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Alimohammadi M, Kahkesh S, Abbasi A, Hashemi M, Khoshnazar SM, Taheriazam A, Hushmandi K. LncRNAs and IgA nephropathy: underlying molecular pathways and clinical applications. Clin Exp Med 2025; 25:140. [PMID: 40328979 PMCID: PMC12055897 DOI: 10.1007/s10238-025-01660-9] [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: 03/06/2025] [Accepted: 04/01/2025] [Indexed: 05/08/2025]
Abstract
IgA nephropathy (IgAN), also known as Berger's disease, is a prevalent kidney disorder caused by the accumulation of IgA antibodies in the glomerular tissue. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs longer than 200 nucleotides, play crucial roles in regulating various cellular and molecular processes, including translation, chromatin remodeling, and transcriptional efficiency. Research has highlighted the significant impact of lncRNA imbalances on the development and progression of kidney diseases, including IgAN. These molecules influence several key signaling pathways, such as PI3K/AKT/mTOR, PTEN, Notch, JNK, and immune-related pathways, with their dysregulation contributing to IgAN pathogenesis. This review aims to provide a comprehensive analysis of the molecular signaling pathways involving lncRNAs in IgAN, underscoring their potential as biomarkers for screening, diagnosis, and prevention. Furthermore, it explores the therapeutic potential of lncRNAs as precise targets for personalized treatment strategies.
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Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amirhosein Abbasi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Seyedeh Mahdieh Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Ye Q, Deng R, Li J, Wang J, Chang X, Zhang H, Chen X, Li J, Huang G, Fei J, Wu C, Fu Q, Liu L, Chen G, Qiu J, Chen L, Chen W, Yang S, Deng S, Gao Y, Wang C. Single-cell transcriptomics reveals the immune mechanisms by which tonsillectomy improves clinical outcomes of recurrent Immuoglobulin A nephropathy after kidney transplant. Mol Immunol 2025; 180:1-10. [PMID: 39985963 DOI: 10.1016/j.molimm.2025.02.010] [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: 11/17/2024] [Revised: 01/16/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
Immunoglobulin A nephropathy recurrence (IgANR) is a major cause of graft function loss in renal transplant patients with IgA nephropathy. Tonsillectomy has been recognized as an effective treatment for IgANR, but the cellular and molecular effects underlying its efficacy remain poorly understood. We aimed to identify the cell types and gene expression profiles in tonsillar tissue and peripheral blood mononuclear cells (PBMCs) to investigate the effectiveness of tonsillectomy in IgANR treatment. Flow cytometry and single-cell mRNA sequencing were performed to comprehensively characterize the cell types of 29 patients with IgANR. Additionally, we analyzed a tonsillar tissue sample and three PBMC samples to gain further insights. Single-cell transcriptome analysis revealed significant changes in gene expression following tonsillectomy in patients with IgANR. Conventional cytometry and transcriptome analysis revealed that B cells played a crucial role in IgANR treatment using tonsillectomy. Notably, the downregulation of IGHA1 expression, memory B cell inactivation, and alterations in related pathways led to a reduction in galactose-deficient IgA1 (Gd-IgA1), which plays a crucial role in IgA nephropathy. The phosphatidylinositol-3-kinase (PI3k)-Akt pathway was significantly downregulated in peripheral B cells, and peripheral B cells in patients with IgANR who underwent tonsillectomy demonstrated downregulated expression of T cell leukemia/lymphoma 1 A (TCL1A), an Akt coactivator. As a result, it is possible that TCL1A plays a major role in the mediation of this therapeutic effect. Tonsillectomy aids in the treatment of IgANR by guiding B cell phenotypes, inducing functional changes, and regulating the immune response, thereby reducing Gd-IgA1 levels and improving clinical outcomes.
