Publications by authors named "Mark A Little"

98 Publications

The Clinical Application of Urine Soluble CD163 in ANCA-Associated Vasculitis.

J Am Soc Nephrol 2021 11 13;32(11):2920-2932. Epub 2021 Sep 13.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Background: Up to 70% of patients with ANCA-associated vasculitis (AAV) develop GN, with 26% progressing to ESKD. Diagnostic-grade and noninvasive tools to detect active renal inflammation are needed. Urinary soluble CD163 (usCD163) is a promising biomarker of active renal vasculitis, but a diagnostic-grade assay, assessment of its utility in prospective diagnosis of renal vasculitis flares, and evaluation of its utility in proteinuric states are needed.

Methods: We assessed a diagnostic-grade usCD163 assay in () a real-world cohort of 405 patients with AAV and 121 healthy and 488 non-AAV disease controls; () a prospective multicenter study of 84 patients with potential renal vasculitis flare; () a longitudinal multicenter cohort of 65 patients with podocytopathy; and () a cohort of 29 patients with AAV (with or without proteinuria) and ten controls.

Results: We established a diagnostic reference range, with a cutoff of 250 ng/mmol for active renal vasculitis (area under the curve [AUC], 0.978). Using this cutoff, usCD163 was elevated in renal vasculitis flare (AUC, 0.95) but remained low in flare mimics, such as nonvasculitic AKI. usCD163's specificity declined in patients with AAV who had nephrotic-range proteinuria and in those with primary podocytopathy, with 62% of patients with nephrotic syndrome displaying a "positive" usCD163. In patients with AAV and significant proteinuria, usCD163 normalization to total urine protein rather than creatinine provided the greatest clinical utility for diagnosing active renal vasculitis.

Conclusions: usCD163 is elevated in renal vasculitis flare and remains low in flare mimics. Nonspecific protein leakage in nephrotic syndrome elevates usCD163 in the absence of glomerular macrophage infiltration, resulting in false-positive results; this can be corrected with urine protein normalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2021030382DOI Listing
November 2021

Dynamic Assay for Profiling Anti-SARS-CoV-2 Antibodies and Their ACE2/Spike RBD Neutralization Capacity.

Viruses 2021 07 15;13(7). Epub 2021 Jul 15.

Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, D08 W9RT Dublin, Ireland.

Serological assays have been widely employed during the coronavirus disease 2019 (COVID-19) pandemic to measure antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to track seroconversion in populations. However, currently available assays do not allow determination of neutralization capacity within the assay protocol. Furthermore, commercial serology assays have a high buy-in cost that is inaccessible for many research groups. We have replicated the serological enzyme-linked immunosorbent assay for the detection of SARS-CoV-2 antibody isotypes, developed at the Icahn School of Medicine at Mount Sinai, New York. Additionally, we have modified the protocol to include a neutralization assay with only a minor modification to this protocol. We used this assay to screen local COVID-19 patient sera ( = 91) and pre-COVID-19 control sera ( = 103), and obtained approximate parity with approved commercial anti-nucleoprotein-based assays with these sera. Furthermore, data from our neutralization assay closely aligns with that generated using a spike-based pseudovirus infection model when a subset of patient sera was analyzed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v13071371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309970PMC
July 2021

A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.

Sci Rep 2021 06 22;11(1):13080. Epub 2021 Jun 22.

Trinity Health Kidney Centre, Trinity College Dublin, The University of Dublin, Dublin, Ireland.

Data surrounding sex-specific differences in ANCA-associated vasculitis glomerulonephritis (ANCA-GN) outcomes is sparse. We hypothesised that the previously observed increased risk of end-stage kidney disease (ESKD) in males is driven by sex-specific variation in immunosuppression dosing. Patients were recruited to the Irish Rare Kidney Disease Registry or followed by the Royal Free Hospital vasculitis team (2012-2020). Inclusion criteria: prior diagnosis of ANCA-GN (biopsy proven pauci-immune glomerulonephritis) and positive serology for anti-MPO or -PR3 antibodies. Renal and patient survival, stratified by sex and Berden histological class, was analysed. The cumulative- and starting dose/kilogram of induction agents and prednisolone, respectively, was compared between sexes. 332 patients were included. Median follow-up was time 40.2 months (IQR 17.3-69.2). 73 (22%) reached ESKD and 47 (14.2%) died. Overall 1- and 5-year renal survival was 82.2% and 76.7% in males and 87.1% and 82.0% in females, respectively (p 0.13). The hazard ratio for ESKD in males versus females, after adjustment for age, ANCA serology, baseline creatinine and histological class was 1.07 (95% CI 0.59-1.93). There was no difference between sexes in the dose/kilogram of any induction agent. We did not observe a strong impact of sex on renal outcome in ANCA-GN. Treatment intensity does not vary by sex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-92629-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219762PMC
June 2021

Acute renal allograft failure in a patient with vasculitis.

