PANCA autoantibody testing by indirect immunofluorescence indicates interstitial arteritis independent of MPO-ANCA immunoassays in ANCA-associated glomerulonephritis.
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ABSTRACT:
SUBMITTER: Hakroush S
PROVIDER: S-EPMC9107432 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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pANCA autoantibody testing by indirect immunofluorescence indicates interstitial arteritis independent of MPO-ANCA immunoassays in ANCA-associated glomerulonephritis.
Hakroush Samy S Kluge Ingmar Alexander IA Baier Eva E Korsten Peter P Tampe Desiree D Ströbel Philipp P Tampe Björn B
Journal of nephrology 20220405 4
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Project description:Although interstitial pneumonia is an important respiratory manifestation in microscopic polyangiitis (MPA), no studies have examined the detailed pathogenesis of interstitial pneumonia during the clinical course of MPA. In addition, it is considered that MPA develops at a certain incidence rate from myeloperoxidase (MPO)- antineutrophil cytoplasmic antibody (ANCA) positive interstitial pneumonia. However, there is a lack of consensus among pulmonologist and rheumatologist regarding whether MPO-ANCA positive interstitial pneumonia, which does not accompany other organ damage related to ANCA-associated vasculitis (AAV) other than interstitial pneumonia, should be included in AAV. In this review article, the clinical questions regarding MPO-ANCA positive interstitial pneumonia have been set, and evidence to date and problems to be solved in future are outlined.
| S-EPMC8787377 | biostudies-literature
Project description:BackgroundRapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN).MethodsClinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed.ResultsIn our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman's capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively).ConclusionIn conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.
| S-EPMC8027492 | biostudies-literature
Project description:Early diagnosis and initiation of appropriate immunosuppressive treatment remain the cornerstone of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis at the cost of significant toxicity. In this report, we present a case of a 69-year-old female who presented with advanced renal insufficiency and evidence of pulmonary hemorrhage and was MPO-ANCA-positive with a clinical phenotype of granulomatosis with polyangiitis. Organ involvement included rapidly progressive glomerulonephritis (GN), along with extrarenal manifestations (skin, upper and lower respiratory system involvement, and onset of saddle-nose deformity). Kidney biopsy established the diagnosis of pauci-immune crescentic, sclerotic GN. She received therapy with glucocorticoids and cyclophosphamide, mainly due to life-threatening extra-renal manifestations, such as pulmonary hemorrhage. She avoided vasculitis-related death but she developed severe therapy-related toxicity, resulting in the discontinuation of immunosuppressive therapy. Continuous re-evaluation of patients with ANCA-associated vasculitis in terms of response to immunosuppressive therapy and treatment-related toxicity is crucial for their management.
| S-EPMC9149920 | biostudies-literature
Project description:The etiopathogenesis underlying myeloperoxidase anti-neutrophil cytoplasmic antibody associated glomerulonephritis (MPO-AAGN) remains incompletely understood. Furthermore, there are only limited treatment options and treatment resistance of MPO-AAGN is still a common problem. To identify new targeted treatment options, intrarenal single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from MPO-AAGN patients and control health kidney tissues to define the transcriptomic landscape at single-cell resolution. Intrarenal scRNAseq was also applied to a pre-clinical mouse model of MPO-AAGN to show that this model of disease can be used to trial new targeted treatments. NF-κB pathway activation was confirmed in a variety of kidney cells in MPO-AAGN patients. Kidney infiltrating immune cells of MPO-AAGN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. These findings were similar in our pre-clinical mouse model of MPO-AAGN. Furthermore, there was an overexpression of inflammasome related genes (AIM2, IFI16) in MPO-AAGN patients. A dynamic gene expression in glomerular resident cells was observed in MPO-AAGN, including increased expression of several genes, including CD9 and SPARC, which were closely related to parietal epithelial hyperplasia and crescent formation and lesion progression. Importantly, overexpression of HSP90AA1 in non-focal mesangial cells and endothelial cells was found and the expression of several chemokines (CCL20, CXCL3, CXCL8, CXCL1, CCL2) were upregulated in non-focal proximal tubule cells. Moreover, MPO-AAGN patients with treatment resistance had higher proportions of kidney infiltrating classical monocytes and CD8+ T cells. Elevated expression of SPARC and LAMA4 in mesangial cells, IL33 in endothelial cells, and CFL1 in several cell clusters (proximal tubule cells, loop of Helen, macrophages) were observed in MPO-AAGN patients with treatment resistance when compared with patients who achieved remission after induction therapy. These results offer new insight into the pathogenesis of the progression and treatment resistance MPO-AAGN. We have identified new therapeutic targets for MPO-AAGN that can be tested in a pre-clinical model of disease.
2024-01-01 | GSE229857 | GEO
Project description:The presence of a lung lesion is common in microscopic polyangiitis (MPA), and interstitial lung disease (ILD) can lead to a poor prognosis. Although myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) are often present in patients with MPA, patients with ILD and MPO-ANCA positivity but without other manifestations of systemic vasculitis have also been reported. Therefore, the possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. This problematic matter has influenced the treatment strategy of MPO-ANCA-positive ILD patients without systemic vasculitis. Clinicians should undertake treatment with careful consideration of the four major causes of death in MPO-ANCA-positive ILD: acute exacerbation of ILD, progressive lung fibrosis, infectious comorbidities, and diffuse alveolar hemorrhage. Further, clinicians need to carefully judge whether inflammation or fibrosis is the dominant condition with reference to the patient's clinical domain and radiopathological lung features. Recently, anti-fibrotic agents such as nintedanib and pirfenidone were shown to be effective in treating various etiologies associated with ILD and have thus led to the widening of treatment options. In this review, the clinical characteristics, radiopathology, prognosis, and therapeutic options in patients with MPO-ANCA-positive ILD are summarized using limited information from previous studies.
| S-EPMC9267459 | biostudies-literature
Project description: Not available
| S-EPMC9091588 | biostudies-literature
Project description:A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.
| S-EPMC9977496 | biostudies-literature
Project description:ObjectiveTo identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.MethodsA previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.Resultsrs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.ConclusionsFemales and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
| S-EPMC10473270 | biostudies-literature
Project description:Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.
| S-EPMC5156375 | biostudies-literature
Project description:Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing. The major focus is on host immunity and microbiological invasion. However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs. Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets. An important immune responder cell population in host defense and autoimmunity is the neutrophil. One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis. This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters). One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments. In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues. The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils. Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney. Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO. It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target. Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury. The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.
| S-EPMC8005609 | biostudies-literature