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Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

ABSTRACT: Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8+ Tm cells expressing high voltage-dependent Kv1.3 potassium channels-key T cell function regulators-in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells (Kv1.3-NPs) reduced CD40L and interferon-? (IFN?) in Tm cells from LN patients in vitro. Kv1.3-NPs were tested in humanized LN mice obtained by engrafting peripheral blood mononuclear cells (PBMCs) from LN patients into immune-deficient mice. LN mice exhibited features of the disease: increased IFN? and CD3+CD8+ T cell renal infiltration, and reduced survival versus healthy donor PBMC engrafted mice. Kv1.3-NP treatment of patient PBMCs before engraftment decreased CD40L/IFN? and prolonged survival of LN mice. These data show the potential benefits of targeting Kv1.3 in LN.

SUBMITTER: Khodoun M

PROVIDER: S-EPMC7673800 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

Khodoun Marat M Chimote Ameet A AA Ilyas Farhan Z FZ Duncan Heather J HJ Moncrieffe Halima H Kant K Shashi KS Conforti Laura L

Science advances 20201118 47

Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8<sup>+</sup> Tm cells expressing high voltage-dependent Kv1.3 potassium channels-key T cell function regulators-in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells ...[more]

PMID: 33208373

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Project description:ObjectivesThis study aims to correlate subclinical echocardiographic features with the clinical, laboratory, and therapeutic profiles of the patients to characterize risks for systemic lupus erythematosus (SLE) cardiac diseases.MethodsThe study included 59 SLE patients. Demographic data, disease characteristics, and current therapies were recorded, and the anthropometric measurements and routine laboratory tests were performed. The disease activity by the SLE Disease Activity Index-2K (SLEDAI2K) and the presence of metabolic syndrome (MetS) were assessed. Two-dimensional echocardiography was performed.ResultsThe mean age of the patients was 31.3 ± 10.5 years, and the disease duration was 5.18 ± 4.1 years. 86.4% of the patients were females. Cardiac presentations by echocardiography were mainly mitral regurgitation (33.9%), tricuspid regurgitation (32.2%), mitral thickening (18.6%), aortic thickening (13.6%), pericardial effusion (13.6%), and pulmonary hypertension (8.5%) in order of frequency. The frequency of different echocardiographic findings with respect to other clinical phenotypes showed peaks with renal disease, MetS, and leukopenia. Components of MetS (triglycerides, high systolic blood pressure) and avascular necrosis were significant predictors for pericardial diseases (OR=1.011 CI 95% 1-1.022, p=0.046, OR=1.157 CI 95% 1.025-1.307, p=0.018, and OR=74.78 CI 95% 2.52-2215.76, p=0.013, respectively), and it is likely that hydroxychloroquine was protective against them. Age of the patients was a significant predictor for tricuspid regurgitation (OR=1.063 CI 95% 1.004-1.126, p=0.036). Mucosal ulcers were negative predictors for mitral thickening and regurgitation (OR=0.2 CI 95% 0.059-0.673, p=0.009). The use of corticosteroids appeared to protect against a number of valve lesions especially tricuspid regurgitation (OR=0.299 CI 95% 0.088-1.019, p=0.054).ConclusionThis study highlighted different echocardiographic features and identified clinical predictors of different cardiac pathologies aiming to determine patients at risk and improve the prognosis of SLE cardiac diseases.

Project description:OBJECTIVE: To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features. METHODS: We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay. RESULTS: We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33 ± 4.50), 64 first-degree relatives (mean age 39.95 ± 5.66), and 57 healthy (mean age 19.30 ± 4.97) controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their first-degree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels. CONCLUSION: Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in longitudinal studies to determine whether elevated interferon alpha levels may predict systemic lupus erythematosus flares.

Dataset Information

Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

Publications

Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

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