Environment and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and a relapsing-remitting course. SLE pathogenesis is the result of complex interactions between ethnic, genetic, epigenetic, immunoregulatory, hormonal and environmental factors, and several aspects of these multifactorial connections are still unclear. Overall, for the disease development, an environmental trigger may induce immunological dysfunction in genetically predisposed individuals. This review aims to summarise the most relevant data on the impact of environmental factors on the incidence of SLE and on disease activity and damage in patients with an established diagnosis of SLE.

Comparative single-cell multiplex immunophenotyping of therapy-naive patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus shed light on disease-specific composition of the peripheral immune system.

Introduction: Systemic autoimmune diseases (SADs) are a significant burden on the healthcare system. Understanding the complexity of the peripheral immunophenotype in SADs may facilitate the differential diagnosis and identification of potential therapeutic targets. Methods: Single-cell mass cytometric immunophenotyping was performed on peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and therapy-naive patients with rheumatoid arthritis (RA), progressive systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). Immunophenotyping was performed on 15,387,165 CD45+ live single cells from 52 participants (13 cases/group), using an antibody panel to detect 34 markers. Results: Using the t-SNE (t-distributed stochastic neighbor embedding) algorithm, the following 17 main immune cell types were determined: CD4+/CD57- T cells, CD4+/CD57+ T cells, CD8+/CD161- T cells, CD8+/CD161+/CD28+ T cells, CD8dim T cells, CD3+/CD4-/CD8- T cells, TCRγ/δ T cells, CD4+ NKT cells, CD8+ NKT cells, classic NK cells, CD56dim/CD98dim cells, B cells, plasmablasts, monocytes, CD11cdim/CD172dim cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Seven of the 17 main cell types exhibited statistically significant frequencies in the investigated groups. The expression levels of the 34 markers in the main populations were compared between HCs and SADs. In summary, 59 scatter plots showed significant differences in the expression intensities between at least two groups. Next, each immune cell population was divided into subpopulations (metaclusters) using the FlowSOM (self-organizing map) algorithm. Finally, 121 metaclusters (MCs) of the 10 main immune cell populations were found to have significant differences to classify diseases. The single-cell T-cell heterogeneity represented 64MCs based on the expression of 34 markers, and the frequency of 23 MCs differed significantly between at least twoconditions. The CD3- non-T-cell compartment contained 57 MCs with 17 MCs differentiating at least two investigated groups. In summary, we are the first to demonstrate the complexity of the immunophenotype of 34 markers over 15 million single cells in HCs vs. therapy-naive patients with RA, SSc, and SLE. Disease specific population frequencies or expression patterns of peripheral immune cells provide a single-cell data resource to the scientific community.

Prevalence of thyroid dysfunctions and thyroid autoantibodies in Thai patients with systemic lupus erythematosus: An age- and sex-matched controlled study.

BACKGROUND/OBJECTIVE: To determine the prevalence of thyroid dysfunctions and thyroid autoantibodies in Thai systemic lupus erythematosus (SLE) patients, and compare them with age- and sex-matched healthy controls (HCs). Associations between thyroid dysfunctions and SLE disease activity, and associated factors for thyroid dysfunctions in SLE also were determined. METHOD: One hundred SLE patients, without apparent clinical thyroid disease, attended the Rheumatology Clinic between November 2021 and October 2022, were enrolled into this study. HCs were matched to SLE cases by age and sex (ratio of 1:1). Clinical manifestations, SLE disease activity and medication received were collected in all SLE patients. Thyroid function tests and thyroid autoantibodies (anti-thyroglobulin: anti-TG and anti-thyroid peroxidase: anti-TPO) were collected from all participants. RESULTS: When compared with HCs, SLE patients had higher prevalence of thyroid dysfunctions, hypothyroidism and euthyroid sick syndrome (28% vs. 7%, p < .001, and 12% vs. 2%, p = .010, and 6% vs. 0%, p = .013, respectively). Prevalence of isolated hypothyroxinemia was higher numerically in SLE patients (9% vs. 3%, p = .074). Prevalence of anti-TG or anti-TPO was no different between SLE patients and HCs (16% vs. 18%, p = .707). There was no association between SLE disease activity and abnormal thyroid functions or thyroid autoantibodies. Family history of thyroid disease and prednisolone use (>10 mg/day) were associated factors for thyroid abnormalities with adjusted OR (95% CI) of 6.13 (1.58-23.75), p = .009 and 4.00 (1.37-11.70), p = .011, respectively. CONCLUSION: Thyroid dysfunctions were more prevalent in SLE patients. Family history of thyroid disease and prednisolone use (>10 mg/day) were independent associated factors of thyroid abnormalities.

