Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management

Trivioli, Giorgio; Márquez, Ana; Martorana, Davide; Tesi, Michelangelo; Kronbichler, Andreas; Lyons, Paul; Vaglio, Augusto

doi:10.1038/s41584-022-00819-y

Cited by 38 publications

(20 citation statements)

References 171 publications

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“…Most HLA genes are closely related to ferroptosis regulators, and many studies have found high expression of HLA-related genes and immune checkpoint-associated proteins in tumor patients with high ferroptosis expression, and they are better predictors of survival in tumor patients 37,38 . Meanwhile, in line with the ndings of this study, other clinical subtypes of AAV have been shown to be linked to HLA genes, including GPA (granulomatosis with polyangiitis) with HLA-DP1, MPA (microscopic polyangiitis) with HLA-DQ, and EGPA (eosinophilic granulomatosis with polyangiitis) with HLA-DRB4 39 . In particular, we found that CD44 exhibited strong correlation with most HLA genes.…”

Section: Discussionsupporting

confidence: 87%

Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Zeng

et al. 2022

Preprint

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Objective: To investigate the role of ferroptosis in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal injury. Methods: GSE104954 and GSE108112 were retrieved from the GEO database and concatenated into one dataset. Expression of ferroptosis-related genes (FRGs) was extracted for differential analysis. The ferroptosis signature genes were identified by LASSO regression and SVM-RFE, and their differential expression levels and diagnostic efficacy were verified by independent data sets. The ceRNA (miRNA-TF-mRNA) regulatory network and clinical diagnostic model were constructed respectively. By using consensus clustering, ferroptosis subtypes were identified. ssGSEA and GSVA were employed to assess immune response and pathway activation. Pan-cancer genes were found in TCGA and GTEx. Differential expression of CD44 in was validated by qPCR and immunohistochemistry from HPA database. Results:Twenty-four FRGs were differentially expressed in patients with AAV kidney injury. Furthermore, five ferroptosis signature genes were identified by two machine learning algorithms. Not only were differentially expressed in independent datasets, the clinical diagnostic model constructed by these genes provided reference for clinical decision-making, but also the ceRNA network revealed their complex regulatory mechanisms. Unsupervised clustering analysis discovered two ferroptosis subtypes with distinct gene expression, immunological microenvironment, and biological functioning pathways. Notably, CD44 was found to be closely associated with many immune cells, most immune responses, and HLA genes, as well as prognosis, immune cell infiltration, TMB, and MSI in patients with a variety of tumors, suggesting it may be a potential intervention target for human diseases including AAV renal injury and tumors. Conclusions:Ferroptosis in AAV with renal injury is significantly correlated with the immunological microenvironment. For AAV with renal injury and tumors, CD44 could be a useful intervention target.

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Section: Discussionsupporting

confidence: 87%

Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Zeng

et al. 2022

Preprint

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“…MPO or PR3 on neutrophil plasma membranes combines with ANCAs that are produced by B cells, which promote the release of destructive proteases, oxygen radicals, as well as autoantigens. Subsequent tissue damage may result in organ dysfunction ( 4 , 5 ).…”

Section: Discussionmentioning

confidence: 99%

Microscopic polyangiitis presenting with persistent cough and hemoptysis in pediatrics: A case report and review of the literature

Zhu

Zheng

2022

Front. Oncol.

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BackgroundMicroscopic polyangiitis (MPA) is a necrotizing vasculitis that involves small- and medium-sized vessels and is associated with the presence of antineutrophil cytoplasmic antibodies with a perinuclear staining pattern (p-ANCA). The kidney and lungs are the organs primarily affected. MPA is rare in children and is easily misdiagnosed. Below is a complete case history of the course of the disease.Case presentationAn 11-year-old girl with a 1-month history of cough and hemoptysis showed no improvement after imipenem-cilastatin treatment. p-ANCA and microscopic hematuria and proteinuria were positive, and a chest CT revealed an area of shadow in the bilateral lower lobe of the lungs. Renal biopsies showed crescentic glomerulonephritis, and MPA was diagnosed based on these criteria. The patient exhibited dramatic clinical and imaging improvements after immunosuppressive treatment.ConclusionThe organs most commonly involved in MPA in children are the lungs, kidneys, skin, nervous system organs, and organs of the gastrointestinal tract. Careful examination should be carried out in these patients while biopsies of the kidney or any other organs remain the gold standard for diagnostic purposes. Pulmonary involvement may be the initial symptom of the disease and should not be confused with pneumonia. A urinalysis should be performed in patients with hemoptysis. Antibiotics should be used with caution.

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“…It has been hypothesized that EGPA patients can be either an ANCA-driven or an eosinophil-driven disorder, as suggested by the different organ involvement in ANCA-positive and ANCA-negative patients [18]. A similar dichotomy is also supported by genetic association studies: human leukocyte -DQ (HLA-DQ) variants (an allele shared with other mieloperoxidase (MPO)-positive ANCA associated vasculitis (AAV)) have been described as a risk factor for ANCA-positive EGPA, while variants of the interferon regulatory factor 1 (IRF1)/IL5 and glycoprotein A33 (GPA33) genes, and in the IL-10 gene promoter have been associated with ANCA-negative [19]. Notably, GPA33 encodes for a surface glycoprotein that contributes to bronchial and gastrointestinal mucosal homeostasis, suggesting a possible role in barrier dysfunction in ANCA-negative EGPA pathogenesis.…”

Section: Disease Phenotypesmentioning

confidence: 86%

Biologics for eosinophilic granulomatosis with polyangiitis

Caminati

Maule

Bello

et al. 2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewThe link between severe asthma and eosinophilic granulomatosis with polyangiitis (EGPA) in terms of pathophysiological background, clinical manifestations and disease evolution has leaded to investigate the relevance of anti T2 monoclonal antibodies licensed for severe asthma patients as a treatment option for EGPA. The present review aimed to provide un update on EGPA pathophysiology and to critically summarize the most robust evidence coming from trials and real-life setting on the use of anti T2 biologics in EGPA patients.Recent findingsMepolizumab, an anti-interleukin-5 monoclonal antibody, is the only biologic drug targeting eosinophilic inflammation currently approved for EGPA treatment at the dose of 300 mg/4 weeks. Its use is restricted by the American College of Rheumatology guidelines to specific diseases phases and severity grades. However the most appropriate mepolizumab positioning and dose is still under investigation in the real life practice, which is providing an increasing amount of evidence confirming its efficacy, alone or in combination with other options in different disease stages. The relevance of other monoclonal antibodies interfering with T2 inflammation, including omalizumab and benralizumab, is under investigation but the evidence is still scarceSummaryTaking into account the suboptimal medium-long term safety profile of conventional EGPA treatments, the opportunity of selectively targeting eosinophilic inflammation certainly represents a revolutionary approach. However, further real-word evidence is required to effectively position the new treatments in the light of the disease complexity, including different immunological drivers, and individual variability.

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Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management

Cited by 38 publications

References 171 publications

Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Analysis and Validation of Antineutrophil cytoplasmic antibody-associated vasculitis with renal injury of the ferroptosis-related gene CD44 and Pan-Cancer

Microscopic polyangiitis presenting with persistent cough and hemoptysis in pediatrics: A case report and review of the literature

Biologics for eosinophilic granulomatosis with polyangiitis

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