Etiology Of Systemic Lupus Erythematosus Research Articles

Identification of Diagnostic Biomarkers in Systemic Lupus Erythematosus Based on Bioinformatics Analysis and Machine Learning.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects several organs and causes variable clinical symptoms. Exploring new insights on genetic factors may help reveal SLE etiology and improve the survival of SLE patients. The current study is designed to identify key genes involved in SLE and develop potential diagnostic biomarkers for SLE in clinical practice. Expression data of all genes of SLE and control samples in GSE65391 and GSE72509 datasets were downloaded from the Gene Expression Omnibus (GEO) database. A total of 11 accurate differentially expressed genes (DEGs) were identified by the “limma” and “RobustRankAggreg” R package. All these genes were functionally associated with several immune-related biological processes and a single KEGG (Kyoto Encyclopedia of Genes and Genome) pathway of necroptosis. The PPI analysis showed that IFI44, IFI44L, EIF2AK2, IFIT3, IFITM3, ZBP1, TRIM22, PRIC285, XAF1, and PARP9 could interact with each other. In addition, the expression patterns of these DEGs were found to be consistent in GSE39088. Moreover, Receiver operating characteristic (ROC) curves analysis indicated that all these DEGs could serve as potential diagnostic biomarkers according to the area under the ROC curve (AUC) values. Furthermore, we constructed the transcription factor (TF)-diagnostic biomarker-microRNA (miRNA) network composed of 278 nodes and 405 edges, and a drug-diagnostic biomarker network consisting of 218 nodes and 459 edges. To investigate the relationship between diagnostic biomarkers and the immune system, we evaluated the immune infiltration landscape of SLE and control samples from GSE6539. Finally, using a variety of machine learning methods, IFI44 was determined to be the optimal diagnostic biomarker of SLE and then verified by quantitative real-time PCR (qRT-PCR) in an independent cohort. Our findings may benefit the diagnosis of patients with SLE and guide in developing novel targeted therapy in treating SLE patients.

The Role of IL-12 in the Aetiology of SLE and its Connection to HBV Infection in Iraqi Patients

Introduction: Systemic lupus erythematosus (SLE) is a significant social and public health issue because the medications used to treat it can only manage the symptoms and halt the progression of the disease, not totally cure it. The purpose of this study is to determine the association between the blood level of IL-12 and SLE, as well as its consequences, such as lupus nephritis (LN), and its active or dormant condition, in Iraqi patients.Method: The study enrolled 90 SLE patients from AL-Sadar teaching hospital, with 66(73.3%) developing lupus nephritis (LN) and 24(26.7%) without LN. Additionally, there were 60 (90.9%) and 6 (9.1) active patients. Only 48 of 90 individuals tested positive for HBsAg, whereas 42(46.6%) tested positive for HBV. Each participant donated 5 ml of blood for anti-dsDNA and IL-12 testing.Results: In SLE patients with LN, IL-12 serum levels were considerably higher than in those without LN(p = 0.05). Different levels of IL-12 were found in the LN groups. Serum IL-12 concentrations were considerably lower in patients with HBV-associated SLE (3.41±0.85 pg/ml), non-HBV-associated SLE (2.05±0.66 pg/ml), and healthy controls (0.53±0.28 pg/ml). WBC count, ESR, anti-ds antibody, and ANA levels were all elevated in lupus patients and in the active groups.Conclusion: Our research established that SLE patients have elevated IL-12 levels. IL-12 levels were significantly greater in SLE with LN as compared to SLE without LN, and they differed significantly between lupus nephritis classes II, IV, and V. Finally, significant differences in IL-12 levels were seen between HBV and non-HBV SLE patients.

The relation of CD4+CD25+Foxp3+ regulatory T cells concentration with disease activity and damage index in systemic lupus erythematosus.

