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Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus

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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 April 2024 | Viewed by 9578

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Dr. Ioannis Parodis

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Department of Medicine Solna, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden
Interests: systemic lupus erythematosus; lupus nephritis; autoantibodies; biomarkers; B cells; outcome measures; treatment; biological therapies; health-related quality of life; patient-reported outcomes
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Prof. Dr. Christopher Sjöwall

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Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, SE-581 85 Linköping, Sweden
Interests: systemic lupus erythematosus; lupus nephritis; autoantibodies; biomarkers; type I interferons; pentraxins; complement; epidemiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The immense heterogeneity of the chronic, inflammatory, autoimmune disease systemic lupus erythematosus (SLE), both with regard to immunological aberrancies and clinical manifestations, poses diagnostic difficulties and challenges in the management of the patients. This is underlined by the lack of generally accepted diagnostic criteria and the numerous clinical trial failures. However, the treatment landscape has witnessed substantial changes during the last decade, facilitated by advances in technology and hence new knowledge on the pathophysiology of SLE.

SLE predominantly affects women during their fertile years of age. Early diagnosis and treatment initiation are important for the prevention of accumulated organ damage. The chronic nature of the disease and its varying course necessitate regular monitoring. The treatment of SLE mainly consists of antimalarial agents; glucocorticoids; non-biological, disease-modifying anti-rheumatic drugs; and, more recently, biological agents, including B-cell-targeted therapies and an agent against the type I interferon receptor. The recent approvals of new targeted therapies for SLE and lupus nephritis, one of the most severe clinical manifestations of SLE, and the increasing awareness of the long-term adverse effects of glucocorticoids, changed the focus of research towards the optimisation of therapeutic decision making, surveillance and treatment evaluations, and technological advances paved the way for a cellular and molecular characterisation of SLE to serve as a basis for disease management. In this regard, the identification of reliable biomarkers is imperative.

Historically, biomarker studies in SLE have focused on serum biomarkers. Nevertheless, urinary, cerebrospinal fluid and tissue biomarkers for organ-specific monitoring and prognostication gain increasing interest. This Special Issue welcomes original works and review articles that focus on the cellular and molecular mechanisms underlying SLE at its different phases, with the goal of contributing novel knowledge of the pathogenesis of SLE and improved diagnostics, surveillance, prevention of long-term damage, and overall patient management. Original works or review articles, which evaluate immune components that serve as diagnostic biomarkers, biomarkers of disease activity, or biomarkers of long-term outcomes are also welcomed.

Dr. Ioannis Parodis
Dr. Christopher Sjöwall
Guest Editors

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Published Papers (7 papers)

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17 pages, 3538 KiB

Open AccessArticle

Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus

by Irene Carrión-Barberà, Laura Triginer, Laura Tío, Carolina Pérez-García, Anna Ribes, Victoria Abad, Ana Pros, Marcelino Bermúdez-López, Eva Castro-Boqué, Albert Lecube, José Manuel Valdivielso, ILERVAS Project Group, Jordi Monfort and Tarek Carlos Salman-Monte

Int. J. Mol. Sci. 2024, 25(5), 3022; https://doi.org/10.3390/ijms25053022 - 05 Mar 2024

Viewed by 664

Abstract

Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients’ data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

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14 pages, 283 KiB

Open AccessArticle

Elevated Serum Levels of Soluble Transferrin Receptor Are Associated with an Increased Risk of Cardiovascular, Pulmonary, and Hematological Manifestations and a Decreased Risk of Neuropsychiatric Manifestations in Systemic Lupus Erythematosus Patients

by Agnieszka Winikajtis-Burzyńska, Marek Brzosko and Hanna Przepiera-Będzak

Int. J. Mol. Sci. 2023, 24(24), 17340; https://doi.org/10.3390/ijms242417340 - 11 Dec 2023

Viewed by 852

Abstract

The aim of this study was to analyze the relationship between the serum levels of soluble transferrin receptor (sTfR) and interleukin 4 (IL-4), and the disease activity and organ manifestations in SLE patients. We studied 200 SLE patients and 50 controls. We analyzed disease activity, organ involvement, serum sTfR, IL-4 and interleukin-6 (IL-6) levels, and antinuclear and antiphospholipid antibody profiles. The median serum levels of sTfR (p > 0.000001) and IL-4 (p < 0.00001) were higher in the study group than in the controls. SLE patients, compared to the controls, had significantly lower HGB levels (p < 0.0001), a lower iron concentration (p = 0.008), a lower value of total iron-binding capacity (TIBC) (p = 0.03), and lower counts of RBC (p = 0.004), HCT (p = 0.0004), PLT (p = 0.04), neutrophil (p = 0.04), and lymphocyte (p < 0.0001). Serum sTfR levels were negatively correlated with lymphocyte (p = 0.0005), HGB (p = 0.0001) and HCT (p = 0.008), and positively correlated with IL-4 (p = 0.01). Elevated serum sTfR > 2.14 mg/dL was associated with an increased risk of myocardial infarction (OR: 10.6 95 CI 2.71–464.78; p = 0.001), ischemic heart disease (OR: 3.25 95 CI 1.02–10.40; p = 0.04), lung manifestations (OR: 4.48 95 CI 1.44–13.94; p = 0.01), and hematological manifestations (OR: 2.07 95 CI 1.13–3.79; p = 0.01), and with a reduced risk of neuropsychiatric manifestations (OR: 0.42 95 CI 0.22–0.80; p = 0.008). Serum IL-4 was negatively correlated with CRP (p = 0.003), and elevated serum IL-4 levels > 0.17 mg/L were associated with a reduced risk of mucocutaneous manifestations (OR: 0.48 95 CI 0.26–0.90; p = 0.02). In SLE patients, elevated serum levels of sTfR were associated with an increased risk of cardiovascular, pulmonary, and hematological manifestations, and with a decreased risk of neuropsychiatric manifestations. In contrast, elevated serum IL-4 levels were associated with a decreased risk of mucocutaneous manifestations. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

