Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

Placzek, William J.; Yanagawa, Hiroyuki; Makita, Yuko; Renfrow, Matthew B.; Julian, Bruce A.; Rizk, Dana V.; Suzuki, Yusuke; Novák, Jan; Suzuki, Hitoshi

doi:10.1371/journal.pone.0190967

Cited by 66 publications

(44 citation statements)

References 26 publications

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“…The contribution of galactose-deficient IgA1 to IgAN pathogenesis has been validated in many studies. [4][5][6] Moreover, the presence of galactose-deficient IgA1(Gd-IgA1) in the glomerular deposits of patients with IgAN has been proven by immunohistochemical staining using the galactose-deficient IgA1-specific monoclonal antibody KM55, 7,8 which reinforces the important role that galactose-deficient IgA1 plays in IgAN.…”

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confidence: 79%

Elevated hsa‐miR‐590‐3p expression down‐regulates HMGB2 expression and contributes to the severity of IgA nephropathy

Zhai

Long

et al. 2019

J Cellular Molecular Medi

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Peripheral blood mononuclear cells (PBMCs) play important roles in the pathogenesis of IgA nephropathy (IgAN). Our study aimed to provide a deep understanding of IgAN and focused on the dysregulation of hsa‐miR‐590‐3p and its target gene HMGB2 in PBMCs. Three gene expression profile datasets (GSE14795, GSE73953 and GSE25590) were downloaded from the GEO database. The DEGs (differentially expressed genes)‐miRNA network that was associated with IgAN was constructed by Cytoscape, and HMGB2 and hsa‐miR‐590‐3p were selected for further exploration. The dual‐luciferase reporter system was utilized to verify their interaction. Then, the expression levels of HMGB2 and hsa‐miR‐590‐3p in PBMCs were detected by qPCR in another cohort, and the correlation of their expression levels with the clinical pathological manifestations and serum Gd‐IgA1(galactose‐deficient IgA1) levels was also investigated. HMGB2 was identified as the target gene of hsa‐miR‐590‐3p. Furtherly, the elderly patients had higher HMGB2 expression levels than the expression levels of the younger patients. As the serum creatinine, serum BUN levels increased, the expression of HMGB2 decreased; Besides, the HMGB2 expression was positively correlated with serum complement 3(C3) levels, and it also had a negative correlation with the diastolic blood pressure, but not reach statistical significance. What is more, both hsa‐miR‐590‐3p and HMGB2 expression had a slight correlation tendency with serum Gd‐IgA1 levels in the whole population. In conclusion, HMGB2, the target gene of hsa‐miR‐590‐3p, was identified to correlate with the severity of IgAN, and this provides more clues for the pathogenesis of IgAN.

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confidence: 79%

Elevated hsa‐miR‐590‐3p expression down‐regulates HMGB2 expression and contributes to the severity of IgA nephropathy

Zhai

Long

et al. 2019

J Cellular Molecular Medi

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“…The formation of circulating immune complexes followed by their renal deposition in patients with IgAN is driven by presence of terminal GalNAc on Gal-deficient IgA1 and its recognition by autoantibodies (Novak et al 2015;Knoppova et al 2016). Patients with IgAN have elevated serum levels of IgA1 with terminal GalNAc that correlate with serum levels of IgG autoantibodies (Placzek et al 2018). Initial theories on the origin of this IgA1 glycosylation phenotype proposed that addition of Gal would be impaired due to C1GALT1 reduced expression caused by a COSMC mutation(s).…”