Regulatory T cells (Treg) deficits, both quantitative and qualitative, are known to be possible triggers for the development of autoimmune disorders by causing T and B cells dysfunction. The contribution of Treg deficiency in the etiology of systemic lupus erythematosus (SLE) is still being debated. The aim of the present study is to evaluate the percentage of circulating CD4+CD25+Foxp3+ Treg cells in a cohort of Egyptian SLE patients and to correlate this value with the activity and damage index of these patients. 50 female patients with SLE together with an equal number of age- and sex-matched healthy controls were enrolled in the study. Flow cytometric determination of peripheral Treg cells was carried out for all participants by detecting the percentage of CD4+CD25+Foxp3+ cells to compare cases with the control group. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), while disease damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI). Both indices were correlated with the percentage of CD4+CD25+Foxp3 T regulatory cells. CD4+CD25+Foxp3+ Treg cells percentage was significantly decreased in patients with SLE as compared to healthy controls. On correlating CD4+CD25+Foxp3+ Treg percentage with SLEDAI-2K, a significantly negative correlation was found. Also, there was a negative significant correlation between CD4+CD25+Foxp3+ Treg cells percentage and SLICC/ACR DI. On correlating SLEDAI-2K with damage index (SLICC/ACR DI), we found highly significant positive correlation. Our study showed impaired production of CD4+CD25+Foxp3+ Tregs in SLE patients, which can play a reciprocal role with some cytokines to affect the activity of the disease and organ damage. CD4+CD25+Foxp3+ Tregs cells should be the target to determine the clinical effectiveness of new therapy to modulate Tregs besides the traditional treatments.

Epigenetic Alterations in Immune Cells of Systemic Lupus Erythematosus and Therapeutic Implications.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by autoantibody production and dysregulated immune cell activation. Although the exact etiology of SLE remains unknown, genetic, hormonal, and complex environmental factors are known to be critical for pathologic immune activation. In addition to the inherited genetic predisposition, epigenetic processes that do not change the genomic code, such as DNA methylation, histone modification, and noncoding RNAs are increasingly appreciated to play important roles in lupus pathogenesis. We herein focus on the up-to-date findings of lupus-associated epigenetic alterations and their pathophysiology in lupus development. We also summarize the therapeutic potential of the new findings. It is likely that advances in the epigenetic study will help to predict individual disease outcomes, promise diagnostic accuracy, and design new target-directed immunotherapies.

CD4+ T Cells Promote IgG Production in MHC-Independent and ICAM-1-Dependent Manners in Pristane-Induced Lupus Mice

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and chronic inflammation. The etiology and pathogenesis of SLE are complicated in which dysfunction of CD4+ T cells is largely engaged. In this study, we investigated the manners of CD4+ T cells in antibody production in a lupus-like mouse model through peritoneal injection of pristane reagent. With the increase in total IgG/IgM and autoantibody production after 6 months, CD4+ T cells exhibited activated phenotypes with the elevated CD44, ICOS, OX40, and PD-1 expression. Pristane injection induced the increase in IgM levels in both wild-type and T cell-deficient TCRα−/− mice whereas IgG, IgG1, and IgG2a production was impaired. When adoptively transferring CD4+ T cells into T cell-deficient mice or coculturing CD4+ T cells and B cells in vitro, it was found that CD4+ T cells derived from pristane-treated mice could help the production of total IgG as well as IgG1/IgG2a in a more efficient manner both in vivo and in vitro. While MHC was dispensable for IgG production, ICAM-1 likely functioned as an attenuating factor for IgG production. Our study thus reveals that CD4+ T cells in pristane-treated mice play important roles in IgG production, which implies the critical roles in the induction of pathological autoantibodies in MHC-independent and ICAM-1-dependent manners.

