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1
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Zhang H, Li S, Deng Z, Wang Y. Molecular Differences in Glomerular Compartment to Distinguish Immunoglobulin A Nephropathy and Lupus Nephritis. J Inflamm Res 2024; 17:11357-11373. [PMID: 39722731 PMCID: PMC11669337 DOI: 10.2147/jir.s496138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/14/2024] [Indexed: 12/28/2024] Open
Abstract
Background Immunoglobulin A nephropathy (IgAN) and lupus nephritis (LN) are the most prevalent primary and secondary glomerular diseases, respectively, with several similarities in clinical presentations. Common pathogenic mechanisms in IgAN and LN have been well investigated by previous studies. However, the manifestation mechanism of these two independent diseases carrying distinct immunofluorescent pathological features is still unknown considering the similarities between them. Therefore, differences in pathogenic mechanisms between IgAN and LN were compared in this study. Methods R packages were used for processing the glomerular gene expression datasets acquired from the Gene Expression Omnibus (GEO) database. Least Absolute Selection and Shrinkage Operator (LASSO) and multivariate logistic regression analysis were used to construct models predicting IgAN and LN. Cibersort was used to process the immune cell infiltration analysis. Immunochemistry was used to validate the findings by bioinformatics analysis. Results In the predicting models based on differentially expressed genes (DEG) and weighted correlation network analysis (WGCNA), retinoic acid receptor γ (RARG) and prolactin releasing hormone (PRLH) were independent risk factors for IgAN, and HECT domain and RCC1-like domain-containing protein 5 (HERC5) and interferon stimulated exonuclease gene 20 (ISG20) were independent risk factors for LN. Gene Ontology (GO) analysis revealed that DEGs mostly correlated to IgAN were enriched in ligand-receptor activity-induced cellular growth and development, while DEGs mostly correlated to LN were enriched in nucleic acid/nucleotide binding-induced type I interferon-related activity and response to virus infection. Immune infiltration analysis showed CD4+ T-cells and M2 macrophage abundance in the glomerular compartment in IgAN and LN, respectively. Immunochemistry validated the predicting models for IgAN and LN and revealed different expression patterns of RARG, PRLH, HERC5, and ISG20. Conclusion We investigated key differences in the pathogenesis between IgAN and LN and provided validated predicting models to distinguish IgAN and LN. RARG and PRLH, HERC5 and ISG20 might play an essential role in the formation of IgAN and LN, respectively.
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Affiliation(s)
- Haidong Zhang
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
| | - Sicong Li
- School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China
| | - Zhenling Deng
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
| | - Yue Wang
- Department of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China
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2
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Uriol-Rivera MG, Obrador-Mulet A, Juliá MR, Daza-Cajigal V, Delgado-Sanchez O, Garcia Alvarez A, Gomez-Lobon A, Carrillo-Garcia P, Saus-Sarrias C, Gómez-Cobo C, Ramis-Cabrer D, Gasco Company J, Molina-Infante J. Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients. Sci Rep 2024; 14:4866. [PMID: 38418932 PMCID: PMC10902332 DOI: 10.1038/s41598-024-55425-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 02/23/2024] [Indexed: 03/02/2024] Open
Abstract
There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.
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Affiliation(s)
- Miguel G Uriol-Rivera
- Nephrology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain.
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain.
| | - Aina Obrador-Mulet
- Nephrology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Maria Rosa Juliá
- Immunology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Vanessa Daza-Cajigal
- Immunology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Olga Delgado-Sanchez
- Pharmacy Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Angel Garcia Alvarez
- Pharmacy Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
| | - Ana Gomez-Lobon
- Pharmacy Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
| | - Paula Carrillo-Garcia
- Pathology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
| | - Carlos Saus-Sarrias
- Pathology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
| | - Cristina Gómez-Cobo
- Laboratory Medicine Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Daniel Ramis-Cabrer
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
| | - Joan Gasco Company
- Nephrology Department, Hospital Universitario Son Espases, Palma de Mallorca, Balearic Islands, Spain
- Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Palma, Spain
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3
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Ho SY, Kao CC, Chang CM, Chou YC, Luo WT, Chou WH, Tsai IL, Wu MS, Chang WC. Characterization of T-Cell receptor repertoire in immunoglobulin a nephropathy. Biomark Res 2024; 12:23. [PMID: 38342914 PMCID: PMC10860214 DOI: 10.1186/s40364-024-00572-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/28/2024] [Indexed: 02/13/2024] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by abnormal IgA deposition in glomerulus. Current diagnosis of IgAN still depends on renal biopsy, an invasive method that might increase the risk of clinical outcomes. Therefore, we aimed to explore the characteristics of T cell repertoire in IgAN from peripheral blood samples for identifying innovative diagnostic biomarkers. Herein, we included 8 IgAN patients, 25 non-IgAN patients, and 10 healthy controls in the study. A high-throughput immune repertoire sequencing was conducted to investigate the T-cell receptor beta-chain (TCRβ) repertoire of peripheral blood. Characteristics of TCRβ repertoire were assessed for these three distinct groups. A reduced TCRβ repertoire diversity was observed in IgAN patients compared to non-IgAN and healthy individuals. A skewed distribution toward shorter TCRβ complementarity determining region (CDR3) length was found in non-IgAN relative to IgAN patients. In addition, the differences in usages of five TRBV genes (TRBV5-4, TRBV6-4, TRBV12-1, TRBV16, and TRBV21-1) were identified between IgAN, non-IgAN, and healthy subjects. Of note, the TRBV6-4 gene, which is associated with mucosal-associated invariant T (MAIT) cells, exhibited higher usage in IgAN patients, suggesting potential importance of MAIT cells in IgAN. In short, our findings supported TCR repertoire characteristics as potential biomarkers for IgAN diagnosis.
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Affiliation(s)
- Szu-Ying Ho
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
| | - Chih-Chin Kao
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Che-Mai Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
| | - Yi-Chien Chou
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
| | - Wei-Tzu Luo
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
| | - Wan-Hsuan Chou
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan
| | - I-Lin Tsai
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan.
- Taipei Medical University Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan.
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, No. 250, Wuxing St., Xinyi District, Taipei City, 11031, Taiwan.