Rheumatology (Oxford) 2021 06;60(Suppl 3):iii43-iii46

Beaumont Hospital Kidney Centre, Trinity Translational Medicine Institute, Dublin, Ireland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210578PMC
June 2021

Neutrophils: Need for Standardized Nomenclature.

Front Immunol 2021 15;12:602963. Epub 2021 Apr 15.

Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin, Ireland.

Neutrophils are the most abundant innate immune cell with critical anti-microbial functions. Since the discovery of granulocytes at the end of the nineteenth century, the cells have been given many names including phagocytes, polymorphonuclear neutrophils (PMN), granulocytic myeloid derived suppressor cells (G-MDSC), low density neutrophils (LDN) and tumor associated neutrophils (TANS). This lack of standardized nomenclature for neutrophils suggest that biologically distinct populations of neutrophils exist, particularly in disease, when in fact these may simply be a manifestation of the plasticity of the neutrophil as opposed to unique populations. In this review, we profile the surface markers and granule expression of each stage of granulopoiesis to offer insight into how each stage of maturity may be identified. We also highlight the remarkable surface marker expression profiles between the supposed neutrophil populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.602963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081893PMC
June 2021

Investigation of type I interferon responses in ANCA-associated vasculitis.

Sci Rep 2021 04 15;11(1):8272. Epub 2021 Apr 15.

Department of Medical Gerontology, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-87760-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050071PMC
April 2021

Risk Factors for Severe Outcomes in Patients With Systemic Vasculitis and COVID-19: A Binational, Registry-Based Cohort Study.

Arthritis Rheumatol 2021 09 27;73(9):1713-1719. Epub 2021 Jul 27.

University of Glasgow, Glasgow, UK.

Objective: COVID-19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and may be at risk of severe outcomes following COVID-19. We undertook this study to establish the risk factors for severe COVID-19 outcomes in these patients, including the impact of immunosuppressive therapies.

Methods: A multicenter cohort was developed through the participation of centers affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes are described. Logistic regression was used to evaluate associations between potential risk factors and a severe COVID-19 outcome, defined as a requirement for advanced oxygen therapy, a requirement for invasive ventilation, or death.

Results: The cohort included 65 patients with systemic vasculitis who developed COVID-19 (median age 70 years, 49% women), of whom 25 patients (38%) experienced a severe outcome. Most patients (55 of 65 [85%]) had antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Almost all patients required hospitalization (59 of 65 [91%]), 7 patients (11%) were admitted to intensive care, and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcomes (adjusted odds ratio [OR] 3.7 [95% confidence interval 1.1-14.9]; P = 0.047), as was comorbid respiratory disease (adjusted OR 7.5 [95% confidence interval 1.9-38.2]; P = 0.006). Vasculitis disease activity and nonglucocorticoid immunosuppressive therapy were not associated with severe outcomes.

Conclusion: In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID-19. These data can inform clinical decision-making relating to the risk of severe COVID-19 in this vulnerable patient group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251299PMC
September 2021

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

Rheumatology (Oxford) 2021 Oct;60(10):4654-4661

Department of Medicine, University of Cambridge, Cambridge, UK.

Objective: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America.

Methods: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs.

Results: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE.

Conclusion: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab071DOI Listing
October 2021

Pro-inflammatory Stimulation of Monocytes by ANCA Is Linked to Changes in Cellular Metabolism.

Front Med (Lausanne) 2020 8;7:553. Epub 2020 Sep 8.

Department of Clinical Medicine, Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland.