Emerging Molecular Markers Towards Potential Diagnostic Panels for Lupus.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease which can affect various tissues and organs, posing significant challenges for clinical diagnosis and treatment. The etiology of SLE is highly complex with contributions from environmental factors, stochastic factors as well as genetic susceptibility. The current criteria for diagnosing SLE is based primarily on a combination of clinical presentations and traditional lab testing. However, these tests have suboptimal sensitivity and specificity. They are unable to indicate disease cause or guide physicians in decision-making for treatment. Therefore, there is an urgent need to develop a more accurate and robust tool for effective clinical management and drug development in lupus patients. It is fortunate that the emerging Omics have empowered scientists in the discovery and identification of potential novel biomarkers of SLE, especially the markers from blood, urine, cerebrospinal fluids (CSF), and other bodily fluids. However, many of these markers have not been carefully validated for clinical use. In addition, it is apparent that individual biomarkers lack sensitivity or specificity. This review summarizes the sensitivity, specificity and diagnostic value of emerging biomarkers from recent studies, and discusses the potential of these markers in the development of biomarker panel based diagnostics or disease monitoring system in SLE.

Cardiovascular Manifestations of Systemic Lupus Erythematosus: An Overview

Systemic Lupus Erythematosus(SLE) is a multisystem autoimmune disease with variable presentations. A proposed mechanism for the etiology of SLE involves the development of autoantibodies that result from a defect in apoptosis. The specific defect involves the “find-me” (adenosine triphosphate [ATP]/uridine triphosphate [UTP]) or “eat-me” (phosphatidylserine) signals activated upon release of red cell nuclei. In the absence of apoptosis, the nuclei break down, causing inflammation and contributing to the development of autoimmunity. Many signs and symptoms of SLE are caused by either circulating immune complexes or direct effects of antibodies on cells. A genetic predisposition for SLE exists, and the concordance rate in monozygotic twins is between 25% and 70%. If a mother has SLE, her daughter’s risk of developing the disease is 1:40, and her son’s risk is 1:250. The course of SLE consists of intermittent remissions punctuated by disease flares, and organ damage often progresses over time. Pericarditis is the most frequent cardiac manifestation; it can be documented by ECG, auscultation of a friction rub, or evidence of pericardial effusion. It usually responds to anti-inflammatory therapy and infrequently leads to tamponade. More serious cardiac manifestations are myocarditis and fibrinous endocarditis of Libman-Sacks. The endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valves, or embolic events. It has not been proven that glucocorticoid or other immunosuppressive therapies improve lupus myocarditis or endocarditis. Still, it is usual practice to administer a trial of high-dose steroids and appropriate supportive treatment for heart failure, arrhythmia, or embolic events. As discussed above, patients with SLE are at increased risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from immune attack, chronic inflammation, and chronic oxidative damage to arteries.

Modern View on the Problem of Systemic Lupus Erythematosus with and without Comorbid Lesions of the Circulatory System (Literature Review, Clinical Case Description) – Second Notice

Introduction. The prevalence and incidence of systemic lupus erythematosus (SLE) in the world is significant. In recent years, there has been a tendency of the SLE prevalence increase. Despite the undoubted progress in understanding the etiology and pathogenesis of SLE, its diagnosis and treatment, the mortality of patients, including ones at young and working age, is higher than in the general population, and circulatory system lesions are ones of its main reasons in these cases. The aim of the study. To analyze the literature, devoted to the modern view on the problem of systemic lupus erythematosus with and without comorbid lesions of the circulatory system, describe the clinical case. Materials and methods. Content analysis, method of system and comparative analysis, bibliosemantic method of studying the current scientific studies on modern principles of diagnosis and treatment of patients with SLE are used. A clinical case is described. Results. A clinical case of a 43-year-old patient S., who was hospitalized for SLE, she considers herself ill for eighteen years and she has been constantly taken outpatient and periodically inpatient treatment due to the frequent deteriorations in her general condition, clinical and laboratory parameters, is described. Based on the received results of the examinations, applying the method of determining the functional class of SLE, the patient was diagnosed with a clinical diagnosis indicating comorbid lesions of various organs and systems (skin, joints, kidneys, vessels, heart, blood system, immune system, eyes). The generally accepted basic medical complex of the patient includes drugs, taking into account the lesions to the circulatory system. The conducted complex pathogenetic treatment gave a positive result. Conclusions. In the described clinical case demonstrated the development of comorbid lesions of many organs and systems, including circulatory system, in a patient with systemic lupus erythematosus. Inclusion in the treatment complex in addition to basic and drugs for the treatment lesions of circulatory system has improved the general condition of the patient, stabilized clinical and laboratory parameters, as evidenced by a prospective study during three years. The information provided in our clinical case is consistent with the results of the literature review. Systemic lupus erythematosus needs further in-depth study due to its widespread prevalence among young and people of working age, lack of accurate knowledge about the etiology and pathogenesis of the disease, comorbid lesions of many organs and systems, including circulatory system, the development of severe and often life-threatening manifestations, the lack of clear recommendations that would predict the differentiated use of drugs taking into account comorbid syntropic lesions. Keywords: SLE, circulatory system lesions, atherosclerosis, diagnosis and treatment of SLE.