Clinical and Immunological Profile of Systemic Lupus Erythematosus: A 5-year Retrospective Analysis from Northeast India.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with a wide range of clinical manifestations having considerable variation in clinical features that are influenced by ethnic, sociocultural, and geographical factors. This disease primarily affects young women aged between 18 and 35 years. The aim of this present study was to delineate the clinical manifestations and immunological patterns of SLE patients from the Northeastern (NE) region of India. MATERIALS AND METHODS: The study was carried out in a tertiary care hospital from January 2016 to January 2021. Adult patients of age >18 years fulfilling systemic lupus international collaborating clinic criteria (SLICC) for classification of SLE were included in this study. Immunology such as antinuclear antibodies (ANA) and double-stranded deoxyribonucleic acid (dsDNA) were also performed followed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Over a period of 5 years, 142 patients were recruited for the study, with an overall female-to-male ratio was 9.9:1, a median age at onset of 25 years (interquartile range age 21-32 years) and a mean disease duration was 15.25 months (range 2-60 months). Our study revealed that ANA was positive in 97.18% of patients while anti-dsDNA was positive in 78.68%, indicating that women from this region have higher positivity rates. CONCLUSION: Our findings support the notion that SLE is a multisystem disorder that predominantly affects young females, especially during the second and third decades of life. Hematological, mucocutaneous, and renal manifestations are common in our patients. Moreover, pulmonary, cardiovascular, and gastrointestinal (GI) manifestations were understudied in other cohorts, which is one of our study's strengths.

Identification of immune subsets with distinct lectin binding signatures using multi-parameter flow cytometry: correlations with disease activity in systemic lupus erythematosus.

Objectives: Cell surface glycosylation can influence protein-protein interactions with particular relevance to changes in core fucosylation and terminal sialylation. Glycans are ligands for immune regulatory lectin families like galectins (Gals) or sialic acid immunoglobulin-like lectins (Siglecs). This study delves into the glycan alterations within immune subsets of systemic lupus erythematosus (SLE). Methods: Evaluation of binding affinities of Galectin-1, Galectin-3, Siglec-1, Aleuria aurantia lectin (AAL, recognizing core fucosylation), and Sambucus nigra agglutinin (SNA, specific for α-2,6-sialylation) was conducted on various immune subsets in peripheral blood mononuclear cells (PBMCs) from control and SLE subjects. Lectin binding was measured by multi-parameter flow cytometry in 18 manually gated subsets of T-cells, NK-cells, NKT-cells, B-cells, and monocytes in unstimulated resting state and also after 3-day activation. Stimulated pre-gated populations were subsequently clustered by FlowSOM algorithm based on lectin binding and activation markers, CD25 or HLA-DR. Results: Elevated AAL, SNA and CD25+/CD25- SNA binding ratio in certain stimulated SLE T-cell subsets correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores. The significantly increased frequencies of activated AALlow Siglec-1low NK metaclusters in SLE also correlated with SLEDAI-2K indices. In SLE, activated double negative NKTs displayed significantly lower core fucosylation and CD25+/CD25- Siglec-1 binding ratio, negatively correlating with disease activity. The significantly enhanced AAL binding in resting SLE plasmablasts positively correlated with SLEDAI-2K scores. Conclusion: Alterations in the glycosylation of immune cells in SLE correlate with disease severity, which might represent potential implications in the pathogenesis of SLE.

The shared circulating diagnostic biomarkers and molecular mechanisms of systemic lupus erythematosus and inflammatory bowel disease.