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
- Department of Medical Education and Research, Integrative Research Center for Critical Care, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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4
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Jash R, Maparu K, Seksaria S, Das S. Decrypting the Pathological Pathways in IgA Nephropathy. RECENT ADVANCES IN INFLAMMATION & ALLERGY DRUG DISCOVERY 2024; 18:43-56. [PMID: 37870060 DOI: 10.2174/0127722708275167231011102924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/17/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023]
Abstract
IgAN is the most common form of glomerulonephritis affecting 2000000 people annually. The disease ultimately progresses to chronic renal failure and ESRD. In this article, we focused on a comprehensive understanding of the pathogenesis of the disease and thus identifying different target proteins that could be essential in therapeutic approaches in the management of the disease. Aberrantly glycosylated IgA1 produced by the suppression of the enzyme β-1, 3 galactosyltransferase ultimately triggered the formation of IgG autoantibodies which form complexes with Gd-IgA1. The complex gets circulated through the blood vessels through monocytes and ultimately gets deposited in the glomerular mesangial cells via CD71 receptors present locally. This complex triggers the inflammatory pathways activating the alternate complement system, various types of T Cells, toll-like receptors, cytokines, and chemokines ultimately recruiting the phagocytic cells to eliminate the Gd-IgA complex. The inflammatory proteins cause severe mesangial and podocyte damage in the kidney which ultimately initiates the repair process following chronic inflammation by an important protein named TGFβ1. TGF β1 is an important protein produced during chronic inflammation mediating the repair process via various downstream transduction proteins and ultimately producing fibrotic proteins which help in the repair process but permanently damage the glomerular cells.
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Affiliation(s)
- Rajiv Jash
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
- Department of Pharmacy, JIS University, Kolkata, 700109, West Bengal, India
| | - Kousik Maparu
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
| | - Sanket Seksaria
- Department of Pharmacology, Sanaka Educational Trust's Group Of Institutions, Malandighi, Durgapur, 713212, West Bengal, India
| | - Saptarshi Das
- Department of Pharmacy, JIS University, Kolkata, 700109, West Bengal, India
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5
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Gentile M, Sanchez-Russo L, Riella LV, Verlato A, Manrique J, Granata S, Fiaccadori E, Pesce F, Zaza G, Cravedi P. Immune abnormalities in IgA nephropathy. Clin Kidney J 2023; 16:1059-1070. [PMID: 37398689 PMCID: PMC10310525 DOI: 10.1093/ckj/sfad025] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Indexed: 09/10/2023] Open
Abstract
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%-40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis.
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Affiliation(s)
- Micaela Gentile
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
- UO Nefrologia, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Luis Sanchez-Russo
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Leonardo V Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alberto Verlato
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Joaquin Manrique
- Nephrology Service, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Simona Granata
- Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Enrico Fiaccadori
- UO Nefrologia, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Francesco Pesce
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “A. Moro”, Bari, Italy
| | - Gianluigi Zaza
- Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Paolo Cravedi
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA
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6
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Tamura H. IgA nephropathy associated with Crohn's disease. World J Methodol 2023; 13:67-78. [PMID: 37456980 PMCID: PMC10348078 DOI: 10.5662/wjm.v13.i3.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/16/2023] [Accepted: 05/12/2023] [Indexed: 06/20/2023] Open
Abstract
The relationship between IgA nephropathy (IgAN) and Crohn’s disease was reported. IgAN is the most common primary glomerulonephritis and one of the leading causes of chronic kidney disease and end-stage renal failure, and up to 50% of cases progressed to end-stage renal disease within 25 years after IgAN diagnosis. However, specific and effective therapeutic strategies are still lacking. In this review, we discuss the possibility of the mechanism involved in IgAN associated with Crohn’s disease based on the findings of basic and clinical studies. Although the etiology of IgAN associated with Crohn’s disease is not permanent and various factors are thought to be involved, the stabilization of the disease condition of Crohn’s disease is believed to help treat IgAN.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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7
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The Diagnostic and Predictive Significance of Immune-Related Genes and Immune Characteristics in the Occurrence and Progression of IgA Nephropathy. J Immunol Res 2022; 2022:9284204. [PMID: 35528619 PMCID: PMC9071862 DOI: 10.1155/2022/9284204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/25/2022] [Accepted: 04/04/2022] [Indexed: 11/18/2022] Open
Abstract
Objective To investigate the potential diagnostic and predictive significance of immune-related genes in IgA nephropathy (IgAN) and discover the abnormal glomerular inflammation in IgAN. Methods GSE116626 was used as a training set to identify different immune-related genes (DIRGs) and establish machine learning models for the diagnosis of IgAN; then, a nomogram model was generated based on GSE116626, and GSE115857 was used as a test set to evaluate its clinical value. Short Time-Series Expression Miner (STEM) analysis was also performed to explore the changing trend of DIRGs with the progression of IgAN lesions. GSE141344 was used with DIRGs to establish the ceRNA network associated with IgAN progression. Finally, ssGSEA analysis was performed on the GSE141295 dataset to discover the abnormal inflammation in IgAN. Results Machine learning (ML) performed excellently in diagnosing IgAN using six DIRGs. A nomogram model was constructed to predict IgAN based on the six DIRGs. Three trends related to IgAN lesions were identified using STEM analysis. A ceRNA network associated with IgAN progression which contained 8 miRNAs, 14 lncRNAs, and 3 mRNAs was established. A higher macrophage ratio and lower CD4+ T cell ratio in IgAN compared to controls were observed, and the correlation between macrophages and monocytes in the glomeruli of IgAN patients was inverse compared to controls. Conclusion This study reveals the diagnostic and predictive significance of DIRGs in IgAN and finds that the imbalance between macrophages and CD4+ immune cells may be an important pathomechanism of IgAN. These results provide potential directions for the treatment and prevention of IgAN.