Clinical and experimental data suggest that pathogenesis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is driven by ANCA-mediated activation of neutrophils and monocytes. While the role of neutrophils has been extensively investigated, the function of monocytes remains relatively understudied. We have previously demonstrated that stimulation of monocytes with anti-myeloperoxidase (MPO), but not anti-proteinase-3 (PR3), antibodies results in production of the pro-inflammatory cytokine IL-1β. Changes in cellular metabolism, particularly a switch to glycolysis, have recently been linked to activation of immune cells and production of IL-1β. Therefore, we investigated the metabolic profile of monocytes following ANCA stimulation. We found a significant increase in glucose uptake in anti-MPO stimulated monocytes. Interestingly, both anti-MPO and anti-PR3 stimulation resulted in an immediate increase in glycolysis, measured by Seahorse extracellular flux analysis. However, this increase in glycolysis was sustained (for up to 4 h) in anti-MPO- but not anti-PR3-treated cells. In addition, only anti-MPO-treated cells exhibited increased oxidative phosphorylation, a metabolic response that correlated with IL-1β production. These data indicate that monocyte metabolism is altered by ANCA, with divergent responses to anti-MPO and anti-PR3 antibodies. These metabolic changes may underlie pathologic immune activation in ANCA associated vasculitis, as well as potentially contributing to the differing clinical phenotype between PR3- and MPO-ANCA positive patients. These metabolic pathways may therefore be potential targets for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2020.00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509421PMC
September 2020

Environmental risk factors associated with ANCA associated vasculitis: A systematic mapping review.

Autoimmun Rev 2020 Nov 15;19(11):102660. Epub 2020 Sep 15.

Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland; ADAPT Centre, Trinity College Dublin, Ireland. Electronic address:

Background: Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a rare multi-system autoimmune disease, characterised by a pauci-immune necrotising small-vessel vasculitis, with a relapsing and remitting course. Like many autoimmune diseases, the exact aetiology of AAV, and the factors that influence relapse are unknown. Evidence suggests a complex interaction of polygenic genetic susceptibility, epigenetic influences and environmental triggers. This systematic mapping review focuses on the environmental risk factors associated with AAV. The aim was to identify gaps in the literature, thus informing further research.

Methods: Articles that examined any environmental risk factor in AAV disease activity (new onset disease or relapse) were included. Studies had to make explicit reference to AAV, which includes the 3 clinico-pathological phenotypes (GPA, MPA and EGPA), rather than isolated ANCA-positivity. All articles identified were English-language, full manuscripts involving adult humans (>16 years). There was no restriction on publication date and all study designs, except single case reports, were included. The systematic search was performed on 9th December 2019, using the following databases: EMBASE, Medline (Ovid), Cochrane Library, CINAHL and Web of Science.

Results: The search yielded a total of 2375 articles. 307 duplicates were removed, resulting in the title and abstract of 2068 articles for screening. Of these, 1809 were excluded. Thus, 259 remained for full-text review, of which 181 were excluded. 78 articles were included in this review. The most notable findings support the role of various pollutants - primarily silica and other environmental antigens released during natural disasters and through farming. Assorted geoepidemiological triggers were also identified including seasonality and latitude-dependent factors such as UV radiation. Finally, infection was tightly associated, but the exact microorganism(s) is not clear - Staphylococcus aureus is the most presently convincing.

Conclusion: The precise aetiology of AAV has yet to be elucidated. It is likely that different triggers, and the degree to which they influence disease activity, vary by subgroup (e.g. ANCA subtype, geographic region). There is a need for more interoperable disease registries to facilitate international collaboration and hence large-scale epidemiological studies, with novel analytical techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2020.102660DOI Listing
November 2020

2020 international consensus on ANCA testing beyond systemic vasculitis.

Autoimmun Rev 2020 Sep 12;19(9):102618. Epub 2020 Jul 12.

Laboratory Medicine, University Hospitals Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2020.102618DOI Listing
September 2020

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

Am J Respir Crit Care Med 2020 Jun 25. Epub 2020 Jun 25.

University of Alberta, Medicine, Edmonton, Alberta, Canada.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work‑up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202005-1628SODOI Listing
June 2020

Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner.

Clin Sci (Lond) 2020 06;134(12):1475-1489

Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20200497DOI Listing
June 2020

Pathogenesis of ANCA-associated vasculitis: an emerging role for immunometabolism.

Rheumatology (Oxford) 2020 05;59(Suppl 3):iii33-iii41

Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.