21 pages, 3017 KiB

Open AccessArticle

Metabolic Markers and Association of Biological Sex in Lupus Nephritis

by Bethany Wolf, Calvin R. K. Blaschke, Sandy Mungaray, Bryan T. Weselman, Mariia Stefanenko, Mykhailo Fedoriuk, Hongxia Bai, Jessalyn Rodgers, Oleg Palygin, Richard R. Drake and Tamara K. Nowling

Int. J. Mol. Sci. 2023, 24(22), 16490; https://doi.org/10.3390/ijms242216490 - 18 Nov 2023

Viewed by 1052

Abstract

Lupus nephritis (LN) is a serious complication for many patients who develop systemic lupus erythematosus, which primarily afflicts women. Our studies to identify biomarkers and the pathogenic mechanisms underlying LN will provide a better understanding of disease progression and sex bias, and lead to identification of additional potential therapeutic targets. The glycosphingolipid lactosylceramide (LacCer) and N-linked glycosylated proteins (N-glycans) were measured in urine and serum collected from LN and healthy control (HC) subjects (10 females and 10 males in each group). The sera from the LN and HC subjects were used to stimulate cytokine secretion and intracellular Ca²⁺ flux in female- and male-derived primary human renal mesangial cells (hRMCs). Significant differences were observed in the urine of LN patients compared to HCs. All major LacCers species were significantly elevated and differences between LN and HC were more pronounced in males. 72 individual N-glycans were altered in LN compared to HC and three N-glycans were significantly different between the sexes. In hRMCs, Ca²⁺ flux, but not cytokine secretion, was higher in response to LN sera compared to HC sera. Ca²⁺ flux, cytokine secretion, and glycosphingolipid levels were significantly higher in female-derived compared to male-derived hRMCs. Relative abundance of some LacCers and hexosylceramides were higher in female-derived compared to male-derived hRMCs. Urine LacCers and N-glycome could serve as definitive LN biomarkers and likely reflect renal disease activity. Despite higher sensitivity of female hRMCs, males may experience greater increases in LacCers, which may underscore worse disease in males. Elevated glycosphingolipid metabolism may poise renal cells to be more sensitive to external stimuli. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

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14 pages, 308 KiB

Open AccessArticle

Relationship between Disease Characteristics and Circulating Interleukin 6 in a Well-Characterized Cohort of Patients with Systemic Lupus Erythematosus

by Julia Mercader-Salvans, María García-González, Fuensanta Gómez-Bernal, Juan C. Quevedo-Abeledo, Antonia de Vera-González, Alejandra González-Delgado, Raquel López-Mejías, Candelaria Martín-González, Miguel Á. González-Gay and Iván Ferraz-Amaro

Int. J. Mol. Sci. 2023, 24(18), 14006; https://doi.org/10.3390/ijms241814006 - 12 Sep 2023

Viewed by 910

Abstract

Interleukin-6 (IL-6) is a proinflammatory cytokine that mediates pleiotropic functions in immune responses and inflammatory diseases. The literature lacks studies, with a clinical perspective, on the relationship between IL-6 serum levels and the characteristics of the disease in patients with systemic lupus erythematosus (SLE). In the present work, we aimed to analyze the association between circulating IL-6 and disease manifestations in a well-characterized series of patients with SLE. Serum IL-6 levels and disease activity (SLEDAI-2K), severity (Katz) and damage index (SLICC-DI), complete lipid profile, and subclinical carotid atherosclerosis were evaluated in 284 patients with SLE. In addition, a complete characterization of the complement system was performed in samples from patients with SLE. A multivariate linear regression analysis was carried out to study the relationship between clinical and laboratory characteristics of the disease and IL-6 levels. Age (beta coef. 0.07 [95%CI 0.01–0.1] pg/mL, p = 0.014), C-reactive protein (beta coef. 0.21 [95%CI 0.16–0.25] pg/mL, p < 0.01), and male gender (beta coef. 2 [95%CI 0.3–0.5] pg/mL, p = 0.024), were positively associated with higher IL-6 levels in SLE patients. Most disease characteristics and damage and activity indices did not show significant relationships with IL-6. However, after multivariate analysis, IL-6 was associated with lower serum levels of HDL cholesterol (beta coef. −0.04 [95%CI −0.08–(−0.1)] pg/mL, p = 0.011), and apolipoprotein A1 (beta coef. −0.02 [95%CI −0.04–(−0.001)] pg/mL, p = 0.035). In contrast, the alternative complement cascade, C1inh, and C3a were all positively and independently associated with higher serum levels of IL-6. Moreover, stratification of the Systematic Coronary Risk Assessment 2 (SCORE2) results according to different categories of cardiovascular risk was associated with higher circulating serum IL-6 levels (beta coef. 0.2 [95%CI 0.02–0.4], pg/mL, p = 0.028). In conclusion, in a large series of SLE patients, IL-6 was not associated with disease-related features of SLE, including damage, severity, or activity indices. However, an association was found between serum IL-6 levels and circulating C3a and cardiovascular risk. Our study emphasizes the importance that IL-6 could have in cardiovascular disease and complement system disruption of SLE patients. Therapies targeting IL-6 could have a role in these two clinical manifestations of patients with SLE. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

