scholarly journals Mediators of Inflammation and Their Effect on Resident Renal Cells: Implications in Lupus Nephritis

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Susan Yung ◽  
Kwok Fan Cheung ◽  
Qing Zhang ◽  
Tak Mao Chan
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Mesangial Cells ◽  
Kidney Injury ◽  
Organ Damage ◽  
Type I Interferons ◽  
Type I ◽  
Renal Cells ◽  
Mediators Of Inflammation ◽  
Gene And Protein Expression

Lupus nephritis affects up to 70% of patients with systemic lupus erythematosus and is a major cause of morbidity and mortality. It is characterized by a breakdown of immune tolerance, production of autoantibodies, and deposition of immune complexes within the kidney parenchyma, resulting in local inflammation and subsequent organ damage. To date, numerous mediators of inflammation have been implicated in the development and progression of lupus nephritis, and these include cytokines, chemokines, and glycosaminoglycans. Of these, type I interferons (IFNs) can increase both gene and protein expression of cytokines and chemokines associated with lupus susceptibility, and interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α) and hyaluronan have been shown to elicit both pro- and anti-inflammatory effects on infiltrating and resident renal cells depending on the status of their microenvironment. Expression of IL-6, TNF-α, type I IFNs, and hyaluronan are increased in the kidneys of patients and mice with active lupus nephritis and have been shown to contribute to disease pathogenesis. There is also evidence that despite clinical remission, ongoing inflammatory processes may occur within the glomerular and tubulointerstitial compartments of the kidney, which further promote kidney injury. In this review, we provide an overview of the synthesis and putative roles of IL-6, TNF-α, IFN-α, and hyaluronan in the pathogenesis of lupus nephritis focusing on their effects on human mesangial cells and proximal renal tubular epithelial cells.

scholarly journals IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuewei Ding ◽  
Yi Ren ◽  
Xiaojie He
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Renal Fibrosis ◽  
Type I Interferons ◽  
Type I ◽  
Renal Cells ◽  
Inflammatory Reactions ◽  
Pathological Mechanism ◽  
New Perspective

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

scholarly journals Autoantibodies and Resident Renal Cells in the Pathogenesis of Lupus Nephritis: Getting to Know the Unknown

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Susan Yung ◽  
Tak Mao Chan
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Surface Proteins ◽  
Kidney Cells ◽  
Renal Cells ◽  
Self Tolerance ◽  
Mediators Of Inflammation ◽  
Kidney Involvement ◽  
Dsdna Antibodies

Systemic lupus erythematosus is characterized by a breakdown of self-tolerance and production of autoantibodies. Kidney involvement (i.e., lupus nephritis) is both common and severe and can result in permanent damage within the glomerular, vascular, and tubulo-interstitial compartments of the kidney, leading to acute or chronic renal failure. Accumulating evidence shows that anti-dsDNA antibodies play a critical role in the pathogenesis of lupus nephritis through their binding to cell surface proteins of resident kidney cells, thereby triggering the downstream activation of signaling pathways and the release of mediators of inflammation and fibrosis. This paper describes the mechanisms through which autoantibodies interact with resident renal cells and how this interaction plays a part in disease pathogenesis that ultimately leads to structural and functional alterations in lupus nephritis.

IMMUNOINFLAMMATORY RHEUMATIC DISEASES ASSOCIATED WITH TYPE I INTERFERON: NEW EVIDENCE

2019 ◽  
Vol 57 (4) ◽  
pp. 452-461 ◽  
Author(s):  
E. L. Nasonov ◽  
A. S. Avdeeva
Keyword(s):  
Rheumatic Diseases ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Organ Damage ◽  
Immunological Tolerance ◽  
Type I Interferons ◽  
Type I ◽  
Pathological Conditions ◽  
New Evidence

Immunoinflammatory rheumatic diseases (IIRDs) are a large group of pathological conditions with impaired immunological tolerance to autogenous tissues, leading to inflammation and irreversible organ damage. The review discusses current ideas on the role of type I interferons in the immunopathogenesis of IIRDs, primarily systemic lupus erythematosus, and new possibilities for personalized therapy.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals Atypical hemolytic uremic syndrome secondary to lupus nephritis, responsive to eculizumab

2016 ◽  
Vol 8 (3) ◽  
Author(s):  
Alexander G. Raufi ◽  
Shruti Scott ◽  
Omar Darwish ◽  
Kevin Harley ◽  
Kanwarpal Kahlon ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Hemolytic Uremic Syndrome ◽  
Lupus Erythematosus ◽  
Multidisciplinary Approach ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Organ Damage ◽  
Atypical Hus ◽  
First Line Therapy ◽  
Autoimmune Attack ◽  
Uremic Syndrome

Among the spectrum of disease manifestations associated with systemic lupus erythematosus, lupus nephritis is particularly concerning due to the potential for renal failure. This autoimmune attack may not, however, be limited to the kidney and is increasingly being recognized as a trigger for atypical Hemolytic Uremic Syndrome (aHUS). Atypical HUS falls under the spectrum of the thrombotic microangiopathies (TMAs) – a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. Although plasma exchange is considered first-line therapy for thrombotic thrombocytopenic purpura – a TMA classically associated with autoimmune depletion of ADAMTS-13 – aHUS demonstrates less reliable responsiveness to this modality. Instead, use of the late complement inhibitor Eculizumab has emerged as an effective modality for the management of such patients. Diagnosis of aHUS, however, is largely clinically based, relying heavily upon a multidisciplinary approach. Herein we present the case of a patient with atypical HUS successfully treated with Eculizumab in the setting of Class IV-G (A) lupus nephritis and hypocomplementemia.

scholarly journals Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults

2017 ◽  
Vol 44 (8) ◽  
pp. 1239-1248 ◽  
Author(s):  
Hermine I. Brunner ◽  
Michael R. Bennett ◽  
Gaurav Gulati ◽  
Khalid Abulaban ◽  
Marisa S. Klein-Gitelman ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Transforming Growth Factor ◽  
Kidney Biopsy ◽  
Characteristic Curve ◽  
Kidney Injury ◽  
Transforming Growth Factor Β ◽  
Response To Therapy ◽  
Spot Urine ◽  
Urine Biomarkers

Objective.To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN).Methods.Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-β (TGF-β), transferrin, and vitamin D binding protein (VDBP).Results.Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-β (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups.Conclusion.Low urine levels of TGF-β and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.

scholarly journals Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus

2020 ◽  
Vol 117 (10) ◽  
pp. 5409-5419 ◽  
Author(s):  
Rishi R. Goel ◽  
Xinghao Wang ◽  
Liam J. O’Neil ◽  
Shuichiro Nakabo ◽  
Kowser Hasneen ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Mesangial Cells ◽  
Human Peripheral Blood ◽  
Immune Dysregulation ◽  
Type I ◽  
Autoantibody Production ◽  
Tissue Inflammation ◽  
Type Iii

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials

Lupus ◽  
2020 ◽  
Vol 29 (14) ◽  
pp. 1845-1853
Author(s):  
Jeffery Wei Heng Koh ◽  
Cheng Han Ng ◽  
Sen Hee Tay
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Meta Analysis ◽  
Type I Interferons ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Type I Ifn ◽  
Tract Infections

Objective The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. Methods A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Results Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88–7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. Conclusion This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

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