Section: Discussionmentioning

confidence: 99%

IgA1 hinge-region clustered glycan fidelity is established early during semi-ordered glycosylation by GalNAc-T2

et al. 2019

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GalNAc-type O-glycans are often added to proteins post-translationally in a clustered manner in repeat regions of proteins, such as mucins and IgA1. Observed IgA1 glycosylation patterns show that glycans occur at similar sites with similar structures. It is not clear how the sites and number of glycans added to IgA1, or other proteins, can follow a conservative process. GalNActransferases initiate GalNAc-type glycosylation. In IgA nephropathy, an autoimmune disease, the sites and O-glycan structures of IgA1 hinge-region are altered, giving rise to a glycan autoantigen. To better understand how GalNAc-transferases determine sites and densities of clustered O-glycans, we used IgA1 hinge-region (HR) segment as a probe. Using LC-MS, we demonstrated a semi-ordered process of glycosylation by GalNAc-T2 towards the IgA1 HR. The catalytic domain was responsible for selection of four initial sites based on amino-acid sequence recognition. Both catalytic and lectin domains were involved in multiple second site-selections, each dependent on initial site-selection. Our data demonstrated that multiple start-sites and follow-up pathways were key to increasing the number of glycans added. The lectin domain predominately enhanced IgA1 HR glycan density by increasing synthesis pathway exploration by GalNAc-T2. Our data indicated a link between site-specific glycan addition and clustered glycan density that defines a mechanism of how conserved clustered O-glycosylation patterns and glycoform populations of IgA1 can be controlled by GalNAc-T2. Together, these findings characterized a correlation between glycosylation pathway diversity and glycosylation density, revealing mechanisms by which a single GalNAc-T isozyme can limit and define glycan heterogeneity in a disease-relevant context.

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“…Histopathologically, IgAN is characterized by mesangial cell proliferation with IgA-IC deposition in the glomerular mesangium, which is indistinguishable from pathologic findings of HSPN [2,12,14]. Regarding the pathogenesis of IgAN, several studies that investigated aberrant IgA1 O-glycosylation indicated that galactose-deficient IgA1 (Gd-IgA1) plays a pivotal role in the progression of IgAN [15][16][17][18][19][20][21][22][23]. According to these studies, patients with IgAN have aberrant IgA1 molecules with a Gal deficiency of O-linked glycans in the hinge region, which indicates that Gd-IgA1 consists of terminal N-acetyl-galactosamine (GalNAc) or sialylated GalNAc [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy

et al. 2020

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Introduction Recent studies noted that Henoch-Schö nlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) share the feature of galactose-deficient IgA1 (Gd-IgA1)-oriented pathogenesis, although there are distinct clinical differences. We aimed to clarify the clinicopathologic differences between these 2 diseases. Methods We cross-sectionally analyzed adult patients with HSPN (n = 24) or IgAN (n = 56) who underwent renal biopsy (RB) between 2008 and 2018 at Showa University Hospital. Serum Gd-IgA1 (s-Gd-IgA1) levels at the time of RB were compared among study groups using enzyme-linked immunosorbent assay (ELISA) with anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for glomerular Gd-IgA1 (g-Gd-IgA1)-deposition using KM55. Serum inflammatory cytokines were measured using ELISA. Results Glomerular endothelial injury with subendothelial IgA deposition was significant in patients with HSPN. Serum IL-8, MCP-1, TNF-α, and IL-6 levels were significantly higher in patients with HSPN than IgAN. Levels of s-Gd-IgA1 were comparable among patients with HSPN and IgAN, and a similar degree of g-Gd-IgA1-deposition was detected in both diseases. Furthermore, g-Gd-IgA1-deposition was evident in patients with histopathologically advanced HSPN or IgAN. In HSPN, significant positive correlations between s-Gd-IgA1 levels and crescent formation or IL-6 elevation were confirmed, and g-Gd-IgA1 intensity showed a significant positive correlation with MCP-1 and a tendency to positively correlate with IL-8. Meanwhile, patients with IgAN showed no correlation between inflammatory cytokines and both-Gd-IgA1. Moreover, most g-Gd-IgA1-positive areas were not double stained with CD31 in HSPN.

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Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

Cited by 66 publications

References 26 publications

Elevated hsa‐miR‐590‐3p expression down‐regulates HMGB2 expression and contributes to the severity of IgA nephropathy

Elevated hsa‐miR‐590‐3p expression down‐regulates HMGB2 expression and contributes to the severity of IgA nephropathy

IgA1 hinge-region clustered glycan fidelity is established early during semi-ordered glycosylation by GalNAc-T2

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy

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