Background: Systemic lupus erythematosus (SLE) is a multi-organ chronic autoimmune disease. Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the gastrointestinal tract. Previous studies have shown that SLE and IBD share common pathogenic pathways and genetic susceptibility, but the specific pathogenic mechanisms remain unclear. Methods: The datasets of SLE and IBD were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using the Limma package. Weighted gene coexpression network analysis (WGCNA) was used to determine co-expression modules related to SLE and IBD. Pathway enrichment was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for co-driver genes. Using the Least AbsoluteShrinkage and Selection Operator (Lasso) regressionand Support Vector Machine-Recursive Feature Elimination (SVM-RFE), common diagnostic markers for both diseases were further evaluated. Then, we utilizedthe CIBERSORT method to assess the abundance of immune cell infiltration. Finally,we used the single-cell analysis to obtain the location of common diagnostic markers. Results: 71 common driver genes were identified in the SLE and IBD cohorts based on the DEGs and module genes. KEGG and GO enrichment results showed that these genes were closely associated with positive regulation of programmed cell death and inflammatory responses. By using LASSO regression and SVM, five hub genes (KLRF1, GZMK, KLRB1, CD40LG, and IL-7R) were ultimately determined as common diagnostic markers for SLE and IBD. ROC curve analysis also showed good diagnostic performance. The outcomes of immune cell infiltration demonstrated that SLE and IBD shared almost identical immune infiltration patterns. Furthermore, the majority of the hub genes were commonly expressed in NK cells by single-cell analysis. Conclusion: This study demonstrates that SLE and IBD share common diagnostic markers and pathogenic pathways. In addition, SLE and IBD show similar immune cellinfiltration microenvironments which provides newperspectives for future treatment.

The role of vitamin D in pediatric systemic lupus erythematosus - a double pawn in the immune and microbial balance.

Having increased popularity during the Covid-19 pandemic, vitamin D3 is currently impressing thanks to the numerous researches aimed at its interactions with the body's homeostasis. At the same time, there is a peak in terms of recommendations for supplementation with it. Some of the studies focus on the link between autoimmune diseases and nutritional deficiencies, especially vitamin D3. Since the specialized literature aimed at children (patients between 0-18 years old) is far from equal to the informational diversity of the adult-centered branch, this review aims to bring up to date the relationship between the microbial and nutritional balance and the activity of pediatric systemic lupus erythematosus (pSLE). The desired practical purpose resides in a better understanding and an adequate, individualized management of the affected persons to reduce morbidity. The center of the summary is to establish the impact of hypovitaminosis D in the development and evolution of pediatric lupus erythematosus. We will address aspects related to the two entities of the impact played by vitamin D3 in the pathophysiological cascade of lupus, but also the risk of toxicity and its effects when the deficiency is over supplemented (hypervitaminosis D). We will debate the relationship of hypovitaminosis D with the modulation of immune function, the potentiation of inflammatory processes, the increase of oxidative stress, the perfusion of cognitive brain areas, the seasonal incidence of SLE and its severity. Finally, we review current knowledge, post-pandemic, regarding the hypovitaminosis D - pSLE relationship.

Animal models of studying the pathogenesis of multi-organ tissue damage in lupus.

Moderate-to-severe systemic lupus erythematosus (SLE) is characterized by extensive autoantibody deposition and persistent autoinflammation. As the existing animal models are limited in accurately reproducing the pathological characteristics of human SLE, we introduced a novel animal model simulating multi-organ autoinflammation through intra-organ injections. The model closely mimicked key features of SLE, including IgG deposition, inflammation, and tissue damage. The model could be used to assess the roles of IgG, immune cells, cytokines, and Fc gamma receptor (FcγR) in the pathogenesis of autoinflammation. The results obtained from this model could be confirmed by lupus MRL/lpr mice. The review suggested that the diagnostic criteria should be reconsidered to incorporate IgG deposition in tissues and highlighted the limitations of current T-cell and B-cell-focused treatments. To summarize, the IgG deposition model can be used to investigate the pathogenesis and treatment of multi-organ tissue damage associated with SLE.

Dexamethasone-Integrated Mesenchymal Stem Cells for Systemic Lupus Erythematosus Treatment via Multiple Immunomodulatory Mechanisms.