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Zhang YM, Liu XZ, Zhou XJ, Liu LJ, Shi SF, Hou P, Lv JC, Zhang H. A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population. Front Immunol 2021; 12:600598. [PMID: 33717080 PMCID: PMC7946973 DOI: 10.3389/fimmu.2021.600598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
C-C chemokine receptor 6 (CCR6) is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN). In this study, we aimed to identify the functional variants. First, we analyzed the associations of CCR6 common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region. Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15, P = 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P = 1.45 × 10−3). It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10−7). Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP, the alleles of rs3093023 (G>A) rather than of CCR6DNP were shown differential nuclear protein binding effect by electrophoretic mobility shift assay. The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated with CCR6 mRNA (r = −0.60, P = 3.94 × 10−9). At the mRNA level, the eQTL effect of CCR6 was validated (P = 4.39 × 10−2), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG. At the protein level, a higher CCR6+ cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P = 3.57 × 10−2), CD3+ T cells (P = 4.54 × 10−2), and CD4+ T cells (P = 1.32 × 10−2), but not in CD8+ T cells. Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis. Overall, the rs3093023 was prioritized as the function variant in CCR6, which may contribute to IgAN susceptibility by regulating Th17 cells.
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Affiliation(s)
- Yue-Miao Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Xing-Zi Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Xu-Jie Zhou
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Li-Jun Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Su-Fang Shi
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Ping Hou
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Ji-Cheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
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9
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Chang S, Li XK. The Role of Immune Modulation in Pathogenesis of IgA Nephropathy. Front Med (Lausanne) 2020; 7:92. [PMID: 32266276 PMCID: PMC7105732 DOI: 10.3389/fmed.2020.00092] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/03/2020] [Indexed: 01/10/2023] Open
Abstract
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with diverse clinical manifestations characterized by recurrent gross hematuria or microscopic hematuria, and pathological changes featuring poorly O-galactosylated IgA1 deposition in the glomerular mesangium. Pathogenesis has always been the focus of IgAN studies. After 50 years of research, most scholars agree that IgAN is a group of clinicopathological syndromes with certain common immunopathological characteristics, and multiple mechanisms are involved in its pathogenesis, including immunology, genetics, and environmental or nutritional factors. However, the precise pathogenetic mechanisms have not been fully determined. One hypothesis about the pathogenesis of IgAN suggests that immunological factors are engaged in all aspects of IgAN development and play a critical role. A variety of immune cells (e.g., dendritic cells, NK cells, macrophages, T-lymphocyte subsets, and B-lymphocytes, etc.) and molecules (e.g., IgA receptors, Toll-like receptors, complements, etc.) in innate and adaptive immunity are involved in the pathogenesis of IgAN. Moreover, the abnormality of mucosal immune regulation is the core of IgAN immunopathogenesis. The roles of tonsil immunity or intestinal mucosal immunity, which have received more attention in recent years, are supported by mounting evidence. In this review, we will explore the latest research insights on the role of immune modulation in the pathogenesis of IgAN. With a better understanding of immunopathogenesis of IgAN, emerging therapies will soon become realized.
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Affiliation(s)
- Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.,Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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10
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Asano Y, Matsumoto Y, Miyazaki T, Ishizu A, Morizane S, Hayashi K, Yamamura Y, Hiramatsu S, Miyawaki Y, Morishita M, Ohashi K, Watanabe H, Watanabe KS, Kawabata T, Sada KE, Makino H, Wada J. Simultaneous development of IgA vasculitis and eosinophilic granulomatosis with polyangiitis. Mod Rheumatol Case Rep 2019; 4:63-69. [PMID: 33086980 DOI: 10.1080/24725625.2019.1673528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Immunoglobulin A (IgA) vasculitis (IgAV) is a small vessel vasculitis presenting cutaneous purpura, arthralgias and/or arthritis, acute enteritis and glomerulonephritis caused by deposition of the IgA1-mediated immune complex. Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by eosinophil-rich and granulomatous inflammation in small to medium-sized vessels. Both IgAV and EGPA are classified as autoimmune systemic vasculitis, but the pathogenesis of immune complex-mediated IgAV and that of pauci-immune EGPA are different. Here we report a rare case of simultaneous development of IgAV and EGPA presenting palpable purpura and numbness in a patient with a history of asthma. Histological examination revealed leukocytoclastic vasculitis with deposition of IgA, IgM and C3 in the upper dermis and necrotising vasculitis with eosinophilic infiltration and granulomatous formation in the lower dermis and subcutaneous fat, indicating the existence of IgAV and EGPA. Our case provides evidence of concurrent development of two different types of vasculitis, which may affect disease-associated complications, therapeutic strategy and prognosis.
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Affiliation(s)
- Yosuke Asano
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshinori Matsumoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Akihiro Ishizu
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Shin Morizane
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Keigo Hayashi
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuriko Yamamura
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Sumie Hiramatsu
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshia Miyawaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Michiko Morishita
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Keiji Ohashi
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Haruki Watanabe
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Katsue Sunahori Watanabe
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tomoko Kawabata
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ken-Ei Sada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirofumi Makino
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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11
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Ruszkowski J, Lisowska KA, Pindel M, Heleniak Z, Dębska-Ślizień A, Witkowski JM. T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. Clin Exp Nephrol 2019; 23:291-303. [PMID: 30406499 PMCID: PMC6394565 DOI: 10.1007/s10157-018-1665-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/25/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN METHODS: We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells' participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. RESULTS We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. CONCLUSIONS T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.
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Affiliation(s)
- Jakub Ruszkowski
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.
| | - Katarzyna A Lisowska
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
| | - Małgorzata Pindel
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
| | - Zbigniew Heleniak
- Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Jacek M Witkowski
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
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12
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Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome. J Clin Immunol 2018. [PMID: 29086100 DOI: 10.1007/s10875-017-0453-z)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder originally described by Dr. Alfred Wiskott in 1937 and Dr. Robert Aldrich in 1954 as a familial disease characterized by infections, bleeding tendency, and eczema. Today, it is well recognized that the syndrome has a wide clinical spectrum ranging from mild, isolated thrombocytopenia to full-blown presentation that can be complicated by life-threatening hemorrhages, immunodeficiency, atopy, autoimmunity, and cancer. The pathophysiology of classic and emerging features is being elucidated by clinical studies, but remains incompletely defined, which hinders the application of targeted therapies. At the same time, progress of hematopoietic stem cell transplantation and gene therapy offer optimistic prospects for treatment options aimed at the replacement of the defective lymphohematopoietic system that have the potential to provide a cure for this rare and polymorphic disease.