ANCA-associated vasculitis (AAV) is a severe systemic autoimmune disease. A key feature of AAV is the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) or proteinase-3 (PR3). ANCA are key to the pathogenesis of AAV, where they activate innate immune cells to drive inflammation. Pre-activation or 'priming' of immune cells appears to be important for complete cellular activation in AAV. The burgeoning field of immunometabolism has illuminated the governance of immune cell function by distinct metabolic pathways. There is ample evidence that the priming events synonymous with AAV alter immune cell metabolism. In this review we discuss the pathogenesis of AAV and its intersection with recent insights into immune cell metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa023DOI Listing
May 2020

Coaxing Anti-Inflammatory Granulocytes to Prevent Ischemic Kidney Injury: A Fine Balance.

J Am Soc Nephrol 2020 04 4;31(4):668-670. Epub 2020 Mar 4.

Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Saint James's Hospital Campus, Dublin, Ireland

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191930PMC
April 2020

Targeting of the cGAS-STING system by DNA viruses.

Biochem Pharmacol 2020 04 28;174:113831. Epub 2020 Jan 28.

Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James' Hospital Campus, Dublin, Ireland. Electronic address:

Innate sensing of viruses by cytosolic nucleic acid sensors is a key feature of anti-viral immunity against these pathogens. The DNA sensing pathway through the sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) has emerged in recent years as a key, front-line means of driving interferons and pro-inflammatory cytokines in response to DNA virus infection in vertebrates. Unsurprisingly, many DNA viruses have evolved effective inhibitors of this signalling system which target at a wide variety of points from sensing all the way down to the activation of Interferon Regulatory Factor (IRF)-family and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-family transcription factors which drive a program of pro-inflammatory and anti-viral gene expression. Here we review DNA viruses that have been shown to inhibit this pathway and the inhibitors they have evolved to do it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2020.113831DOI Listing
April 2020

Towards European harmonisation of healthcare for patients with rare immune disorders: outcome from the ERN RITA registries survey.

Orphanet J Rare Dis 2020 01 30;15(1):33. Epub 2020 Jan 30.

UOSID Centro Trial, PRINTO, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network is a European Research Network (ERN) that brings together the leading centres for rare immune disorders. On April 2018 an online survey was sent to all RITA members in order to facilitate the harmonization of data collection in rare immune disorders registries. Currently, as many as 52 different registries collect data on rare immune disorders, of whom 30 (58%) are dedicated primarily to autoimmune diseases, 15 (29%) to primary immunodeficiencies and 12 (23%) to autoinflammatory disorders. Improving data on patient safety, outcome, and quality of life measures is warranted to unfold the full potential of RITA registries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-1308-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993334PMC
January 2020

Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease.

Clin Transplant 2020 02 5;34(2):e13783. Epub 2020 Feb 5.

Nephrology Department, Beaumont Hospital, Dublin, Ireland.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure.

Methods: Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non-ADTKD renal transplant recipients.

Results: We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite-ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow-up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty-five transplant biopsies were performed during follow-up, and none of these showed signs of recurrent ADTKD post-transplant.

Conclusion: In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ctr.13783DOI Listing
February 2020

A novel 4-dimensional live-cell imaging system to study leukocyte-endothelial dynamics in ANCA-associated vasculitis.

Autoimmunity 2020 05 23;53(3):148-155. Epub 2019 Dec 23.

Renal Unit, Aberdeen Royal Infirmary, Aberdeen, Scotland.

Neutrophils, monocytes and the endothelium are critical to ANCA-associated vasculitis (AAV) pathogenesis. This study aimed to develop a 4-dimensional (4D) live-cell imaging system that would enable investigation of spatial and temporal dynamics of these cells in health and disease. We further aimed to validate this system using autologous donor serum from AAV patients and polyclonal ANCA IgG, as well as exploring its potential in the pre-clinical testing of putative therapeutic compounds. Neutrophils and monocytes were isolated from peripheral venous blood of AAV patients or healthy controls and co-incubated on an endothelial monolayer in the presence of autologous serum. Alternatively, polyclonal ANCA IgG was used, following TNF-α priming, and imaged in 4-dimensions for 3 h using a spinning disc confocal microscope. Volocity 6.3 analysis software was used for quantification of leukocyte dynamics. The use of autologous serum resulted in increased neutrophil degranulation ( = .002), transmigration ( = .0096) and monocyte transcellular transmigration ( = .0013) in AAV patients. Polyclonal MPO-ANCA IgG induced neutrophil degranulation ( < .001) in this system. C5aR1 antagonism reduced neutrophil degranulation ( < .0002). We have developed a novel 4D system that allows accurate quantification of multiple neutrophil- and monocyte-endothelial interactions in AAV in a single assay. This system has the potential to highlight dynamics key to pathophysiology of disease, as well investigating the impact of potential therapeutics on these functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08916934.2019.1704274DOI Listing
May 2020

Utility of Genomic Testing after Renal Biopsy.