The therapeutic application of mesenchymal stem cells (MSCs) has good potential as a treatment strategy for systemic lupus erythematosus (SLE), but traditional MSC therapy still has limitations in effectively modulating immune cells. Herein, we present a promising strategy based on dexamethasone liposome-integrated MSCs (Dexlip-MSCs) for treating SLE via multiple immunomodulatory pathways. This therapeutic strategy prolonged the circulation time of dexamethasone liposomes in vivo, restrained CD4+T-cell proliferation, and inhibited the release of proinflammatory mediators (IFN-γ and TNF-α) by CD4+T cells. In addition, Dexlip-MSCs initiated cellular reprogramming by activating the glucocorticoid receptor (GR) signaling pathway to upregulate the expression of anti-inflammatory factors such as cysteine-rich secretory protein LCCL-containing domain 2 (CRISPLD2) and downregulate the expression of proinflammatory factors. In addition, Dexlip-MSCs synergistically increased the anti-inflammatory inhibitory effect of CD4+T cells through the release of dexamethasone liposomes or Dex-integrated MSC-derived exosomes (Dex-MSC-EXOs). Based on these synergistic biological effects, we demonstrated that Dexlip-MSCs alleviated disease progression in MRL/lpr mice more effectively than Dexlip or MSCs alone. These features indicate that our stem cell delivery strategy is a promising therapeutic approach for clinical SLE treatment.

A global view of T cell metabolism in systemic lupus erythematosus.

Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in Systemic Lupus Erythematosus (SLE). Over the last two decades, we have acquired significant knowledge about the signaling and transcriptomic programs related to metabolic rewiring in healthy and SLE T cells. However, our understanding of metabolic network activity derives largely from studying metabolic pathways in isolation. Here, we argue that enzymatic activities are necessarily coupled through mass and energy balance constraints with in-built network-wide dependencies and compensation mechanisms. Therefore, metabolic rewiring of T cells in SLE must be understood in the context of the entire network, including changes in metabolic demands such as shifts in biomass composition and cytokine secretion rates as well as changes in uptake/excretion rates of multiple nutrients and waste products. As a way forward, we suggest cell physiology experiments and integration of orthogonal metabolic measurements through computational modeling towards a comprehensive understanding of T cell metabolism in lupus.

Altered X-chromosome inactivation predisposes to autoimmunity.

In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may participate in these sex biases. We perturbed the expression of the trigger of XCI, the noncoding RNA Xist, in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal center B cells, and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.

A new perspective on therapies involving B-cell depletion in autoimmune diseases.

It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.

Aberrant CD8+T cells drive reproductive dysfunction in female mice with elevated IFN-γ levels.

Introduction: Interferon-gamma (IFN-γ) is pivotal in orchestrating immune responses during healthy pregnancy. However, its dysregulation, often due to autoimmunity, infections, or chronic inflammatory conditions, is implicated in adverse reproductive outcomes such as pregnancy failure or infertility. Additionally, the underlying immunological mechanisms remain elusive. Methods: Here, we explore the impact of systemic IFN-γ elevation on cytotoxic T cell responses in female reproduction utilizing a systemic lupus-prone mouse model with impaired IFN-γ degradation. Results: Our findings reveal that heightened IFN-γ levels triggered the infiltration of CD8+T cells in the pituitary gland and female reproductive tract (FRT), resulting in prolactin deficiency and subsequent infertility. Furthermore, we demonstrate that chronic IFN-γ elevation increases effector memory CD8+T cells in the murine ovary and uterus. Discussion: These insights broaden our understanding of the role of elevated IFN-γ in female reproductive dysfunction and suggest CD8+T cells as potential immunotherapeutic targets in female reproductive disorders associated with chronic systemic IFN-γ elevation.

Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states.

OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

Systemic Lupus Erythematosus: A Review.

Importance: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE. Observations: Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE). Conclusions and Relevance: Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.

Modelling the Impact of NETosis During the Initial Stage of Systemic Lupus Erythematosus.

The development of autoimmune diseases often takes years before clinical symptoms become detectable. We propose a mathematical model for the immune response during the initial stage of Systemic Lupus Erythematosus which models the process of aberrant apoptosis and activation of macrophages and neutrophils. NETosis is a type of cell death characterised by the release of neutrophil extracellular traps, or NETs, containing material from the neutrophil's nucleus, in response to a pathogenic stimulus. This process is hypothesised to contribute to the development of autoimmunogenicity in SLE. The aim of this work is to study how NETosis contributes to the establishment of persistent autoantigen production by analysing the steady states and the asymptotic dynamics of the model by numerical experiment.