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13
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Tatsumoto N, Miyauchi T, Arditi M, Yamashita M. Quantification of Infectious Sendai Virus Using Plaque Assay. Bio Protoc 2018; 8:e3068. [PMID: 30547053 DOI: 10.21769/bioprotoc.3068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Sendai virus (SeV) is an enveloped, single-stranded RNA virus of the family Paramyxoviridae. SeV is a useful tool to study its infectious pathomechanism in immunology and the pathomechanism of a murine model of IgA nephropathy. Virus quantification is essential not only to determine the original viral titers for an appropriate application, but also to measure the viral titers in samples from the harvests from experiments. There are mainly a couple of units/titers for Sendai viral quantification: plaque-forming units (PFU) and hemagglutination (HA) titer. Of these, we here describe a protocol for Sendai virus plaque assay to provide PFU using LLC-MK2 cells (a rhesus monkey kidney cell lines) and Guinea pig red blood cells. This traditional protocol enables us to determine Sendai virus PFU in viral stock as well as samples from your experiments.
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Affiliation(s)
- Narihito Tatsumoto
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Takamasa Miyauchi
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Moshe Arditi
- Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, USA.,Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Michifumi Yamashita
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
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14
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Abstract
Sendai virus is a member of the family Paramyxoviridae, and an enveloped virus with a negative-stranded RNA genome. Sendai virus is not pathogenic to humans, but for mice and can cause pneumonia in mice. Easy and efficient techniques for propagating Sendai virus are required for studying virus replication, virus-induced innate- and adaptive-immunity, Sendai-virus-based virotherapy and IgA nephropathy. Here, we describe a protocol for Sendai virus propagation using chicken eggs. This traditional protocol enables us to generate a large amount of virus enough for animal experiments as well as cell culture experiments in a relatively inexpensive way.
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Affiliation(s)
- Narihito Tatsumoto
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Moshe Arditi
- Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, USA.,Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Michifumi Yamashita
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, USA
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15
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Kim AH, Chung JJ, Akilesh S, Koziell A, Jain S, Hodgin JB, Miller MJ, Stappenbeck TS, Miner JH, Shaw AS. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2017; 2:81836. [PMID: 29093269 DOI: 10.1172/jci.insight.81836] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 10/05/2017] [Indexed: 12/13/2022] Open
Abstract
The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4-deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines.
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Affiliation(s)
- Alfred Hj Kim
- Division of Rheumatology, Department of Internal Medicine, and
| | - Jun-Jae Chung
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Shreeram Akilesh
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ania Koziell
- Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London and Department of Paediatric Nephrology, Evelina Children's Hospital, London, United Kingdom
| | - Sanjay Jain
- Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark J Miller
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Thaddeus S Stappenbeck
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jeffrey H Miner
- Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Andrey S Shaw
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.,Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA
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16
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Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome. J Clin Immunol 2017; 38:13-27. [PMID: 29086100 DOI: 10.1007/s10875-017-0453-z] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 10/13/2017] [Indexed: 02/07/2023]
Abstract
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder originally described by Dr. Alfred Wiskott in 1937 and Dr. Robert Aldrich in 1954 as a familial disease characterized by infections, bleeding tendency, and eczema. Today, it is well recognized that the syndrome has a wide clinical spectrum ranging from mild, isolated thrombocytopenia to full-blown presentation that can be complicated by life-threatening hemorrhages, immunodeficiency, atopy, autoimmunity, and cancer. The pathophysiology of classic and emerging features is being elucidated by clinical studies, but remains incompletely defined, which hinders the application of targeted therapies. At the same time, progress of hematopoietic stem cell transplantation and gene therapy offer optimistic prospects for treatment options aimed at the replacement of the defective lymphohematopoietic system that have the potential to provide a cure for this rare and polymorphic disease.
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17
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Kim MJ, Schaub S, Molyneux K, Koller MT, Stampf S, Barratt J. Effect of Immunosuppressive Drugs on the Changes of Serum Galactose-Deficient IgA1 in Patients with IgA Nephropathy. PLoS One 2016; 11:e0166830. [PMID: 27930655 PMCID: PMC5145158 DOI: 10.1371/journal.pone.0166830] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 11/06/2016] [Indexed: 12/25/2022] Open
Abstract
Galactose-deficient IgA1 (Gd-IgA1) and IgA-IgG complexes are known to play an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed therefore to determine the impact of immunosuppression on the serum levels of Gd-IgA1, total IgA1 and IgA-IgG complexes in IgAN patients. In a retrospective study, serum samples from IgAN patients collected before transplantation (t0) and at 3- and 6-month posttransplant (t3 & t6) were used to measure the levels of Gd-IgA1, total IgA1 and IgA-IgG complexes. The area under the curves (AUC) of immunosuppressants was calculated by the plot of plasma trough level or dosage of each immunosuppressant versus time and was interpreted as the extent of drug exposure. Thirty-six out of 64 IgAN patients, who underwent kidney transplantation between 2005 and 2012, were enrolled. From t0 to t3, serum Gd-IgA1 and total IgA1 decreased significantly (24.7 AU (18.6-36.1) to 17.2 (13.1-29.5) (p<0.0001); 4.1 mg/ml (3.6-5.1) to 3.4 (3.0-4.1) (p = 0.0005)), whereas IgA-IgG complexes remained similar. From t3 to t6, Gd-IgA1 and IgA-IgG complexes significantly increased (17.2 AU (13.1-29.5) to 23.9 (16.8-32.0) (p = 0.0143); OD 0.16 (0.06-0.31) to 0.26 (0.14-0.35) (p = 0.0242)), while total IgA1 remained similar. According to median regression analysis, AUC of prednisone t0-6 was significantly associated with the decrease of Gd-IgA1 t0-6 (P = 0.01) and IgA1 t0-6 (p = 0.002), whereas AUC of tacrolimus t0-6 was associated with the decrease of IgA1 t0-6 (p = 0.02). AUC of prednisone t0-3 was associated with the decrease of IgA-IgG complexes t0-3 (p = 0.0036). The association of AUC prednisone t0-6 with Gd-IgA1 t0-6 remained highly significant after adjustment for other immunosuppressants (p = 0.0036). Serum levels of Gd-IgA1, total IgA1 and IgA-IgG in patients with IgAN vary according to the changing degrees of immunosuppression. The exposure to prednisone most clearly influenced the serum levels of Gd-IgA1.