Am J Nephrol 2020 10;51(1):43-53. Epub 2019 Dec 10.

Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.

Background: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment.

Methods: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared.

Results: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39).

Conclusions: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000504869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957728PMC
February 2021

Low Density Granulocytes in ANCA Vasculitis Are Heterogenous and Hypo-Responsive to Anti-Myeloperoxidase Antibodies.

Front Immunol 2019 7;10:2603. Epub 2019 Nov 7.

Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.

Low Density Granulocytes (LDGs), which appear in the peripheral blood mononuclear cell layer of density-separated blood, are seen in cancer, sepsis, autoimmunity, and pregnancy. Their significance in ANCA vasculitis (AAV) is little understood. As these cells bear the autoantigens associated with this condition and have been found to undergo spontaneous NETosis in other diseases, we hypothesized that they were key drivers of vascular inflammation. We found that LDGs comprise a 3-fold higher fraction of total granulocytes in active vs. remission AAV and disease controls. They are heterogeneous, split between cells displaying mature (75%), and immature (25%) phenotypes. Surprisingly, LDGs (unlike normal density granulocytes) are hyporesponsive to anti-myeloperoxidase antibody stimulation, despite expressing myeloperoxidase on their surface. They are characterized by reduced CD16, CD88, and CD10 expression, higher LOX-1 expression and immature nuclear morphology. Reduced CD16 expression is like that observed in the LDG population in umbilical cord blood and in granulocytes of humanized mice treated with G-CSF. LDGs in AAV are thus a mixed population of mature and immature neutrophils. Their poor response to anti-MPO stimulation suggests that, rather than being a primary driver of AAV pathogenesis, LDGs display characteristics consistent with generic emergency granulopoiesis responders in the context of acute inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856659PMC
September 2020

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.

Nat Commun 2019 11 12;10(1):5120. Epub 2019 Nov 12.

Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12515-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851141PMC
November 2019

Monogenic causes of chronic kidney disease in adults.

Kidney Int 2019 04 14;95(4):914-928. Epub 2019 Feb 14.

National Paediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children's University Hospital, Dublin, Ireland.

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2018.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431580PMC
April 2019

Predictors of Renal Outcomes in Sclerotic Class Anti-Neutrophil Cytoplasmic Antibody Glomerulonephritis.

Am J Nephrol 2018 23;48(6):465-471. Epub 2018 Nov 23.

Johns Hopkins University, Baltimore, Maryland, USA.

Background: The prognostic value of the anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (GN) classification has been demonstrated in several cohorts with sclerotic class having the worst renal outcome. Relevant published data on factors predicting outcomes in sclerotic ANCA GN is limited.

Methods: Sclerotic ANCA GN patients were recruited from 5 centers worldwide for this retrospective cohort study. We describe the clinical characteristics of this cohort and evaluate predictors of 1-year glomerular filtration rate (GFR) and end-stage renal disease (ESRD). Kidney function at 12 months as measured by Modification of Diet in Renal Disease estimated GFR (eGFR) was modeled by simple and multiple linear regression analyses. We used Cox proportional hazards regression modeling to evaluate ESRD-free survival.

Results: Of the 50 patients, 92% were Caucasian and 60% male with a mean age of 61 years. While 72% had renal limited disease, 82% were MPO ANCA positive. Kidney biopsies contained a median of 20 (interquartile range [IQR] 15-34) glomeruli with 96% showing moderate to severe interstitial fibrosis. Overall, 96% of patients received immunosuppressive drug therapy and 16% received plasmapheresis. Treatment response was achieved in all but 1 patient. The median (IQR) eGFR at entry was 14.5 (9-19) mL/min/1.73 m2. Over a median (IQR) follow-up of 33.5 (17-82) months, 26 patients reached ESRD. Ten patients died with 6 of the deaths occurring within the first year of diagnosis. The hazard of progression to ESRD was significantly higher in those with lower GFR at study entry (p = 0.003) and with higher degree of tubular atrophy (p = 0.043).

