Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases
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ABSTRACT:
SUBMITTER: Park J
PROVIDER: S-EPMC7530979 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases
| PRJEB39311 | ENA
Project description:BackgroundIgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN.MethodsWe used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0-8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2-44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed.ResultsMore than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-β inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings.ConclusionsThe present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria.
| S-EPMC10182656 | biostudies-literature
Project description:IgA nephropathy (IgAN) is characterized by high serum IgA levels and IgA deposition in the renal mesangium. Recent research has indicated that pathogenic IgA may originate from affected tonsils, where present enhancement of IgA production by IgA class switching and immuno-activation. Tripterygium Wilfordii (TW) was found to be especially effective in IgAN by its' immunosuppression effect. Given this background, we investigated the mechanisms underlying the role of TW in the generation of IgA and IgA class switching in tonsillar GCs of IgAN patients. Immunohistochemistry and RT-PCR revealed that the expression of thymic stromal lymphopoietin (TSLP) and IgA inducing cytokines were decreased in the tonsils of IgAN patients with TW treatment compared with those without treatment, followed by significantly decreased of IgA-bearing cells. The location of TSLP and IgA inducing cytokines in tonsillar tissue was confirmed by double immunofluorescence. Importantly, TW inhibit TSLP and IgA production in isolated FDC-associated clusters. Serum TSLP levels were decreased and correlated with IgA downregulation in the tonsils and serum of IgAN patients. These data indicated that TW may be involved in IgA production in the tonsils of IgAN patients, inhibiting IgA class switching in IgAN patients through the cooperative roles of AID, TGF-β1, BAFF, and APRIL, highlighting a promising strategy for therapeutic intervention in IgAN.
| S-EPMC5752501 | biostudies-literature
Project description:Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale.
| S-EPMC3139900 | biostudies-literature
Project description:We applied scRNAseq analysis to investigate the mouse kidney glomerular injury in IgA nephropathy
2022-02-01 | GSE166793 | GEO
Project description:Enhanced intrarenal renin-angiotensin system (RAS) is implicated in the development and progression of renal injury. To investigate whether angiotensinogen (AGT) expression is involved in glomerular RAS activity and glomerular injury, we examined glomerular AGT expression and its correlation with expression of other RAS components, and levels of glomerular injury in samples from patients with immunoglobulin A nephropathy (IgAN) (23) and minor glomerular abnormalities (MGA) (8). Immunohistochemistry showed that AGT protein was highly expressed by glomerular endothelial cells (GEC) and mesangial cells in nephritic glomeruli of IgAN compared with glomeruli of MGA. Levels of glomerular AGT protein were well correlated with levels of glomerular angiotensin II (ang II), transforming growth factor-beta (TGF-beta), alpha-smooth-muscle actin, glomerular cell number, and glomerulosclerosis score but not with those of glomerular angiotensin-converting enzyme and ang II type 1 receptor. Real-time polymerase chain reaction (RT-PCR) and Western blot analyses using cultured human GEC indicated that ang II upregulated AGT messenger ribonucleic acid (mRNA) and protein expression in a dose- and time-dependent manner. These data suggest that activated glomerular AGT expression is likely involved in elevated local ang II production and, thereby, may contribute to increased TGF-beta production and development of glomerular injury in IgAN. Augmentation of GEC-AGT production with ang II stimulation might drive further glomerular injury in a positive-feedback loop.
| S-EPMC2441593 | biostudies-other
Project description:Anti-glomerular basement membrane (GBM) nephritis is characterized by circulating anti-GBM antibodies and crescentic glomerulonephritis (GN) with deposition of IgG along the GBM. In a limited number of cases, glomerular immune complexes have been identified in anti-GBM nephritis. A 38-year-old female presented azotemia, hematuria, and proteinuria without any pulmonary symptoms. A renal biopsy showed crescentic GN with linear IgG deposition along the GBM and mesangial IgA deposition. The patient was diagnosed as concurrent anti-GBM nephritis and IgA nephropathy. Therapies with pulse methylprednisolone and cyclophosphamide administration were effective. Concurrent cases of both anti-GBM nephritis and IgA nephropathy are rare among cases of anti-GBM diseases with deposition of immune complexes. This rare case of concurrent anti-GBM nephritis and IgA nephropathy with literature review is noteworthy.