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Affiliation(s)
- Min Jeong Kim
- Clinic for Transplantationsimmunology & Nephrology, University Hospital Basel, Basel, Switzerland
- * E-mail:
| | - Stefan Schaub
- Clinic for Transplantationsimmunology & Nephrology, University Hospital Basel, Basel, Switzerland
| | - Karen Molyneux
- Department of Infection, Immunity & Inflammation, University of Leicester, Leicester, United Kingdom
| | - Michael T. Koller
- Clinic for Transplantationsimmunology & Nephrology, University Hospital Basel, Basel, Switzerland
- Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
| | - Susanne Stampf
- Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland
| | - Jonathan Barratt
- Department of Infection, Immunity & Inflammation, University of Leicester, Leicester, United Kingdom
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18
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MicroRNA-155-induced T lymphocyte subgroup drifting in IgA nephropathy. Int Urol Nephrol 2016; 49:353-361. [DOI: 10.1007/s11255-016-1444-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 10/18/2016] [Indexed: 01/09/2023]
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19
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Release from Th1-type immune tolerance in spleen and enhanced production of IL-5 in Peyer’s patch by cholera toxin B induce the glomerular deposition of IgA. Immunobiology 2016; 221:577-85. [DOI: 10.1016/j.imbio.2015.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/01/2015] [Accepted: 12/01/2015] [Indexed: 12/28/2022]
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20
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Wuhrer M, Stavenhagen K, Koeleman CAM, Selman MHJ, Harper L, Jacobs BC, Savage COS, Jefferis R, Deelder AM, Morgan M. Skewed Fc Glycosylation Profiles of Anti-proteinase 3 Immunoglobulin G1 Autoantibodies from Granulomatosis with Polyangiitis Patients Show Low Levels of Bisection, Galactosylation, and Sialylation. J Proteome Res 2015; 14:1657-65. [DOI: 10.1021/pr500780a] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Manfred Wuhrer
- Center
for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Division
of BioAnalytical Chemistry, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
- Department
of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands
| | - Kathrin Stavenhagen
- Center
for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Division
of BioAnalytical Chemistry, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Carolien A. M. Koeleman
- Center
for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Maurice H. J. Selman
- Center
for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Lorraine Harper
- School
of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, U.K
| | - Bart C. Jacobs
- Department
of Immunology and Department of Neurology, Erasmus MC, University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands
| | - Caroline O. S. Savage
- School
of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, U.K
| | - Roy Jefferis
- School
of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, U.K
| | - André M. Deelder
- Center
for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Matthew Morgan
- School
of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, U.K
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21
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Esser-von Bieren J, Volpe B, Kulagin M, Sutherland DB, Guiet R, Seitz A, Marsland BJ, Verbeek JS, Harris NL. Antibody-mediated trapping of helminth larvae requires CD11b and Fcγ receptor I. THE JOURNAL OF IMMUNOLOGY 2014; 194:1154-63. [PMID: 25548226 DOI: 10.4049/jimmunol.1401645] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow-derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI-driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.
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Affiliation(s)
- Julia Esser-von Bieren
- Swiss Vaccine Research Institute, Global Health Institute, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Beatrice Volpe
- Swiss Vaccine Research Institute, Global Health Institute, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Manuel Kulagin
- Swiss Vaccine Research Institute, Global Health Institute, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Duncan B Sutherland
- Swiss Vaccine Research Institute, Global Health Institute, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Romain Guiet
- Bioimaging and Optics Core Facility, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Arne Seitz
- Bioimaging and Optics Core Facility, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland
| | - Benjamin J Marsland
- Faculty of Biology and Medicine, Respiratory Division, University Hospital, Vaud, University of Lausanne, 1011 Lausanne, Switzerland; and
| | - J Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Nicola L Harris
- Swiss Vaccine Research Institute, Global Health Institute, Swiss Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
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22
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Abstract
Henoch-Schönlein purpura (HSP) is the most common vasculitis in children, in whom prognosis is mostly dependent upon the severity of renal involvement. Nephritis is observed in about 30% of children with HSP. Renal damage eventually leads to chronic kidney disease in up to 20% of children with HSP nephritis in tertiary care centres, but in less than 5% of unselected patients with HSP, by 20 years after diagnosis. HSP nephritis and IgA nephropathy are related diseases resulting from glomerular deposition of aberrantly glycosylated IgA1. Although both nephritides present with similar histological findings and IgA abnormalities, they display pathophysiological differences with important therapeutic implications. HSP nephritis is mainly characterized by acute episodes of glomerular inflammation with endocapillary and mesangial proliferation, fibrin deposits and epithelial crescents that can heal spontaneously or lead to chronic lesions. By contrast, IgA nephropathy normally presents with slowly progressive mesangial lesions resulting from continuous low-grade deposition of macromolecular IgA1. This Review highlights the variable evolution of similar clinical and histological presentations among paediatric patients with HSP nephritis, which constitutes a challenge for their management, and discusses the treatment of these patients in light of current guidelines based on clinical evidence from adults with IgA nephropathy.
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23
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Chen X, Liu H, Peng Y, He L, Zhang Y, Xie Y, Peng X, Liu C, Liu F. Expression and correlation analysis of IL-4, IFN-γ and FcαRI in tonsillar mononuclear cells in patients with IgA nephropathy. Cell Immunol 2014; 289:70-5. [DOI: 10.1016/j.cellimm.2014.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 02/18/2014] [Accepted: 03/14/2014] [Indexed: 01/13/2023]
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24
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He L, Peng Y, Liu H, Yin W, Chen X, Peng X, Shao J, Liu Y, Liu F. Th1/Th2 polarization in tonsillar lymphocyte form patients with IgA nephropathy. Ren Fail 2013; 36:407-12. [PMID: 24295274 DOI: 10.3109/0886022x.2013.862809] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Imbalance of Th1/Th2 pro-inflammatory cytokines plays an important role in the development and progression of IgA nephropathy (IgAN). Clinical development and exacerbation of IgAN are frequently preceded by episodes of upper respiratory tract infection, and palatine tonsils represent the predominant immunocompetent tissue of the upper respiratory tract. This study examined tonsillar lymphocytes of IgAN who suffered from tonsillitis (n = 22), and using tonsils derived from patients with chronic tonsillitis (n = 24) but without renal disease as a control. We identified a polarization toward Th2 response in tonsils of IgAN patients. TH0 cells are differentially mobilized during contact sensitization and by adjuvants such as lipopolysaccharide (LPS) that induce T-helper type 1 (Th1) responses, or α-hemolytic streptococcus (HS) that induces T-helper type 2 (Th2) responses. Th1:Th2 ratio is correlated with proteinuria and renal pathologic changes in IgAN group. Our study suggests that IgAN is associated with the change in Th1/Th2 balance in favor of Th2 lymphocytes.
