The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy

AbstractImmunoglobulin A Nephropathy (IgAN) is the most common glomerulonephritis worldwide. In IgAN, immune complex deposite in glomerular mesangium, which induce inflammation and affect the kidney’s normal functions. However, the exact pathogenesis of IgAN is still incompletely understood. Further, in current practice the clinical diagnosis relies on needle biopsy on renal tissue. Therefore, a non-invasive method for clinical diagnosis and prognosis surveillance of the disease is in high demand. In this paper, we investigated both the T cell receptor bata chain (TCRB) and immunoglobulin heavy chain (IGH) repertoire of kidney infiltrating and circulating lymphocytes of IgAN patients by immune repertoire high throughput sequencing. We found that the features of TCRB and IGH in the renal tissues were remarkably different from that in blood, including a decreased repertoire diversity and increased IgA and IgG frequency, and more activated B cells. The CDR3 length of PBMC TCRB and IGH in patients is significantly shorter than that in healthy controls, which is the result of both VDJ rearrangement and clone selection. We also found that the IgA1 frequency in the PBMC of IgAN is significant higher than that in other Nephropathy (NIgAN) and healthy control, which is consistent with the previous reports on the level of IgA1 producing B cells and serum IgA1. Significantly, we identified a set of IgAN disease related TCRB and IGH CDR3s, which can be used to distinguish IgAN from NIgAN and healthy controls from the blood with high accuracy. These results indicated that TCRB and IGH repertoire can potentially serve as non-invasive biomarkers for IgAN diagnosis. The characteristics of kidney infiltrating and circulating lymphocytes repertoire shed light on IgAN detection, treatment and surveillance.

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The landscape and diagnostic potential of T and B cell repertoire in Immunoglobulin A Nephropathy

Journal of Autoimmunity ◽

10.1016/j.jaut.2018.10.018 ◽

2019 ◽

Vol 97 ◽

pp. 100-107 ◽

Cited By ~ 7

Author(s):

Chen Huang ◽

Xuemei Li ◽

Jinghua Wu ◽

Wei Zhang ◽

Shiren Sun ◽

...

Keyword(s):

B Cell ◽

Immunoglobulin A ◽

Immunoglobulin A Nephropathy ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Diagnostic Potential

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High levels of gut-homing immunoglobulin A–positive+B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa264 ◽

2020 ◽

Author(s):

Fabio Sallustio ◽

Claudia Curci ◽

Nada Chaoul ◽

Giulia Fontò ◽

Gabriella Lauriero ◽

...

Keyword(s):

B Cells ◽

B Lymphocytes ◽

Immunoglobulin A ◽

Serum Levels ◽

Memory B Cells ◽

Immunoglobulin A Nephropathy ◽

Pathogenic Role ◽

Significant Difference ◽

Activated B Cells

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. Methods We studied the intestinal–renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. Results IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ β7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. Conclusions Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal–renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.

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A Comparative Study of the Gut Microbiota Associated with Immunoglobulin A Nephropathy and Membranous Nephropathy

10.21203/rs.2.24727/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

shiren sun ◽

Ruijuan Dong ◽

Ming Bai ◽

Jin Zhao ◽

Di Wang ◽

...

Keyword(s):

Gut Microbiota ◽

Membranous Nephropathy ◽

Kidney Biopsy ◽

Immunoglobulin A ◽

Amplicon Sequencing ◽

Healthy Controls ◽

Immunoglobulin A Nephropathy ◽

Positive Correlation ◽

16S Rdna Amplicon Sequencing ◽

The Oxford Classification

Abstract Background The pathogenesis of immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) is characterized by immune dysregulation, which is related to gut dysbiosis. The aim of the study was to compare the gut microbiota of patients with IgAN and MN versus healthy controls. We used 16S rDNA amplicon sequencing to investigate the bacterial communities of 44 patients with kidney biopsy-proven IgAN, 40 patients with kidney biopsy-proven MN, and 30 matched healthy controls (HC). Results The abundance of Escherichia-Shigella and Defluviitaleaceae_incertae_sedis were significantly higher in IgAN than in HC, whereas lower abundances were observed for Roseburia, Lachnospiraceae_ unclassified, Clostridium_sensu_stricto_1, and Fusobacterium . Furthermore, the abundance of Escherichia-Shigella, Peptostreptococcaceae_incertae_sedis , Streptococcus, and Enterobacteriaceae_ unclassified increased, while that of Lachnospira, Lachnospiraceae_ unclassified, Clostridium_sensu_stricto_1, and Veillonella decreased in MN. The abundance of Megasphaera and Bilophila was higher, whereas that of Megamonas, Veillonella, Klebsiella, and Streptococcus was lower in patients with IgAN than in those with MN. Analysis of the correlations showed that in the IgAN group, Prevotella was positively correlated, while Klebsiella , Citrobacter, and Fusobacterium were negatively correlated with the level of serum albumin. Positive correlation also existed between Bilophila and Crescents in the Oxford classification of IgAN. In the MN group, negative correlation was observed between Escherichia-Shigella and proteinuria, Bacteroides and Klebsiella showed positive correlation with the MN stage. Conclusions Patients with IgAN and MN exhibited gut microbial signatures distinct from healthy controls. Our study suggests the potential of gut microbiota as specific biomarker and contributor in the pathogenesis of IgAN and MN.