Macrophage Polarization and Plasticity in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that attacks almost every organ. The condition mostly happens to adults but is also found in children, and the latter have the most severe manifestations. Among adults, females, especially non-Caucasian, are mostly affected. Even if the etiology of SLE remains unclear, studies show a close relation between this disease and both genetics and environment. Despite the large number of published articles about SLE, we still do not have a clear picture of its pathogenesis, and no specific drug has been found to treat this condition effectively. The implication of macrophages in SLE development is gaining ground, and studying it could answer these gaps. Indeed, both in vivo and in vitro studies increasingly report a strong link between this disease and macrophages. Hence, this review aims to explore the role of macrophages polarization and plasticity in SLE development. Understanding this role is of paramount importance because in-depth knowledge of the connection between macrophages and this systemic disease could clarify its pathogenesis and provide a foundation for macrophage-centered therapeutic approaches.

Lupus gut microbiota transplants cause autoimmunity and inflammation

BackgroundThe etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16 s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free (GF) mice. ResultsCompared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to GF mice caused GF mice to develop a series of lupus-like phenotypic features, including increased serum autoimmune antibodies, imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. ConclusionsOverall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.

Immunological Involvement of MicroRNAs in the Key Events of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an archetype autoimmune disease characterized by a myriad of immunoregulatory abnormalities that drives injury to multiple tissues and organs. Due to the involvement of various immune cells, inflammatory cytokines, and related signaling pathways, researchers have spent a great deal of effort to clarify the complex etiology and pathogenesis of SLE. Nevertheless, current understanding of the pathogenesis of SLE is still in the early stages, and available nonspecific treatment options for SLE patients remain unsatisfactory. First discovered in 1993, microRNAs (miRNAs) are small RNA molecules that control the expression of 1/3 of human genes at the post-transcriptional level and play various roles in gene regulation. The aberrant expression of miRNAs in SLE patients has been intensively studied, and further studies have suggested that these miRNAs may be potentially relevant to abnormal immune responses and disease progression in SLE. The aim of this review was to summarize the specific miRNAs that have been observed aberrantly expressed in several important pathogenetic processes in SLE, such as DCs abnormalities, overactivation and autoantibody production of B cells, aberrant activation of CD4+ T cells, breakdown of immune tolerance, and abnormally increased production of inflammatory cytokines. Our summary highlights a novel perspective on the intricate regulatory network of SLE, which helps to enrich our understanding of this disorder and ignite future interest in evaluating the molecular regulation of miRNAs in autoimmunity SLE.

Gut Microbiome and Metabolites in Systemic Lupus Erythematosus: Link, Mechanisms and Intervention.