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Affiliation(s)
- Liyu He
- Key Lab of Kidney Disease and Blood Purification, Nephrology Department, 2nd Xiangya Hospital, Central South University , Changsha, Hunan , People's Republic of China
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Li LT, Shi MY, Wei SY, Li T, Li B. Huai Qi Huang ameliorates proteinuria and hematuria in mild IgA nephropathy patients: a prospective randomized controlled study. J Formos Med Assoc 2013; 112:766-72. [PMID: 24280442 DOI: 10.1016/j.jfma.2013.10.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 10/09/2013] [Accepted: 10/25/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/PURPOSE Huai Qi Huang (HQH) is a compound Chinese herbal medicine that contains Trametes robiniophila murr, wolfberry fruit, and Polygonatum. In the present study, we investigated the effects of HQH on patients with mild immunoglobulin A nephropathy (IgAN) through a prospective randomized controlled study. METHODS Forty-five adults diagnosed with IgAN according to renal pathology, who had hematuria or/and proteinuria (≤ 2 g/day), were randomly assigned to receive HQH or no treatment for 12 weeks. Twenty-four hour urinary protein excretion and hematuria were measured at Weeks 0, 4, 8, and 12. The rate of complete remission of proteinuria and hematuria was evaluated. Any adverse events induced by HQH were also observed during the treatment period. RESULTS Twenty-four hour urinary protein excretion was significantly reduced by HQH treatment compared with that in the control group at Weeks 8 and 12. A much higher rate of complete remission of proteinuria was observed in the HQH group than in control group at Week 12. HQH administration also obviously reduced the extent of hematuria compared with that in the control group at Week 12. HQH treatment dramatically increased the rate of complete remission of hematuria compared with that in control group at Weeks 8 and 12. No obvious adverse events caused by HQH were observed. CONCLUSION HQH could be a new conservative therapy for IgAN patients who cannot tolerate steroids and immunosuppressive agents. The relapse rate after discontinuing treatment still needs further investigation.
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Affiliation(s)
- Lei-Ting Li
- Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Ming-Yang Shi
- Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Shi-Yao Wei
- Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Tong Li
- Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
| | - Bing Li
- Department of Nephrology, Second Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China.
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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations. PLoS One 2013; 8:e78736. [PMID: 24223846 PMCID: PMC3817077 DOI: 10.1371/journal.pone.0078736] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 09/16/2013] [Indexed: 01/05/2023] Open
Abstract
The link between glomerular IgA nephropathy (IgAN) and T helper 2 (Th2) response has been implicated, however, the mechanisms are poorly defined because of the lack of an appropriate model. Here we report a novel murine model characterized by lineage-restricted deletion of the gene encoding MAD homologue 4 (Smad4) in T cells (Smad4(co/co;Lck-cre) ). Loss of Smad4 expression in T cells results in overproduction of Th2 cytokines and high serum IgA levels. We found that Smad4(co/co;Lck-cre) mice exhibited massive glomerular IgA deposition, increased albumin creatinine ratio, aberrant glycosylated IgA, IgA complexed with IgG1 and IgG2a, and polymeric IgA, all known features of IgAN in humans. Furthermore, we examined the β1, 4-galactosyltransferases (β4GalT) enzyme which is involved in the synthesis of glycosylated murine IgA, and we found reduced β4GalT2 and β4GalT4 mRNA levels in B cells. These findings indicate that Smad4(co/co;Lck-cre) mice could be a useful model for studying the mechanisms between IgAN and Th2 response, and further, disruption of Smad4-dependent signaling in T cells may play an important role in the pathogenesis of human IgAN and contributing to a Th2 T cell phenotype.
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He L, Peng Y, Liu H, Yin W, Chen X, Peng X, Shao J, Liu Y, Liu F. Activation of the interleukin-4/signal transducer and activator of transcription 6 signaling pathway and homeodomain-interacting protein kinase 2 production by tonsillar mononuclear cells in IgA nephropathy. Am J Nephrol 2013; 38:321-32. [PMID: 24107646 DOI: 10.1159/000355393] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 08/29/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND/AIM Clinical development and exacerbation of IgA nephropathy (IgAN) are frequently preceded by episodes of upper respiratory tract infection such as tonsillitis. This study aimed to determine the role of the interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) signaling pathway and homeodomain-interacting protein kinase 2 (HIPK2) in aberrant IgA1 O-glycosylation production, and identify potential therapeutic targets in IgAN. METHODS Expression levels of IL-4, STAT6, core1β1,3-galactosyltransferase (C1GALT1C1), core1β3GalT-specific molecular chaperone (Cosmc) and HIPK2 in tonsil components were examined by immunohistochemical and immunofluorescence staining. Lymphocytes isolated from 22 patients with IgAN and 24 patients with chronic tonsillitis (CT) as controls were cultured for 72 h with or without IL-4, lipopolysaccharide (LPS) and α-hemolytic streptococcus (HS) stimulation. Expression levels of STAT6, C1GALT1C1, Cosmc, HIPK2-mRNA and protein were measured by real-time PCR and Western blot analysis, respectively. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia villosa (VV) lectin-binding assay. To determine the contribution of HIPK2 in IgA secretion and O-glycosylation, cells were subjected to experiments for evaluation of HIPK2 silencing by Hipk2-siRNA transfection. RESULTS The IL-4/STAT6 signaling pathway was highly activated in all tonsil tissues (including the germinal center and tonsillar crypt epithelium) of IgAN patients, but the gene or protein expression of β1,3-Gal transferase (C1GALT1) and COSMC decreased significantly in patients with IgAN in comparison with those with CT. Hipk2 production in the tonsils derived from IgAN patients was significantly higher than that of CT patients. HIPK2-mRNA expression significantly negatively correlated with renal function as expressed by the estimated glomerular filtration rate, and also significantly positively correlated with daily proteinuria. The level of IL-4, STAT6 and HIPK2 were closely related with Lee's pathological grading system. The levels of mRNA and protein encoding STAT6 and Hipk2 in cells coincubated with IL-4, LPS and HS were significantly higher than those in the controls without stimulation; however, in the IgAN group the levels of mRNA and protein encoding C1GALT1 and Cosmc were significantly lower compared to the controls. IgA1 concentrations of supernatants in IgAN patients were remarkably higher under conditions of external stimulation. As expected, the optical density value of VV lectin binding to IgA1 increased after external stimulation in the IgAN group. By siRNA transfection, our results clearly indicate that Hipk2 negatively regulates C1GALT1 and Cosmc expression. Importantly, HIPK2-siRNA attenuates the aberrant glycosylation of IgA1 secretion. CONCLUSION We identified and confirmed that activation of the IL-4/STAT6 signaling pathway has a crucial role in aberrant glycosylation of IgA1 secretion. HIPK2, a protein kinase previously unrecognized in kidney disease, may mediate the glycosylation of IgA1. We believe that HIPK2 could be a new therapeutic target for IgAN, especially as protein kinases are 'drugable' targets.