Conclusions: Renal recovery is rare among sclerotic ANCA GN patients requiring dialysis at entry and 12% of patients died in the first year. Entry GFR and tubular atrophy were significant predictors of GFR at 12 months and renal survival in patients with sclerotic class ANCA GN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000494840DOI Listing
November 2019

Effect of Disease Activity at Three and Six Months After Diagnosis on Long-Term Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2019 05 28;71(5):784-791. Epub 2019 Mar 28.

University of Cambridge, Cambridge, UK.

Objective: The treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) aims to suppress disease activity and prevent subsequent disease flare. This study sought to explore the association of early disease control with long-term outcomes to validate early disease control as an end point for future clinical trials in AAV.

Methods: Data from 4 European Vasculitis Society inception clinical trials in AAV (1995-2002) and subsequent data on long-term outcomes from the trial data registry were studied. Clinical parameters in patients with AAV at baseline and at 3 and 6 months after diagnosis were assessed to study the long-term risk of death and end-stage renal failure (ESRF). At 6 months, outcomes were defined based on a disease status of either sustained remission (remission by 3 months, sustained to 6 months), late remission (remission after 3 months and by 6 months), relapsing disease (remission by 3 months but relapse by 6 months), or refractory disease (no remission by 6 months).

Results: Of the 354 patients with AAV who were followed up for a median of 5.7 years, 46 (13%) developed ESRF, 66 (18.6%) died, and 89 (25.1%) had either died or developed ESRF. At 6 months, predictors of the composite end point of death or ESRF were as follows: age (hazard ratio [HR] 1.02, 95% confidence interval [95% CI] 1-1.05; P = 0.012), estimated glomerular filtration rate (HR 0.94, 95% CI 0.92-0.95; P < 0.001), and disease status at 6 months (late remission, HR 2.94, 95% CI 1.1-7.85 [P = 0.031]; relapsing disease, HR 8.21, 95% CI 2.73-24.65 [P < 0.001]; refractory disease, HR 4.89, 95% CI 1.96-12.18 [P = 0.001]). Similar results were observed when these analyses were performed separately for death and for ESRF.

Conclusion: The results of this study suggest that disease status at 3 and 6 months following the diagnosis of AAV may be predictive of the long-term risk of mortality and ESRF, and therefore these may be valid end points for induction trials in AAV. The current findings need to be validated in a larger data set.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40776DOI Listing
May 2019

Urinary soluble CD163 and monocyte chemoattractant protein-1 in the identification of subtle renal flare in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Nephrol Dial Transplant 2020 02;35(2):283-291

Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland.

Background: Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1).

Methods: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV.

Results: Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8-1.2] in remission and 1.4 mg/dL (IQR 1.0-1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79-337), 44 (17-104) and 38 (7-76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6-23.5), 4.1 (2.5-8.4) and 4.1 (1.9-6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2.

Conclusion: A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfy300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205505PMC
February 2020

A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis.

Rheumatology (Oxford) 2019 02;58(2):260-268

University College London Centre for Nephrology, Royal Free Hospital, London, UK.

Objectives: Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV.

Methods: Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded.

Results: A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04).

Conclusion: Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/key288DOI Listing
February 2019

Comparisons of Guidelines and Recommendations on Managing Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Kidney Int Rep 2018 Sep 24;3(5):1039-1049. Epub 2018 May 24.

Department of Medicine, Mount Sinai Hospital, University Health Network, Toronto, Ontario, Canada.

Antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) is associated with high morbidity or mortality, especially if not promptly diagnosed and treated. Many inroads have been made in the understanding of the pathophysiology that leads to exploration of novel therapies. Randomized controlled trials over the last 2 decades have better delineated and expanded therapeutic options and set the stage for an evidence-based approach. Since 2014, 4 scientific societies have systematically reviewed the existing data and have formulated evidence-based recommendations for the management of AAV. These recommendations cover diagnosis, remission induction and maintenance treatment, and prevention of long-term complications. This review is a comparative analysis of the recently published recommendations of the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association, the British Society of Rheumatology, the Canadian Vasculitis Research Network, and the Brazilian Society of Rheumatology, and aims to determine common ground among them and highlights the differences among the recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2018.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127414PMC
September 2018
-->