ABSTRACT: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.
Project description:Systemic lupus erythematosus (SLE) is the prototypic autoimmune condition, often affecting multiple organ systems, including the skin. Cutaneous lupus erythematosus (CLE) is distinct from SLE and may be skin limited or associated with systemic disease. Histopathologically, the hallmark of lupus-specific manifestations of SLE and CLE is an interface dermatitis. The cause of SLE and CLE is likely multifactorial and may include shared genetic factors. In this review, we will discuss the genetic findings related to the cutaneous manifestations of SLE and isolated CLE, with a particular focus on the lupus-specific CLE subtypes.Several major histocompatibility complex and nonmajor histocompatibility complex genetic polymorphisms have been identified which may contribute to the cutaneous manifestations of SLE and to CLE. Most of these genetic variants are associated with mechanisms attributed to the pathogenesis of SLE, including pathways involved in interferon and vitamin D regulation and ultraviolet light exposure. Although there is overlap between the genetic factors associated with SLE and CLE, there appear to be unique genetic factors specific for CLE.Improved understanding of the genetics of CLE may lead to the creation of targeted therapies, improving outcomes for patients with this challenging dermatologic condition.
Project description:Glucosteroids (GS) are widely used drugs for various inflammatory pathologies (Nephrotic syndrome, Proliferative glomerulonephritis, Extramembrane glomerulonephritis, Nephropathy of the Nodous Poliarterita (PAN), Nephropathy from purple Henoch-Schonlein, lupus nephropathy (LN), Acute adrenal insufficiency Waterhouse-Friederichsen, Chronic adrenal insufficiency Addison, Systemic Lupus Erythematosus (SLE), Polymyositis and dermatomyositis, Chronic granulomatosis, Crohn's disease, Hemorrhagic rectocolitis, Hemolytic anemias, Acute leukemias and chronic lymphocytic leukemia, Hodgkin's lymphoma). Although they are prescribed for their anti-inflammatory and immunosuppressive properties, they also have many side effects, hyperglycemia being one of the most common and representative, which is why these drugs need careful monitoring when administered over the long term. This paper presents the case of a 39 year old patient diagnosed with systemic lupus erythematosus (SLE) with class IV lupus nephropathy (LN) who developed numerous complications due to the pathogenic side effects: diabetes, amenorrhea, recurrent infections, and depression.
Project description:Systemic lupus erythematosus (SLE) is the prototype of complex autoimmune diseases. Studies have suggested that genetic, hormonal, and environmental factors contribute to the development of the disease. Interestingly, several recent studies involving SLE patients and mouse models of the disease have suggested a role for interferon (IFN)-stimulated genes (ISGs) in the development of SLE. One family of ISGs is the Ifi200-family, which includes mouse (Ifi202a, Ifi202b, Ifi203, Ifi204, and Ifi205) and human (IFI16, MNDA, AIM2, and IFIX) genes. The mouse genes cluster between serum amyloid P-component (Apcs) and alpha-spectrin (Spna-1) genes on chromosome 1 and the human genes cluster in syntenic region 1q23. The Ifi200-family genes encode structurally and functionally related proteins (the p200-family proteins). Increased expression of certain p200-family proteins in cells is associated with inhibition of cell proliferation, modulation of apoptosis, and cell differentiation. Our studies involving generation of B6.Nba2 congenic mice, coupled with gene expression analyses, identified the Ifi202 as a candidate lupus-susceptibility gene. Importantly, recent studies using different mouse models of SLE have suggested that increased expression of Ifi202 gene (encoding p202 protein) in immune cells contributes to lupus susceptibility. Consistent with a functional role for the p202 protein in lupus susceptibility, increased levels of IFI16 protein in human SLE patients are associated with the diseases. This review summarizes recent findings concerning the regulation and role of p200-family proteins in the development of SLE.
Project description:The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNF?, IFN?, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.
Project description:Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that is driven by autoantibodies that target multiple organ systems. B-lymphocyte stimulator (BLyS) and its receptors on B-cell subsets play an important role in autoimmune B-cell development and SLE pathogenesis. Targeted therapy with belimumab, the monoclonal antibody against BLyS, has shown clinical benefit in two large-scale, multicenter phase III trials leading to US Food and Drug Administration approval for patients with serologically positive SLE who have active disease despite standard therapy. This review will discuss the challenges in lupus drug development and clinical trials, the basics of B-cell pathogenesis in SLE, the recent lupus clinical trials of B-cell targeted treatments, and other potential targeted therapies under investigation for patients with lupus.
