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

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: closed (30 April 2023) | Viewed by 26393

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 which 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, in spite of 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 and explains the disease satisfactorily. In the course of SLE, several immunological phenomena may be observed as the loss of tolerance to self-antigens, autoreactive T- and B-cell activation, the synthesis of autoantibodies, and the activation of interferon. In the last years, advances in immunology 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 Olesiñska
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 (8 papers)

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Editorial

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3 pages, 190 KiB  
Editorial
Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus
by Przemysław Kotyla and Marzena Olesińska
Int. J. Mol. Sci. 2023, 24(11), 9470; https://doi.org/10.3390/ijms24119470 - 30 May 2023
Cited by 2 | Viewed by 1318
Abstract
Systemic lupus erythematosus is a chronic connective tissue disease of unknown origin and unpredictable course [...] Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)

Research

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9 pages, 873 KiB  
Article
Lack of Effect of Cenerimod, a Selective S1P1 Receptor Modulator, on the Pharmacokinetics of a Combined Oral Contraceptive
by Pierre-Eric Juif, Markus S. Mueller, Hakim Charfi and Jasper Dingemanse
Int. J. Mol. Sci. 2022, 23(23), 14986; https://doi.org/10.3390/ijms232314986 - 29 Nov 2022
Cited by 1 | Viewed by 2507
Abstract
Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 [...] Read more.
Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10–25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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15 pages, 2567 KiB  
Article
Cathepsin S Inhibition Suppresses Experimental Systemic Lupus Erythematosus-Associated Pulmonary Arterial Remodeling
by Tzung-Hai Yen, Wan-Jing Ho, Yung-Hsin Yeh and Ying-Ju Lai
Int. J. Mol. Sci. 2022, 23(20), 12316; https://doi.org/10.3390/ijms232012316 - 14 Oct 2022
Cited by 2 | Viewed by 2170
Abstract
Patients with systemic lupus erythematosus (SLE) associated with pulmonary arterial hypnertension (PAH) receive targeted therapy for PAH to decrease pulmonary arterial systolic pressure and significantly prolong their survival. Cysteine cathepsin proteases play critical roles in the progression of cardiovascular disease. Inhibition of cathepsin [...] Read more.
Patients with systemic lupus erythematosus (SLE) associated with pulmonary arterial hypnertension (PAH) receive targeted therapy for PAH to decrease pulmonary arterial systolic pressure and significantly prolong their survival. Cysteine cathepsin proteases play critical roles in the progression of cardiovascular disease. Inhibition of cathepsin S (Cat S) has been shown to improve SLE and lupus nephritis. However, the effect of Cat S inhibitors on SLE-associated PAH (SLE-PAH) remains unclear, and there is no animal model for translational research on SLE-PAH. We hypothesized that the inhibition of Cat S may affect PAH development and arterial remodeling associated with SLE. A female animal model of SLE-PAH, female MRL/lpr (Lupus), was used to evaluate the role of pulmonary arterial remodeling in SLE. The key finding of the research work is the establishment of an animal model of SLE associated with PAH in female MRL/lpr mice that is able to evaluate pulmonary arterial remodeling starting from the age of 11 weeks to 15 weeks. Cat S protein level was identified as a marker of experimental SLE. Pulmonary hypertension in female MRL/lpr (Lupus) mice was treated by administering the selective Cat S inhibitor Millipore-219393, which stimulated peroxisome proliferator-activated receptor-gamma (PPARγ) in the lungs to inhibit Cat S expression and pulmonary arterial remodeling. Studies provide an animal model of female MRL/lpr (Lupus) associated with PAH and a deeper understanding of the pathogenesis of SLE-PAH. The results may define the role of cathepsin S in preventing progressive and fatal SLE-PAH and provide approaches for therapeutic interventions in SLE-PAH. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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20 pages, 2474 KiB  
Article
Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R
by Krisztina Szabó, Ilona Jámbor, Kitti Pázmándi, Nikolett Nagy, Gábor Papp and Tünde Tarr
Int. J. Mol. Sci. 2022, 23(20), 12209; https://doi.org/10.3390/ijms232012209 - 13 Oct 2022
Cited by 8 | Viewed by 2225
Abstract
Systemic lupus erythematosus (SLE) is characterized by the breakdown of self-tolerance, the production of high-affinity pathogenic autoantibodies and derailed B cell responses, which indicates the importance of central players, such as follicular T helper (TFH) subsets and follicular T regulatory (T [...] Read more.
Systemic lupus erythematosus (SLE) is characterized by the breakdown of self-tolerance, the production of high-affinity pathogenic autoantibodies and derailed B cell responses, which indicates the importance of central players, such as follicular T helper (TFH) subsets and follicular T regulatory (TFR) cells, in the pathomechanism of the disease. In this study, we aimed to analyze the distribution of the circulating counterparts of these cells and their association with disease characteristics and B cell disproportions in SLE. We found that the increased percentage of activated circulating TFH (cTFH) and cTFR cells was more pronounced in cutaneous lupus; however, among cTFH subsets, the frequency of cTFH17 cells was decreased in patients with lupus nephritis. Furthermore, the decreased proportion of cTFH17 cells was associated with low complement C4 levels and high disease activity scores. We also investigated whether the blocking of the IL-21 receptor (IL-21R) with an anti-IL-21R monoclonal antibody inhibits the B cell response, since IL-21 primarily produced by TFH cells potentially promotes humoral immunity. We observed that anti-IL-21R inhibited plasmablast generation and immunoglobulin production. Our study demonstrated that, besides cTFR/cTFH imbalance, cTFH17 cells play a crucial role in SLE pathogenesis, and modulating cTFH-B cell interaction through the IL-21/IL-21R pathway may be a promising therapeutic strategy to suppress the pathological B cell response. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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17 pages, 4168 KiB  
Article
Impact of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Rheumatic Disease Patients on T Helper Cell Differentiation
by Ewa Kuca-Warnawin, Magdalena Plebańczyk, Marzena Ciechomska, Marzena Olesińska, Piotr Szczęsny and Ewa Kontny
Int. J. Mol. Sci. 2022, 23(10), 5317; https://doi.org/10.3390/ijms23105317 - 10 May 2022
Cited by 5 | Viewed by 2585
Abstract
Complex pathogenesis of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is associated with an imbalance of various Th-cell subpopulations. Mesenchymal stem cells (MSCs) have the ability to restore this balance. However, bone marrow-derived MSCs of SLE and SSc patients exhibit many abnormalities, [...] Read more.
Complex pathogenesis of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is associated with an imbalance of various Th-cell subpopulations. Mesenchymal stem cells (MSCs) have the ability to restore this balance. However, bone marrow-derived MSCs of SLE and SSc patients exhibit many abnormalities, whereas the properties of adipose derived mesenchymal stem cells (ASCS) are much less known. Therefore, we examined the effect of ASCs obtained from SLE (SLE/ASCs) and SSc (SSc/ASCs) patients on Th subset differentiation, using cells from healthy donors (HD/ASCs) as controls. ASCs were co-cultured with activated CD4+ T cells or peripheral blood mononuclear cells. Expression of transcription factors defining Th1, Th2, Th17, and regulatory T cell (Tregs) subsets, i.e., T-bet, GATA3, RORc, and FoxP3, were analysed by quantitative RT-PCR, the concentrations of subset-specific cytokines were measured by ELISA, and Tregs formation by flow cytometry. Compared with HD/ASCs, SLE/ASCs and especially SSc/ASCs triggered Th differentiation which was disturbed at the transcription levels of genes encoding Th1- and Tregs-related transcription factors. However, we failed to find functional consequences of this abnormality, because all tested ASCs similarly switched differentiation from Th1 to Th2 direction with accompanying IFNγ/IL-4 ratio decrease, up-regulated Th17 formation and IL-17 secretion, and up-regulated classical Tregs generation. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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Review