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Affiliation(s)
- Qianyu Ye
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ronghai Deng
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian Li
- Department of Otorhinolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China; Guangzhou Key Laboratory of Otorhinolaryngology, Guangzhou, China
| | - Jiali Wang
- Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinhua Chang
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huanxi Zhang
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xutao Chen
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gang Huang
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiguang Fei
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chenglin Wu
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qian Fu
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guodong Chen
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiang Qiu
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lizhong Chen
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenfang Chen
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shicong Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Suxiong Deng
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Yifang Gao
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Changxi Wang
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Kano T, Suzuki H, Makita Y, Nihei Y, Fukao Y, Nakayama M, Lee M, Aoki R, Yamada K, Muto M, Suzuki Y. Lessons from IgA Nephropathy Models. Int J Mol Sci 2024; 25:11484. [PMID: 39519036 PMCID: PMC11546737 DOI: 10.3390/ijms252111484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide; however, the underlying mechanisms of this disease are not fully understood. This review explores several animal models that provide insights into IgAN pathogenesis, emphasizing the roles of aberrant IgA1 glycosylation and immune complex formation. It discusses spontaneous, immunization, and transgenic models illustrating unique aspects of IgAN development and progression. The animal models, represented by the grouped ddY (gddY) mouse, have provided guidance concerning the multi-hit pathogenesis of IgAN. In this paradigm, genetic and environmental factors, including the dysregulation of the mucosal immune system, lead to increased levels of aberrantly glycosylated IgA, nephritogenic immune complex formation, and subsequent glomerular deposition, followed by mesangial cell activation and injury. Additionally, this review considers the implications of clinical trials targeting molecular pathways influenced by IgAN (e.g., a proliferation-inducing ligand [APRIL]). Collectively, these animal models have expanded the understanding of IgAN pathogenesis while facilitating the development of therapeutic strategies that are currently under clinical investigation. Animal-model-based studies have the potential to facilitate the development of targeted therapies with reduced side effects for IgAN patients.
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Affiliation(s)
- Toshiki Kano
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
- Department of Nephrology, Juntendo University Urayasu Hospital, Chiba 279-0021, Japan
| | - Yuko Makita
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yoshihito Nihei
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yusuke Fukao
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Maiko Nakayama
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Mingfeng Lee
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Ryosuke Aoki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Koshi Yamada
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Masahiro Muto
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan
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Suzuki Y. B cell targeting in IgA nephropathy. Nephrology (Carlton) 2024; 29 Suppl 2:39-43. [PMID: 39327767 DOI: 10.1111/nep.14367] [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: 03/04/2024] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 09/28/2024]
Abstract
The "multi-hit theory/4-hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll-like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti-APRIL drugs, anti-BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti-CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs.
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Affiliation(s)
- Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Suzuki Y. IgA nephropathy 'Treatment to Prevention'. Nephrology (Carlton) 2024; 29 Suppl 2:47-50. [PMID: 39327750 DOI: 10.1111/nep.14299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 03/15/2024] [Indexed: 09/28/2024]
Affiliation(s)
- Yusuke Suzuki
- Department of Nephrology, Juntendo University School of Medicine, Tokyo, Japan
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Pillebout E. IgA Vasculitis and IgA Nephropathy: Two Sides of the Same Coin? Semin Nephrol 2024; 44:151571. [PMID: 40069065 DOI: 10.1016/j.semnephrol.2025.151571] [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] [Indexed: 04/06/2025]
Abstract
IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN). The two diseases share similar geographic and ethnic distribution, along with common variants in genetic association studies. The pathophysiology of IgAN and IgA vasculitis nephritis (IgAVN) can be explained by the four-hit hypothesis. Key molecules involved at each step in both diseases were evaluated as diagnostic and prognostic biomarkers with many common factors, most prominently serum galactose-deficient IgA1. On kidney biopsy, the two diseases are indistinguishable, and the established histological Oxford classification for IgAN will soon be validated for IgAVN. Chronic lesions (segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis) seem more frequent in IgAN, while proliferative lesions (endocapillary hypercellularity and crescents) are more frequent in IgAVN, which could explain the worse IgAN renal prognosis. Due to characteristic skin rash, IgAVN patients are diagnosed precociously. Conversely, the frequent absence of overt clinical signs in IgAN leads to a delayed diagnostic kidney biopsy in the disease evolution, which explains the chronic pathologic lesions. From a therapeutic perspective, while impressive advances have been made in recent years for IgAN, there is a glaring lack of evidence-based guidelines for the treatment of IgAVN. Large therapeutic clinical studies are required, and future IgAN trials should include IgAVN.
