Repeat Kidney Biopsies in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis: Clinical and Histologic Progression.
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SUBMITTER: Aqeel F
PROVIDER: S-EPMC10577318 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Repeat Kidney Biopsies in Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis: Clinical and Histologic Progression.
Aqeel Faten F Xu Lillian L Geetha Duvuru D
Kidney international reports 20230729 10
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Project description:The morbidity burden associated with anti-neutrophil cytoplasmic autoantibody-associated vasculitis is increasing, and many novel biological therapies are now entering the drug development pipeline. There is thus an urgent need to develop a representative animal model to facilitate testing of these agents. We previously examined the effect of antineutrophil cytoplasmic autoantibody on leukocyte-endothelial interactions in WKY rats via immunization with human myeloperoxidase. We now seek to extend this model so that all animals reliably develop crescentic glomerulonephritis and lung hemorrhage. We also wish to investigate whether there is a genetic contribution to vasculitis development in this rat strain. Using escalating doses of human myeloperoxidase, we found that a dose of 1600 microg/kg induced pauci-immune crescentic glomerulonephritis and lung hemorrhage in all immunized animals. We also found that the addition of pertussis toxin and killed Mycobacterium tuberculosis to the adjuvant when immunizing with 400 microg/kg of myeloperoxidase resulted in crescentic glomerulonephritis and lung hemorrhage in all animals. However, when Lewis, Wistar Furth, or Brown Norway rats were immunized using a similar protocol, no animals developed hematuria or glomerulonephritis, despite having identical levels of anti-human myeloperoxidase antibodies. We conclude that, by adjusting the immunization regimen, all WKY rats immunized with myeloperoxidase develop experimental autoimmune vasculitis, thus facilitating future therapeutic studies. The resistance of Lewis rats to experimental autoimmune vasculitis provides a genetic basis for future studies of anti-myeloperoxidase antibody-associated vasculitis.
| S-EPMC2671354 | biostudies-literature
Project description: Not available
| S-EPMC9727511 | biostudies-literature
Project description:IntroductionVenous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE.MethodsIn this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTEpos) were compared with patients without VTE (VTEneg, n = 29) and healthy controls (HC, n = 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed.ResultsVTEpos patients had higher MPTFa (peak median = 14.0, interquartile range = 4.3-36.6) than HC (0, 0-3.5) and VTEneg patients (0, 0-1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01-1.08) and remission (1.4; 1.11-1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03-1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5-12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE.ConclusionElevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.
| S-EPMC6933462 | biostudies-literature
Project description:BackgroundAnti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).MethodsThe expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.ResultsBoth GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).ConclusionsThe percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.
| S-EPMC6408823 | biostudies-literature
Project description:Anti-neutrophil cytoplasmic antibody-associated vasculitis is an uncommon inflammatory disease of small to medium-sized vessels that frequently presents with rapidly progressive glomerulonephritis and renal failure though it can affect any organ system. If untreated, the vast majority of patients will die within a year. Current treatments improve prognosis but affected patients remain at a substantially higher risk of death and adverse outcomes. We review the classification of the disease, our understanding of the pathogenesis and epidemiology, and propose future directions for research. We also evaluate the evidence supporting established treatment regimens and the progress of clinical trials for newer treatments to inform the design of future studies.
| S-EPMC4795442 | biostudies-literature
Project description:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO+ AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27+IgM+ B cells whereas MPO-specific IgG+ cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM+ anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO+ AAV etiology and thereby serve as potential target for therapy.
| S-EPMC11822119 | biostudies-literature
Project description:Two patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background.
| S-EPMC6366126 | biostudies-literature
Project description:Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epitopes in inflamed tissue. This review gives a brief overview on current knowledge about genetic and epigenetic factors, barrier dysfunction and chronic non-resolving inflammation, necro-inflammatory auto-amplification of cellular death and inflammation, altered autoantigen presentation, alternative complement pathway activation, alterations within peripheral and inflamed tissue-residing T- and B-cell populations, ectopic lymphoid tissue neoformation, the characterization of PR3-specific T-cells, properties of ANCA, links between autoimmune disease and infection-triggered pathology, and animal models in AAV.
| S-EPMC5900791 | biostudies-literature
Project description:BackgroundAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may coexist with rheumatoid arthritis (RA). However, it is unclear whether the manifestations of AAV with and without coexisting RA are similar. This observational study aimed to investigate the clinicopathological manifestations of AAV with coexisting RA and to explore potential predictors for identifying AAV superimposed on RA.MethodsPatients with both AAV and RA were identified by searching our hospital database and the literature. Data including age, sex, clinical manifestation, laboratory tests, renal pathology, and therapeutic regimens were retrieved. To assess the difference in clinical features and renal pathology between AAV patients with and without RA, we conducted 1:4 matched case-control studies.ResultsA total of 47 patients were identified, 15 from our hospital and 32 from the literature, and 33 (70.2%) were women. AAV was diagnosed later than RA in 83.0% of the patients and manifested as microscopic polyangiitis (MPA) in 78.7% of the patients. The kidney was the most frequently involved extra-articular organ (74.5%), followed by the lung (51.1%), and skin (8.5%). Patients with both AAV and RA were more likely to be asymptomatic (26.7% vs 3.3%, p = 0.013) than those with isolated AAV. However, they did not differ in other clinicopathological features. In RA patients, those with ANCA associated glomerulonephritis, were more likely to have decreased renal function at renal biopsy as opposed to those with primary glomerulonephritis.ConclusionsAAV can coexist with RA. In this coexistence, AAV usually develops after RA, is more likely to be asymptomatic, and manifests predominately as MPA with renal involvement. Thus, we should remain vigilant to superimposed AAV on RA.
| S-EPMC9026933 | biostudies-literature
Project description:•AAV is characterized by necrotizing small vessel vasculitis with positive serum ANCA.•MPO/PR3-ANCA and neutrophils play central roles in AAV pathogenicity.•Dysregulated complement system primes neutrophils.•MPO-ANCA directly activates neutrophils to induce NETosis followed by releasing NETs.•B cells, T cells, and dendritic cells also contribute to the pathogenicity of AAV.
| S-EPMC8063861 | biostudies-literature