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33 pages, 4068 KiB  
Review
Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis
by Chang-Youh Tsai, Ko-Jen Li, Chieh-Yu Shen, Cheng-Hsun Lu, Hui-Ting Lee, Tsai-Hung Wu, Yee-Yung Ng, Yen-Po Tsao, Song-Chou Hsieh and Chia-Li Yu
Int. J. Mol. Sci. 2023, 24(12), 10066; https://doi.org/10.3390/ijms241210066 - 13 Jun 2023
Cited by 11 | Viewed by 3172
Abstract
Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA–anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause [...] Read more.
Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA–anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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16 pages, 790 KiB  
Review
Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies
by Barbara Infante, Silvia Mercuri, Andrea Dello Strologo, Rossana Franzin, Valeria Catalano, Dario Troise, Emanuela Cataldo, Paola Pontrelli, Carlo Alfieri, Valentina Binda, Giulia Frontini, Giuseppe Stefano Netti, Elena Ranieri, Loreto Gesualdo, Giuseppe Castellano and Giovanni Stallone
Int. J. Mol. Sci. 2022, 23(24), 15998; https://doi.org/10.3390/ijms232415998 - 15 Dec 2022
Cited by 7 | Viewed by 3160
Abstract
Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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17 pages, 1633 KiB  
Review
Understanding Ocular Findings and Manifestations of Systemic Lupus Erythematosus: Update Review of the Literature
by Wojciech Luboń, Małgorzata Luboń, Przemysław Kotyla and Ewa Mrukwa-Kominek
Int. J. Mol. Sci. 2022, 23(20), 12264; https://doi.org/10.3390/ijms232012264 - 14 Oct 2022
Cited by 17 | Viewed by 8143
Abstract
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease. Up to one-third of patients suffering from SLE have various ocular manifestations. The ocular findings may represent the initial manifestation of the systemic disease and may lead to severe ocular complications, and even [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease. Up to one-third of patients suffering from SLE have various ocular manifestations. The ocular findings may represent the initial manifestation of the systemic disease and may lead to severe ocular complications, and even loss of vision. Ocular manifestations are often associated with degree of systemic inflammation, but also can precede the occurrence of systemic symptoms. Early diagnosis and adequate management of patients with SLE are crucial and require cooperation between various specialists. Proper preparation of ophthalmologists can help to differentiate between complication of SLE and other ocular disorders. New therapies for SLE are promising for potential benefits, however, ocular side effects are still unknown. Full article
(This article belongs to the Special Issue Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus)
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