| S-EPMC6877440 | biostudies-literature
Project description:ObjectivesKidney transplant (KTx) recipients with IgAN as primary disease, were compared with recipients with other causes of renal failure, in terms of long-term outcomes.MethodsNinety-nine KTx recipients with end-stage kidney disease (ESKD) due to IgAN, were retrospectively compared to; i/ a matched case-control group of patients with non-glomerular causes of ESKD, and ii/ four control groups with ESKD due to glomerular diseases; 44 patients with primary focal segmental glomerulosclerosis (FSGS), 19 with idiopathic membranous nephropathy (IMN), 22 with lupus nephritis (LN) and 21 with pauci-immune glomerulonephritis (PIGN).ResultsAt end of the observation period, graft function and survival, were similar between KTx recipients with IgAN and all other groups, but the rate of disease recurrence in the graft differed significantly across groups. The rate of IgAN recurrence in the graft was 23.2%, compared to 59.1% (p<0.0001) in the FSGS group, 42.1% (p = 0.17) in the IMN group, and 0% in the LN and PIGN groups (p = 0.01). IgAN recipients, who were maintained with a regimen containing tacrolimus, experienced recurrence less frequently, compared to those maintained with cyclosporine (p = 0.01). Graft loss attributed to recurrence was significantly higher in patients with FSGS versus all others.ConclusionRecipients with IgAN as primary disease, experienced outcomes comparable to those of recipients with other causes of ESKD. The rate of IgAN recurrence in the graft was significantly lower than the rate of FSGS recurrence, but higher than the one recorded in recipients with LN or PIGN. Tacrolimus, as part of the KTx maintenance therapy, was associated with lower rates of IgAN recurrence in the graft, compared to the rate cyclosporine.
| S-EPMC8370606 | biostudies-literature
Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear.MethodsBiopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils.ResultsTonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients.ConclusionsThese findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
| S-EPMC7771982 | biostudies-literature
Project description:ObjectiveWe aimed to explore the relationship between the presence and intensity of glomerular IgG deposition and the occurrence of kidney progression events in IgA nephropathy (IgAN).MethodsThis retrospective study encompassed a total of 1207 patients with IgAN spanning the period from 2010 to 2022, and complete follow-up data were accessible for 736 patients. The IgG intensity was categorized as follows: low-level, defined as IgG (±) and IgG (+), and high-level, defined as IgG (++) and IgG (+++).ResultsWe found that the IgG-positive deposited group (N = 113, 9.36%) had significantly higher levels of ESR, TC, LDL, uric acid, proteinuria, and blood glucose, and lower serum albumin level compared to the IgG-negative deposited group (N = 1094, 90.64%). In terms of pathology, the IgG-positive deposited group had a significantly higher percentage of T2 score compared to the IgG-negative deposited group (p = 0.002). At the end of the follow-up period, the IgG-positive deposited group had a higher eGFR decline (-5.7 ± 4.37 ml/year) compared to the IgG-negative deposited group (-4 ± 2.52 ml/year), however, there was not a statistically significant difference between the two groups (p = 0.096). We observed that the high-IgG group had significantly higher level of TG compared to the low-IgG group (p = 0.042). Further analysis revealed that the group of patients with high level of IgG deposition in the kidney experienced a higher incidence of composite kidney outcomes compared to the group with low level of IgG deposition (p = 0.009). Logistic regression analyses showed that high level IgG deposition was an independent risk factor for kidney progression of IgAN (HR 13.419; 95% CI 2.690-66.943, P = 0.029). Further analyses for a solid conclusion using Cox regression that we found high level IgG deposition (HR 115.277; 95% CI 2.299-5.779E3, P = 0.017), eGFR (HR 0.932; 95% CI 0.870-0.999, P = 0.047), and urine protein excretion (HR 1.001; 95% CI 1.000-1.002, P = 0.015) were independent risk factor for kidney progression of IgAN.ConclusionsThe intensity of IgG deposition has been found to be associated with the progression of IgAN. Future prospective studies should provide more robust evidence on the impact of IgG deposition on kidney outcomes in patients with IgAN.
| S-EPMC10988001 | biostudies-literature