Systemic lupus erythematosus (SLE), often considered the prototype of autoimmune diseases, is characterized by over-activation of the autoimmune system with abnormal functions of innate and adaptive immune cells and the production of a large number of autoantibodies against nuclear components. Given the highly complex and heterogeneous nature of SLE, the pathogenesis of this disease remains incompletely understood and is presumed to involve both genetic and environmental factors. Currently, disturbance of the gut microbiota has emerged as a novel player involved in the pathogenesis of SLE. With in-depth research, the understanding of the intestinal bacteria-host interaction in SLE is much more comprehensive. Recent years have also seen an increase in metabolomics studies in SLE with the attempt to identify potential biomarkers for diagnosis or disease activity monitoring. An intricate relationship between gut microbiome changes and metabolic alterations could help explain the mechanisms by which gut bacteria play roles in the pathogenesis of SLE. Here, we review the role of microbiota dysbiosis in the aetiology of SLE and how intestinal microbiota interact with the host metabolism axis. A proposed treatment strategy for SLE based on gut microbiome (GM) regulation is also discussed in this review. Increasing our understanding of gut microbiota and their function in lupus will provide us with novel opportunities to develop effective and precise diagnostic strategies and to explore potential microbiota-based treatments for patients with lupus.

Modern View on the Problem of Systemic Lupus Erythematosus with and without Comorbid Lesions of the Circulatory System (Literature Review, Clinical Case Description) (first notice)

Context. The prevalence and incidence of systemic lupus erythematosus (SLE) in the world is significant. In recent years, there has been a tendency of the SLE prevalence increase. despite the undoubted progress in understanding the etiology and pathogenesis of SLE, its diagnosis and treatment, the mortality of patients, including ones at young and working age, is higher than in the general population, and circulatory system lesions are ones of its main reasons in these cases. Objective. To analyze the literature, dedicated to the modern view on the problem of systemic lupus erythematosus with and without comorbid lesions of the circulatory system, describe the clinical case. Materials and methods. Content analysis, method of system and comparative analysis, bibliosemantic method of studying the current scientific investigations on modern principles of diagnosis and treatment of patients with SLE are used. A clinical case is described. Results. The article presents modern ideas about the etiological factors and pathogenesis of the disease. The clinical manifestations of SLE are very diverse. The problem of comorbidity and syntropy of lesions is relevant. Lesions of the cardiovascular system in the case of SLE can manifest itself in the form of pericarditis, myocarditis, endocarditis, lesions of the heart valves, coronary arteries, aorta, conduction system, pulmonary hypertension occurrence. The basic principles of drug therapy are also briefly considered. Conclusions. The results of the literature review indicate the importance of the problem of systemic lupus erythematosus, due to its widespread prevalence among the young and people of working age, lack of accurate knowledge about the etiology and pathogenesis of the disease, comorbid lesions of many organs and systems, including circulatory system, the development of severe and often life-threatening manifestations, the lack of clear recommendations that would predict the differentiated use of drugs taking into account comorbid syntropic lesions, which is also demonstrated in the described clinical case. Given this, systemic lupus erythematosus needs further in-depth study.

Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

Gut Microbiota in Lupus: a Butterfly Effect?

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that typically displays chronic inflammatory tissue damage and miscellaneous circulatory autoantibodies, as well as distinctive type 1 interferon signatures. The etiology of SLE is unclear and currently is attributed to genetic predisposition and environmental triggers. Gut microbiota has recently been considered a critical environmental pathogenic factor in immune-related disorders, and studies are ongoing to uncover the key pathogens and the imputative mechanisms. Fundamental advancements on the role of the microbiota in SLE pathology have been achieved in recent years and are summarized in this review. Recent findings suggested that gut commensals could propagate autoimmunity via molecular mimicry in which ortholog-carrying microbes cross-activate autoreactive T/B cells and trigger the response against host autoantigens, or via bystander activation by stimulating antigen-presenting cells that present autoantigens and enhancing the expression of co-stimulatory molecules and cytokines, thus leading to the loss of self-tolerance and the production of autoantibodies. Additionally, the break of gut barrier and the translocation of gut commensals to inner organs can trigger immune dysregulation and inappropriate systemic inflammation. All these microbiota-mediated mechanisms could contribute to lupus immunopathogenesis and promote disease development in susceptible individuals. Evidence of the causative role of disturbed gut microbiome in SLE is still limited, and the related molecular mechanisms and pathways are largely elusive. However, the modification of gut microbiota, such as pathobiont vaccine, special diet, restricted consortium transplantation, as well as regulatory metabolites supplementation, might be promising strategies for lupus prophylaxis and treatment.