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Increased frequencies of memory and activated B cells and follicular helper T cells are positively associated with high levels of activation-induced cytidine deaminase in patients with immunoglobulin A nephropathy

Molecular Medicine Reports ◽

10.3892/mmr.2015.4071 ◽

2015 ◽

Vol 12 (4) ◽

pp. 5531-5537 ◽

Cited By ~ 5

Author(s):

YING SUN ◽

ZHIHONG LIU ◽

YING LIU ◽

XIA LI

Keyword(s):

T Cells ◽

B Cells ◽

Cytidine Deaminase ◽

Immunoglobulin A ◽

Helper T Cells ◽

Immunoglobulin A Nephropathy ◽

Follicular Helper T Cells ◽

Follicular Helper ◽

Activation Induced Cytidine Deaminase ◽

Activated B Cells

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A non-invasive diagnostic model of immunoglobulin A nephropathy and serological markers for evaluating disease severity

Chinese Medical Journal ◽

10.1097/cm9.0000000000000121 ◽

2019 ◽

Vol 132 (6) ◽

pp. 647-652

Author(s):

Qiu-Xia Han ◽

Yong Wang ◽

Han-Yu Zhu ◽

Dong Zhang ◽

Jing Gao ◽

...

Keyword(s):

Disease Severity ◽

Immunoglobulin A ◽

Diagnostic Model ◽

Serological Markers ◽

Immunoglobulin A Nephropathy ◽

Non Invasive

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Periostin Contributes to Immunoglobulin a Nephropathy by Promoting the Proliferation of Mesangial Cells: A Weighted Gene Correlation Network Analysis

Frontiers in Genetics ◽

10.3389/fgene.2020.595757 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jingkui Wu ◽

Qisheng Lin ◽

Shu Li ◽

Xinghua Shao ◽

Xuying Zhu ◽

...

Keyword(s):

Network Analysis ◽

Mesangial Cells ◽

Immunoglobulin A ◽

Kidney Tissue ◽

B Cell Lymphoma ◽

Correlation Network ◽

Healthy Controls ◽

Immunoglobulin A Nephropathy ◽

Variable Expression ◽

Gene Correlation

Immunoglobulin A nephropathy (IgAN) is a known cause of end-stage kidney disease, but the pathogenesis and factors affecting prognosis are not fully understood. In the present study, we carried out weighted gene correlation network analysis (WGCNA) to identify hub genes related to the occurrence of IgAN and validated candidate genes in experiments using mouse mesangial cells (MMCs) and clinical specimens (kidney tissue from IgAN patients and healthy controls). We screened the GSE37460 and GSE104948 differentially expressed genes common to both datasets and identified periostin (POSTN) as one of the five key genes using the cytoHubba plugin of Cytoscape software and by receiver-operating characteristic curve analysis. The top 25% of genes in the GSE93798 dataset showing variable expression between IgAN and healthy tissue were assessed by WGCNA. The royalblue module in WGCNA was closely related to creatinine and estimated glomerular filtration rate (eGFR) in IgAN patients. POSTN had very high module membership and gene significance values for creatinine (0.82 and 0.66, respectively) and eGFR (0.82 and −0.67, respectively), indicating that it is a co-hub gene. In MMCs, POSTN was upregulated by transforming growth factor β1, and stimulation of MMCs with recombinant POSTN protein resulted in an increase in the level of proliferating cell nuclear antigen (PCNA) and a decrease in that of B cell lymphoma-associated X protein, which were accompanied by enhanced MMC proliferation. POSTN gene knockdown had the opposite effects. Immunohistochemical analysis of kidney tissue specimens showed that POSTN and PCNA levels were elevated, whereas the rate of apoptosis was reduced in IgAN patients relative to healthy controls. POSTN level in the kidney tissue of IgAN patients was positively correlated with creatinine level and negatively correlated with eGFR. Thus, POSTN promotes the proliferation of MCs to promote renal dysfunction in IgAN.