12 pages, 1207 KiB

Open AccessArticle

Limited Association between Antibodies to Oxidized Low-Density Lipoprotein and Vascular Affection in Patients with Established Systemic Lupus Erythematosus

by Lina Wirestam, Frida Jönsson, Helena Enocsson, Christina Svensson, Maria Weiner, Jonas Wetterö, Helene Zachrisson, Per Eriksson and Christopher Sjöwall

Int. J. Mol. Sci. 2023, 24(10), 8987; https://doi.org/10.3390/ijms24108987 - 19 May 2023

Viewed by 1250

Abstract

Patients with systemic lupus erythematosus (SLE) are at an increased risk of cardiovascular disease. We aimed to evaluate whether antibodies to oxidized low-density lipoprotein (anti-oxLDL) were associated with subclinical atherosclerosis in patients with different SLE phenotypes (lupus nephritis, antiphospholipid syndrome, and skin and joint involvement). Anti-oxLDL was measured by enzyme-linked immunosorbent assay in 60 patients with SLE, 60 healthy controls (HCs) and 30 subjects with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Intima-media thickness (IMT) assessment of vessel walls and plaque occurrence were recorded using high-frequency ultrasound. In the SLE cohort, anti-oxLDL was again assessed in 57 of the 60 individuals approximately 3 years later. The levels of anti-oxLDL in the SLE group (median 5829 U/mL) were not significantly different from those in the HCs group (median 4568 U/mL), while patients with AAV showed significantly higher levels (median 7817 U/mL). The levels did not differ between the SLE subgroups. A significant correlation was found with IMT in the common femoral artery in the SLE cohort, but no association with plaque occurrence was observed. The levels of anti-oxLDL antibodies in the SLE group were significantly higher at inclusion compared to 3 years later (median 5707 versus 1503 U/mL, p < 0.0001). Overall, we found no convincing support for strong associations between vascular affection and anti-oxLDL antibodies in SLE. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

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17 pages, 914 KiB

Open AccessArticle

B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab

by Ioannis Parodis, Alvaro Gomez, Julius Lindblom, Jun Weng Chow, Christopher Sjöwall, Savino Sciascia and Mariele Gatto

Int. J. Mol. Sci. 2022, 23(22), 13941; https://doi.org/10.3390/ijms232213941 - 11 Nov 2022

Cited by 7 | Viewed by 1989

Abstract

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19⁺ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19⁺CD20⁺CD138⁺ short-lived plasma cells (−50.4% vs. −16.7%; p = 0.019) and CD19⁺CD20^-CD27^bright plasmablasts (−50.0% vs. −29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19⁺CD27^-CD24^brightCD38^bright transitional B cells (−42.9% vs. −75.0%; p = 0.038) and CD19⁺CD20^-CD138⁺ peripheral long-lived plasma cells (−11.3% vs. −29.2%; p = 0.019) were seen in belimumab-treated—but not placebo-treated—patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

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Review

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22 pages, 429 KiB

Open AccessReview

Lupus Nephritis Biomarkers: A Critical Review

by Fatima K. Alduraibi and George C. Tsokos

Int. J. Mol. Sci. 2024, 25(2), 805; https://doi.org/10.3390/ijms25020805 - 09 Jan 2024

Cited by 1 | Viewed by 1509

Abstract

Lupus nephritis (LN), a major complication in individuals diagnosed with systemic lupus erythematosus, substantially increases morbidity and mortality. Despite marked improvements in the survival of patients with severe LN over the past 50 years, complete clinical remission after immunosuppressive therapy is achieved in only half of the patients. Therefore, timely detection of LN is vital for initiating prompt therapeutic interventions and improving patient outcomes. Biomarkers have emerged as valuable tools for LN detection and monitoring; however, the complex role of these biomarkers in LN pathogenesis remains unclear. Renal biopsy remains the gold standard for the identification of the histological phenotypes of LN and guides disease management. However, the molecular pathophysiology of specific renal lesions remains poorly understood. In this review, we provide a critical, up-to-date overview of the latest developments in the field of LN biomarkers. Full article

(This article belongs to the Special Issue Immune Mechanisms and Biomarkers in Systemic Lupus Erythematosus)

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