Giusca, Mihai Onofriescu, Adrian C. Covic, Cristina Gena Dascalu and Irina-Draga Căruntu
Int. J. Mol. Sci. 2024, 25(19), 10775; https://doi.org/10.3390/ijms251910775 - 7 Oct 2024
Viewed by 2584
Abstract
Lupus nephritis (LN) is a common clinical manifestation of systemic lupus erythematosus (SLE). Our study aims to quantitatively analyze CD4+ and CD8+ lymphocytes in different areas and LN classes and describe a specific distribution pattern that is correlated with the severity of LN-specific [...] Read more.
Lupus nephritis (LN) is a common clinical manifestation of systemic lupus erythematosus (SLE). Our study aims to quantitatively analyze CD4+ and CD8+ lymphocytes in different areas and LN classes and describe a specific distribution pattern that is correlated with the severity of LN-specific lesions. In total, 53 LN renal biopsies were immunohistochemically investigated using anti-CD4 and anti-CD8 antibodies. T lymphocytes were counted in 3 areas, including intraglomerular, periglomerular, and interstitial regions. The severity of glomerular and tubulo-interstitial lesions was assessed using an original semi-quantitative algorithm based on the renal corpuscle score (RC_S) and the tubulo-interstitial score (TI_S). The number of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes in each of the three areas and in each LN class, showing statistically significant differences. ANOVA analysis of all LN classes showed significant differences between periglomerular and interstitial CD4+ and CD8+ T lymphocytes, respectively. Irrespective of location, the number of CD8+ T lymphocytes statistically correlates with the RC_S and the TI_S; no significant correlations were found between the number of CD4+ T lymphocytes and the RC_S and the TI_S for all three considered areas. Our data provide strong evidence supporting the major role of CD8+ lymphocytes in LN lesion progression, with CD4+ lymphocytes playing a limited role. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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11 pages, 249 KiB  
Article
The Impact of the IL-10 Gene Polymorphism on mRNA Expression and IL-10 Serum Concentration in Polish Lupus Patients
by Agnieszka Żak-Gołąb, Paweł Cieślik, Urszula Siekiera, Dariusz Kuśmierz, Antoni Hrycek and Michał Holecki
Int. J. Mol. Sci. 2024, 25(10), 5511; https://doi.org/10.3390/ijms25105511 - 18 May 2024
Viewed by 945
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies against a lot of nuclear components. Despite many studies on the genetic background of this disease, the pathogenesis remains unclear. The aim of the study is to comprehensively [...] Read more.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies against a lot of nuclear components. Despite many studies on the genetic background of this disease, the pathogenesis remains unclear. The aim of the study is to comprehensively evaluate the polymorphism of the IL-10 promoter gene, its mRNA expression, and the serum IL-10 concentration of SLE female patients and females age-matched controls. Analyzing the association between the level of the tested cytokine and the polymorphism genotype-1082; -819; -592, we found statistically higher serum IL-10 levels in SLE patients compared to in healthy controls (11.9 ± 2.2 pg/mL vs. 9.4 ± 1.7 pg/mL, accordingly; p < 0.0001). We did not find statistically significant differences in the gene polymorphism of IL-10 among SLE patients and controls. The most significant observation derived from our study is that IL-10 mRNA transcripts are upregulated in SLE patients compared to in healthy controls (p < 0.0001). According to our results, the presence of the IL-10 genetic polymorphism has no clinical significance for the development of SLE, and subsequent differences in mRNA and IL-10 concentration results from the influence of other factors which should be the subject of further research. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
19 pages, 5086 KiB  
Article
Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells
by Cristina Solé, Maria Royo, Sebastian Sandoval, Teresa Moliné, Alejandra Gabaldón and Josefina Cortés-Hernández
Int. J. Mol. Sci. 2024, 25(8), 4226; https://doi.org/10.3390/ijms25084226 - 11 Apr 2024
Cited by 2 | Viewed by 2013
Abstract
Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the [...] Read more.
Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell–cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA+ B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA+ B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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Review

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46 pages, 3756 KiB  
Review
Lupus Nephritis from Pathogenesis to New Therapies: An Update
by Annalisa Roveta, Emanuele Luigi Parodi, Brigida Brezzi, Francesca Tunesi, Valentina Zanetti, Guido Merlotti, Alessia Francese, Antonio G. Maconi and Marco Quaglia
Int. J. Mol. Sci. 2024, 25(16), 8981; https://doi.org/10.3390/ijms25168981 - 18 Aug 2024
Viewed by 4190
Abstract
Lupus Nephritis (LN) still represents one of the most severe complications of Systemic Lupus Erythematosus (SLE) and a major risk factor for morbidity and mortality. However, over the last few years, several studies have paved the way for a deeper understanding of its [...] Read more.
Lupus Nephritis (LN) still represents one of the most severe complications of Systemic Lupus Erythematosus (SLE) and a major risk factor for morbidity and mortality. However, over the last few years, several studies have paved the way for a deeper understanding of its pathogenetic mechanisms and more targeted treatments. This review aims to provide a comprehensive update on progress on several key aspects in this setting: pathogenetic mechanisms of LN, including new insight into the role of autoantibodies, complement, vitamin D deficiency, and interaction between infiltrating immune cells and kidney resident ones; the evolving role of renal biopsy and biomarkers, which may integrate information from renal histology; newly approved drugs such as voclosporin (VOC) and belimumab (BEL), allowing a more articulate strategy for induction therapy, and other promising phase III-immunosuppressive (IS) agents in the pipeline. Several adjunctive treatments aimed at reducing cardiovascular risk and progression of chronic renal damage, such as antiproteinuric agents, represent an important complement to IS therapy. Furthermore, non-pharmacological measures concerning general lifestyle and diet should also be adopted when managing LN. Integrating these therapeutic areas requires an effort towards a holistic and multidisciplinary approach. At the same time, the availability of an increasingly wider armamentarium may translate into improvements in patient’s renal outcomes over the next decades. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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22 pages, 943 KiB  
Review
Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus
by Han-Rong Weng
Int. J. Mol. Sci. 2024, 25(7), 3602; https://doi.org/10.3390/ijms25073602 - 22 Mar 2024
Viewed by 1906
Abstract
Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to [...] Read more.
Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (MRL/lpr lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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25 pages, 1595 KiB  
Review
Potential Therapeutic Application and Mechanism of Action of Stem Cell-Derived Extracellular Vesicles (EVs) in Systemic Lupus Erythematosus (SLE)
by Sushmitha Rajeev Kumar, Rajalingham Sakthiswary and Yogeswaran Lokanathan
Int. J. Mol. Sci. 2024, 25(4), 2444; https://doi.org/10.3390/ijms25042444 - 19 Feb 2024
Cited by 2 | Viewed by 2781
Abstract
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping [...] Read more.
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping review aims to highlight the latest research findings on the therapeutic mechanisms of action of EVs in SLE. Relevant research articles were identified using the PRISMA framework from databases such as PubMed/MEDLINE (National Library of Medicine), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) from July 2023 to October 2023. Eleven studies met the inclusion criteria and thus were included in this scoping review. The findings showed that EVs have therapeutic effects on ameliorating the disease progression of SLE. EVs can reduce the pro-inflammatory cytokines and increase the anti-inflammatory cytokines. Moreover, EVs can increase the levels of regulatory T cells, thus reducing inflammation. EVs also have the potential to regulate B cells to alleviate SLE and reduce its adverse effects. The scoping review has successfully analysed the therapeutic potential in ameliorating the disease progression of SLE. The review also includes prospects to improve the effects of EVs further to increase the therapeutic effects on SLE. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus 2.0)
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