Heme supplementation ameliorates lupus nephritis through rectifying the disorder of splenocytes and alleviating renal inflammation and oxidative damage

Heme is an important iron-containing porphyrin molecule expressed ubiquitously in organisms. Recently, this endogenous molecule has been widely reported to be involved in the pathogenesis of numerous diseases such as sepsis, atherosclerosis and inflammatory bowel disease. However, the role of heme during systemic lupus erythematosus (SLE) pathogenesis has not been previously evaluated. Herein, we have measured the levels of heme in lupus-prone mice and explored the influence of heme on the pathogenesis of lupus. We revealed that heme levels in serum, kidney and spleen lymphocytes are all negatively associated with the levels of proteinuria in lupus-prone mice. Heme supplementation at 15 mg/kg could significantly ameliorate the syndromes of lupus in MRL/lpr mice, extending lifespan, reducing the level of proteinuria and alleviating splenomegaly and lymphadenopathy. Further study demonstrated that heme replenishment corrected the abnormal compartment of T cell subsets, plasma cells and macrophages in the spleen and alleviates inflammation and oxidative damage in kidney of MRL/lpr mice. Our study well defined heme as a relevant endogenous molecule in the etiology of SLE, as well as a potential therapeutic target for treating this autoimmune disease. Meanwhile, heme replenishment might be a new choice to therapeutically modulate immune homeostasis and prevent SLE.

Antibodies to an Epstein Barr Virus protein that cross-react with dsDNA have pathogenic potential

Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis.

Preclinical Testing of Viral Therapeutic Efficacy in Pristane-Induced Lupus Nephritis and Diffuse Alveolar Hemorrhage Mouse Models.

Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.

Association of the Polymorphism rs13259960 in SLEAR With Predisposition to Systemic Lupus Erythematosus.

Genome-wide association studies have identified many susceptibility loci for systemic lupus erythematosus (SLE). However, most of these loci are located in noncoding regions of the genome. Long noncoding RNAs (lncRNAs) are pervasively expressed and have been reported to be involved in various diseases. This study aimed to explore the genetic significance of lncRNAs in SLE. A genome-wide survey of SLE risk variants in lncRNA gene loci was performed in Han Chinese subjects (4,556 with SLE and 9,451 healthy controls). The functional relevance of an SLE risk variant in one of the lncRNA genes was explored using biochemical and molecular cell biology analyses. In vitro loss-of-function and gain-of-function strategies were used to clarify the functional and phenotypic relevance of this SLE susceptibility lncRNA. Moreover, correlation of this lncRNA with the degree of apoptosis in the peripheral blood of SLE patients was evaluated. A novel SLE susceptibility locus in a lncRNA gene, designated SLEAR (for SLE-associated RNA), was identified at the single-nucleotide polymorphism rs13259960 (odds ratio 1.35, Pcombined = 1.03 × 10-11 ). The A>G variation at rs13259960, located in an intronic enhancer, was found to impair STAT1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR production in peripheral blood mononuclear cells from patients with SLE (3 with the G/G genotype, 22 with A/G, and 103 with A/A at rs13259960; P = 0.0241). Moreover, SLEAR interacted with the RNA binding proteins interleukin enhancer binding factor 2, heterogeneous nuclear RNP F, and TATA-binding protein-associated factor 15, to form a complex for transcriptional activation of the downstream antiapoptotic genes. In addition, SLEAR regulated apoptosis of Jurkat cells in vitro, and its expression level was correlated with the degree of cell death in the peripheral blood of patients with SLE (r = 0.824, P = 2.15 × 10-8 ; n = 30). These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and confers a predisposition to SLE. Taken together, these results may give insights into the etiology of SLE.

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond.

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.