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Affiliation(s)
- Liyu He
- Nephrology Department, 2nd Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, PR China
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Kemmochi S, Hayashi H, Taniai E, Hasumi K, Sugita-Konishi Y, Kumagai S, Mitsumori K, Shibutani M. Protective Effect of Stachybotrys microspora Triprenyl Phenol-7on the Deposition of IgA to the Glomerular Mesangium in Nivalenol-induced IgA Nephropathy Using BALB/c Mice. J Toxicol Pathol 2012; 25:149-54. [PMID: 22907981 PMCID: PMC3392907 DOI: 10.1293/tox.25.149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/18/2012] [Indexed: 11/19/2022] Open
Abstract
Activators of tissue proteolysis including Stachybotrys microspora triprenyl phenol (SMTP)-7 are a new class of agents that are expected to be effective for amelioration of chronic tissue destructive diseases. The present study was performed to examine whether SMTP-7 is effective for the amelioration or protection of early-stage IgA nephropathy (IgAN) induced by nivalenol (NIV) in female BALB/c mice. In Experiment 1, mice were administered NIV at 24 ppm in diet for 8 weeks, and during the NIV treatment, they were intraperitoneally injected with SMTP-7 (10 mg/kg) three times a week. In Experiment 2, mice were injected similarly with SMTP-7 during the last 4 weeks of a 16-week NIV treatment. Immunofluorescence analysis revealed an inhibitory effect of SMTP-7 on the glomerular deposition of IgA in Experiment 1; however, it was ineffective in Experiment 2. On the other hand, SMTP-7 did not affect the serum concentration of IgA in both experiments. These results suggest that SMTP-7 has a potential to decrease the progression of IgAN induced by NIV through inhibition of local accumulation of IgA in the glomerular mesangium, while it was ineffective for suppression of IgA production. On the other hand, SMTP-7 was found to be ineffective for already deposited IgA, suggesting that SMTP-7 may not be effective for ameliorating advanced IgAN.
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Lundberg S, Lundahl J, Gunnarsson I, Sundelin B, Jacobson SH. Soluble interleukin-2 receptor alfa predicts renal outcome in IgA nephropathy. Nephrol Dial Transplant 2011; 27:1916-23. [PMID: 21940483 DOI: 10.1093/ndt/gfr554] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Both systemic and mucosal IgA production are controlled by T lymphocytes and infiltrating T lymphocytes are involved in the progression of interstitial fibrosis in chronic kidney disease (CKD). Since the concentration of soluble interleukin-2 receptor alfa (sIL-2Ra) reflects the degree of T cell activation over time, we studied the impact of interleukin-2 receptor alfa levels on disease progression in patients with biopsy-proven IgA nephropathy (IgAN), a disease in which 20-30% of the patients progress to end-stage renal failure. METHODS sIL-2Ra plasma levels were measured in 194 patients (median age 39 years, 70% men) and 84 matched controls. One hundred and seventy-nine of the patients, with an estimated glomerular filtration rate (GFR) of ≥15 mL/min/1.73m(2) at baseline (CKD Stages 1-4), were followed for up to 15 years (median 52 months; range 12-188). sIL-2Ra was evaluated as a risk marker for severe renal progression, here defined by the development of CKD Stage 5 (GFR <15 mL/min/1.73m(2)), a 50% decline in GFR during the follow-up period or a 30% GFR decline within 5 years of follow-up. In 51 patients, upon whom a renal biopsy had been performed within 2 years of IL2-Ra measurement, the biopsies were scored according to the Oxford classification. The correlations between the histopathological findings and the sIL-2Ra levels were examined. RESULTS sIL2-Ra levels were significantly higher in patients than in controls (P < 0.001). sIL-2Ra levels in the upper third tertile predicted a severe renal outcome, even after adjustment for the main clinical risk factors: time average albuminuria and GFR at baseline (Relative risk 5.35, P < 0.001). sIL-2Ra levels also correlated significantly to the yearly GFR slope (β = -0.24, P = 0.01). According to the Oxford classification, the presence of >25% tubular atrophy/interstitial fibrosis (T1-2) was associated with higher sIL-2Ra levels, after adjustment for serum creatinine levels, if analysed within 4 months [n = 24, odds ratio (OR) 1.0, P = 0.044] or within 2 years from the kidney biopsy (n = 51, OR 1.0, P = 0.017). CONCLUSIONS The plasma levels of sIL-2Ra were predictive of long-term renal disease progression in a large cohort of patients with biopsy-proven IgAN. Further studies are warranted to evaluate if sIL-2Ra levels can feasibly contribute in the monitoring of effects of treatment, aimed to prevent the progression of interstitial fibrosis and progressive glomerulosclerosis in IgAN.