Project description:Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by autoantibodies directed against numerous self-nuclear antigens. Because of the heterogeneous nature of lupus, it has been challenging to identify markers that are sensitive and specific enough for its diagnosis and monitoring. However, with the sequencing of the human genome, rapid development of high-throughput approaches has allowed for a better understanding of the etiopathogenesis of complex diseases, including SLE. Here we present a review of the latest advancements in biomarker discovery during the "omics" era, using these novel technologies, for assisting in the diagnosis and prognosis of patients with SLE.
Project description:Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by a loss of tolerance to self-antigens and the production of high titers of serum autoantibodies. Lupus nephritis can affect up to 74% of SLE patients, particularly those of Hispanic and African ancestries, and remains a major cause of morbidity and mortality. A genetic etiology in SLE is now well substantiated. Thanks to extensive collaborations, extraordinary progress has been made in the past few years and the number of confirmed genes predisposing to SLE has catapulted to approximately 30. Studies of other forms of genetic variation, such as copy number variants and epigenetic alterations, are emerging and promise to revolutionize our knowledge about disease mechanisms. However, to date little progress has been made on the identification of genetic factors specific to lupus nephritis. On the near horizon, two large-scale efforts, a collaborative meta-analysis of lupus nephritis based on all genome-wide association data in Caucasians and parallel scans in four other ethnicities, are poised to make fundamental discoveries in the genetics of lupus nephritis. Collectively, these findings will show that a broad array of pathways underlines the genetic heterogeneity of SLE and lupus nephritis, and provide potential avenues for the development of novel therapies.
Project description:B-cell activating factor of the TNF family (BAFF) promotes the maturation and survival of B cells. Because BAFF levels are elevated in systemic lupus erythematosus (SLE) patients, BAFF has been the target of emerging therapies for SLE, such as belimumab. Levels of BAFF and its receptors in discoid lupus erythematosus (DLE) patients are unknown.To compare skin and blood mRNA and protein levels of BAFF and its receptors BAFF-R, TACI, and BCMA in DLE subjects with (DLE+/SLE+ (N=28)) and without SLE (DLE+/SLE- (N=35)), psoriasis subjects (N=11), and normal subjects (N=42).We used quantitative real-time PCR to measure blood and skin BAFF, BAFF-R, TACI, and BCMA mRNA, sandwich ELISAs to measure sera BAFF, and immunohistochemistry to evaluate BAFF and BAFF-R skin protein expression.BAFF mRNA and protein levels were highest in DLE+/SLE+blood, followed by DLE+/SLE-, psoriasis, and normal blood. BAFF protein also correlated with anti-nuclear antibodies, and autoantibodies against double-stranded DNA, single-stranded DNA, and ribonucleoprotein, and Systemic Lupus Erythematosus Disease Activity Index scores in DLE patients. While showing no difference between DLE+/SLE+ and DLE+/SLE- skin, BAFF and its receptors mRNA were up-regulated in DLE skin vs. normal and psoriasis skin. DLE skin had higher percentages of BAFF-R? inflammatory cells, likely T cells and macrophages, than psoriasis and normal skin.BAFF may be a serologic marker of systemic disease in DLE patients. BAFF and its receptors are elevated in DLE skin, suggesting that targeted therapies against these proteins could treat refractory DLE patients.
Project description:Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, in which pathogenic macrophages, myeloid-lineage cells, and their secreted products perpetuate inflammation, whereas OA was characterized by fibroblasts and RA of lymphocytes. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers (GCs). Gene Set Variation Analysis (GSVA) confirmed activation of specific immune cell types in LA. Numerous therapies were predicted to target LA, including TNF, NF?B, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease with extreme heterogeneity and potentially involvement of any organ or system. Numerous unanswered questions and challenges in SLE always prompt further exploration. In 2019, great progress in various aspects of SLE emerged. Both the classification criteria and management recommendation for SLE were updated. New promising medications have been widely developed and tested, although subsequent clinical studies are warranted. As an emerging number of most notable studies in SLE were published in both clinical area and basic research in 2019, we aim to summarize the highest quality data on SLE regarding novel insights of pathogenesis, updated recommendations, hot-spot issues on clinical manifestations, new understanding of disease prognosis, and most importantly, the therapeutic advances in SLE in this review.