Dataset Information

Differences in the frequency of macrophage and T cell markers between focal and crescentic classes of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.

ABSTRACT: BACKGROUND:Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) can be classified into; focal, crescentic, mixed and sclerotic classes. Macrophages and T lymphocytes are key players in mediating renal injury. The frequency of macrophage and T lymphocytes in different histological classes is unclear. OBJECTIVES:We examined the frequency of macrophage and T lymphocyte markers in AAGN and assessed their correlation with renal function at presentation. PATIENTS AND METHODS:Renal biopsies from 38 patients were included in immunohistochemistry analysis of macrophages (CD68, sialoadhesin [Sn] and mannose receptor [MR]) and T cells (CD4 and CD8) markers. The frequency of these markers in glomerular, periglomerular and interstitial compartments were measured in a blinded fashion. Biopsies were allocated a histological class of focal, crescentic, mixed or sclerotic. Scores were then matched to histological class and assessed for correlation with renal function. RESULTS:The biopsies were crescentic 19 (50%), focal 10 (26.3%), mixed 6 (15.7%) and sclerotic 3 (8%). Interstitial CD68+ macrophages and CD8+ T lymphocytes showed best correlation with renal function at the time of presentation. CD68+ macrophages were significantly increased in crescentic compared to focal AAGN. MR+ macrophages, CD4 and CD8 T cells were also elevated in the interstitium of crescentic compared to focal group. CONCLUSIONS:In this study interstitial CD68 and CD8 showed the highest association with the renal function at presentation. Differences in the cellular infiltrate between focal and crescentic AAGN were related to CD68+ macrophages and to interstitial MR+ macrophages and T lymphocytes. Further studies are needed to assess these differences across all four histological categories.

SUBMITTER: Kidder D

PROVIDER: S-EPMC5418077 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Differences in the frequency of macrophage and T cell markers between focal and crescentic classes of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.

Kidder Dana D Bray Susan E SE Fleming Stewart S

Journal of nephropathology 20161225 2

<h4>Background</h4>Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) can be classified into; focal, crescentic, mixed and sclerotic classes. Macrophages and T lymphocytes are key players in mediating renal injury. The frequency of macrophage and T lymphocytes in different histological classes is unclear.<h4>Objectives</h4>We examined the frequency of macrophage and T lymphocyte markers in AAGN and assessed their correlation with renal function at presentation.<h4>P ...[more]

PMID: 28491860

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Project description:BackgroundMyeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN.MethodsWe evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis.ResultsAll biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses.ConclusionsMyeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Project description:BackgroundFunction and efficiency of a transcription factor (TF) are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis (Crgn) where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto (WKY) strain.ResultsTo evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains (WKY and WKY.LCrgn2) that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD/Jun and JunD/ATF complexes (i.e., AP1 complex), which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide (LPS) stimulation we found that 2.4 fold more JunD/ATF-target genes were up-regulated as compared with JunD/Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response (P = 6.9 × 10⁻⁴) and antigen processing and presentation functions (P = 2.4 × 10⁻⁵), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF.ConclusionsIn summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis.

Dataset Information

Differences in the frequency of macrophage and T cell markers between focal and crescentic classes of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.

Publications

Differences in the frequency of macrophage and T cell markers between focal and crescentic classes of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.

Similar Datasets

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