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Affiliation(s)
- Sigrid Lundberg
- Nephrology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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Ka SM, Hsieh TT, Lin SH, Yang SS, Wu CC, Sytwu HK, Chen A. Decoy receptor 3 inhibits renal mononuclear leukocyte infiltration and apoptosis and prevents progression of IgA nephropathy in mice. Am J Physiol Renal Physiol 2011; 301:F1218-30. [PMID: 21900455 DOI: 10.1152/ajprenal.00050.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis, is associated with high levels of mononuclear leukocyte infiltration into the kidney. These cells consist mainly of T cells and macrophages. Our previous study showed that a decoy receptor 3 (DCR3) gene therapy can prevent the development of a mouse autoimmune glomerulonephritis model by its potent immune modulating effects (Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A. J Am Soc Nephrol 18: 2473-2485, 2007). Here, we tested the hypothesis that DCR3 might prevent the progression of IgAN, an immune complex-mediated primary glomerulonephritis, by inhibiting T cell activation, renal T cell/macrophage infiltration, and protecting the kidney from apoptosis. We used a progressive IgAN (Prg-IgAN) model in B cell-deficient mice, because the mice are characterized by a dramatic proliferation of activated T cells systemically and progressive NF-κB activation in the kidney. We treated the animals with short-term gene therapy with DCR3 plasmids by hydrodynamics-based gene delivery. When the mice were euthanized on day 21, we found that, compared with empty vector-treated (disease control) Prg-IgAN mice, DCR3 gene therapy resulted in 1) systemic inhibition of T cell activation and proliferation; 2) lower serum levels of proinflammatory cytokines; 3) improved proteinuria, renal function, and renal pathology (inhibiting the development of marked glomerular proliferation, crescent formation, glomerulosclerosis, and interstitial inflammation); 5) suppression of T cell and macrophage infiltration into the periglomerular interstitium of the kidney; and 5) a reduction in apoptotic figures in the kidney. On the basis of these findings, DCR3 might be useful therapeutically in preventing the progression of IgAN.
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Affiliation(s)
- Shuk-Man Ka
- Dept. of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325 Sec. 2 Cheng-Gung Road, Taipei, Taiwan
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Dewa Y, Kemmochi S, Kawai M, Saegusa Y, Harada T, Shimamoto K, Mitsumori K, Kumagai S, Sugita-Konishi Y, Shibutani M. Rapid deposition of glomerular IgA in BALB/c mice by nivalenol and its modifying effect on high IgA strain (HIGA) mice. ACTA ACUST UNITED AC 2011; 63:17-24. [DOI: 10.1016/j.etp.2009.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2009] [Revised: 08/07/2009] [Accepted: 09/01/2009] [Indexed: 10/20/2022]
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Phillips-Quagliata JM. Structural correlates of mouse IgA allotypes. Immunogenetics 2009; 62:1-13. [PMID: 20012955 DOI: 10.1007/s00251-009-0414-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Accepted: 11/13/2009] [Indexed: 11/25/2022]
Abstract
A set of mouse IgAs containing amino acids differing amongst the six alpha-chain allotypes was constructed by mutating an S107-IgA plasmid and transfecting it into a non-producer myeloma cell line along with a kappa-chain plasmid. The secreted IgAs were examined for their possession of a covalent bond between alpha- and light (L)-chains and for their ability to bind to three anti-allotypic monoclonal antibodies, HIS-M2, HY-15, and HY-16. IgA of the Igh-2(a) allotype was found to be unique in its total lack of a covalent bond between alpha and L: -chains, formation of which apparently depends on the presence of an "extra" Cys in the hinges of all of the other five allotypes. The allotypic epitopes are associated with identifiable amino acids in the Calpha1 region of the molecule. Binding to HIS-M2 requires Ala 216 whereas binding to HY-15 requires Pro 216 and Asp 222. Binding to Hy-16 requires Arg 183 and either Pro 216 or Ser 216 but not Ala 216. However, binding to HY-16 by all of the IgAs produced by transfectants is impaired by defective glycosylation in the transfected myeloma and is only revealed after deglycosylation.
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Oracki SA, Tsantikos E, Quilici C, Light A, Schmidt T, Lew AM, Martin JE, Smith KG, Hibbs ML, Tarlinton DM. CTLA4Ig alters the course of autoimmune disease development in Lyn-/- mice. THE JOURNAL OF IMMUNOLOGY 2009; 184:757-63. [PMID: 19966213 DOI: 10.4049/jimmunol.0804349] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Lyn-deficient (Lyn(-/-)) mice develop an age-dependent autoimmune disease similar to systemic lupus erythematosus, characterized by the production of IgG anti-nuclear Ab. To determine the extent to which this autoimmune phenotype is driven by T cell costimulation, we generated Lyn(-/-) mice expressing a soluble form of the T cell inhibitory molecule, CTLA4 (CTLA4Ig). Surprisingly, although CTLA4Ig prevented myeloid hyperplasia, splenomegaly and IgG anti-nuclear Ab production in Lyn(-/-) mice, it did not inhibit immune complex deposition and tissue destruction in the kidney. In fact, regardless of CTLA4Ig expression, Lyn(-/-) serum contained elevated titers of IgA anti-nuclear Ab, although generally IgA deposition in the kidney was only revealed in the absence of self-reactive IgG. This demonstrated that activation of autoreactive B cell clones in Lyn(-/-) mice can still occur despite impaired costimulation. Indeed, CTLA4Ig did not alter perturbed Lyn(-/-) B cell development and behavior, and plasma cell frequencies were predominantly unaffected. These results suggest that when self-reactive B cell clones are unimpeded in acquiring T cell help, they secrete pathogenic IgG autoantibodies that trigger the fulminant autoimmunity normally observed in Lyn(-/-) mice. The absence of these IgG immune complexes reveals an IgA-mediated axis of autoimmunity that is not sufficient to cause splenomegaly or extramedullary myelopoiesis, but which mediates destructive glomerulonephritis. These findings have implications for the understanding of the basis of Ab-mediated autoimmune diseases and for their treatment with CTLA4Ig.
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Affiliation(s)
- Sarah A Oracki
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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