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Osteopontin Gene Polymorphism and Urinary OPN Excretion in Patients with Immunoglobulin A Nephropathy

Cells ◽

10.3390/cells8060524 ◽

2019 ◽

Vol 8 (6) ◽

pp. 524 ◽

Cited By ~ 1

Author(s):

Beata Kaleta ◽

Natalia Krata ◽

Radosław Zagożdżon ◽

Krzysztof Mucha

Keyword(s):

Immunoglobulin A ◽

Clinical Manifestations ◽

Clinicopathological Parameters ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Immunoglobulin A Nephropathy ◽

Inflammatory Conditions ◽

Caucasian Patients ◽

Secreted Phosphoprotein 1

Osteopontin (OPN) is a glycoprotein involved in the pathogenesis of multiple autoimmune and inflammatory conditions. However, the association of variants of secreted phosphoprotein 1 gene (SPP1), which encodes OPN, with immunoglobulin A nephropathy (IgAN) has not been examined up to date. Moreover, the role of OPN in disease pathogenesis and clinical manifestations is not fully known. Therefore, the aim of the study was to determine the frequency of four single nucleotide polymorphisms (SNiPs) of SPP1 gene, as well as the urinary OPN excretion in IgAN patients and healthy controls. In total, 58 Caucasian patients with biopsy-proven IgAN and 184 gender-, age-, and ethnically-matched healthy controls were genotyped for rs1126616, rs1126772, rs9138, and rs7687316/rs3841116 polymorphisms by real time polymerase chain reaction (RT-PCR). Urinary OPN concentration was determined by enzyme-linked immunosorbent assay (ELISA) in 58 IgAN patients and 19 controls. SPP1 SNiPs, as well as urinary OPN excretion, were analyzed in relation to their possible associations with the clinicopathological parameters. The frequency of the minor TT/CT genotypes of rs1126616 was significantly higher in IgAN patients compared to controls (P = 0.0217). Similarly, the minor (CC/AC) genotypes and the C allele of rs9138 were more frequent in IgAN patients (P = 0.0425 and P = 0.0112, respectively). Moreover, these two SNiPs were associated with the higher urinary OPN excretion (P < 0.05). These findings suggest that rs1126616, as well as rs9138, may be associated with IgAN development, however future studies in this field are required.

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Gut microbiota in Immunoglobulin A Nephropathy: a Malaysian Perspective

BMC Nephrology ◽

10.1186/s12882-021-02315-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Agni Nhirmal Kumar Sugurmar ◽

Rozita Mohd ◽

Shamsul Azhar Shah ◽

Hui-min Neoh ◽

Rizna Abdul Cader

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Immunoglobulin A ◽

Alpha Diversity ◽

Rrna Gene ◽

Healthy Controls ◽

Control Cohort ◽

Immunoglobulin A Nephropathy ◽

Ckd Stage ◽

The Mean

Abstract Introduction The alteration of the gut microbiome in the gut-kidney axis has been associated with a pro-inflammatory state and chronic kidney disease (CKD). A small-scaled Italian study has shown an association between the gut microbiome and Immunoglobulin A Nephropathy (IgAN). However, there is no data on gut microbiota in IgAN in the Asian population. This study compares the gut microbial abundance and diversity between healthy volunteers and Malaysian IgAN cohort. Methods A comparative cross-sectional study was conducted involving biopsy-proven IgAN patients in clinical remission with matched controls in a Malaysian tertiary centre. Demographic data, routine blood and urine results were recorded. Stool samples were collected and their DNA was extracted by 16S rRNA gene sequencing to profile their gut microbiota. Results Thirty-six IgAN patients (13 male; 23 female) with the mean age of 45.5 ± 13.4 years and median estimated glomerular filtration rate (eGFR) of 79.0 (62.1–92.2) mls/min/1.73m2 with median remission of 7 years were analysed and compared with 12 healthy controls (4 male; 8 female) with the mean age of 46.5 ± 13.5 years and eGFR of 86.5 (74.2–93.7) mls/min/1.73m2. Other demographic and laboratory parameters such as gender, ethnicity, body mass index (BMI), haemoglobin, serum urea and serum albumin were comparable between the two groups. There were no significant differences seen in the Operational Taxonomic Unit (OTU) and alpha diversity (Shannon index) between IgAN and healthy controls. Alpha diversity increased with increasing CKD stage (p = 0.025). Firmicutes/Bacteroidetes (F/B) ratio was low in both IgAN and healthy cohort. Fusobacteria phylum was significantly increased (p = 0.005) whereas Euryarchaoeota phylum was reduced (p = 0.016) in the IgAN group as compared to the control cohort. Conclusion Although we found no differences in OTU and alpha diversity between IgAN in remission and control cohort, there were some differences between the two groups at phylum level.

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