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Affiliation(s)
- Evangéline Pillebout
- Nephrology and Renal Transplant Unit, St Louis Hospital, 1 Avenue Claude Vellefaux 75010, Paris, France.
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Suzuki H, Novak J. IgA Nephropathy: Significance of IgA1-Containing Immune Complexes in Clinical Settings. J Clin Med 2024; 13:4495. [PMID: 39124764 PMCID: PMC11313413 DOI: 10.3390/jcm13154495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 08/12/2024] Open
Abstract
IgA nephropathy (IgAN) is considered to be an autoimmune disease characterized by the formation of IgA1-containing immune complexes in the circulation and glomerular immunodeposits. Extensive research has identified multiple genetic, immunological, and environmental factors contributing to disease development and progression. The pathogenesis of IgAN is considered a multifactorial process involving the formation of immune complexes wherein aberrantly O-glycosylated IgA1 is recognized as an autoantigen. Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria. Whereas some patients may exhibit a slowly progressive form of IgAN, others may present with a rapidly progressive glomerulonephritis leading to kidney failure. Development of the treatment for IgAN requires an understanding of the characteristics of the pathogenic IgA1-containing immune complexes that enter the glomerular mesangium and induce kidney injury. However, not all details of the mechanisms involved in the production of galactose-deficient IgA1 and immune-complex formation are fully understood. Here, we review what we have learned about the characteristics of nephritogenic IgA1 in the half-century since the first description of IgAN in 1968.
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Affiliation(s)
- Hitoshi Suzuki
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu 279-0021, Chiba, Japan
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Roberts LE, Williams CEC, Oni L, Barratt J, Selvaskandan H. IgA Nephropathy: Emerging Mechanisms of Disease. Indian J Nephrol 2024; 34:297-309. [PMID: 39156850 PMCID: PMC11326799 DOI: 10.25259/ijn_425_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 08/20/2024] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis reported across the world and is characterized by immunoglobulin A (IgA) dominant mesangial deposits, which are poorly O-glycosylated. This deposition leads to a cascade of glomerular and tubulointerstitial inflammation and fibrosis, which can progress to chronic kidney disease. The variability in rate of progression reflects the many genetic and environmental factors that drive IgAN. Here, we summarize the contemporary understanding of the disease mechanisms that drive IgAN and provide an overview of new and emerging therapies, which target these mechanisms.
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Affiliation(s)
- Lydia E Roberts
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
| | - Chloe E C Williams
- Royal Liverpool and Broadgreen University Hospital Trusts, Liverpool, United Kingdom
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Louise Oni
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
- Department of Paediatric Nephrology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom
| | - Jonathan Barratt
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
| | - Haresh Selvaskandan
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, United Kingdom
- Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
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Ueda H, Joh K, Ueda Y, Marumoto H, Okabe M, Isaka N, Tsuboi N, Kojima H, Miyazaki Y, Yokoo T. Accelerated involution of germinal center in palatine tonsils in IgA nephropathy. PLoS One 2024; 19:e0301853. [PMID: 38709804 PMCID: PMC11073668 DOI: 10.1371/journal.pone.0301853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 03/22/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.
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Affiliation(s)
- Hiroyuki Ueda
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshimi Ueda
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Hirokazu Marumoto
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Masahiro Okabe
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Nao Isaka
- Department of Otorhinolaryngology, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuo Tsuboi
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiromi Kojima
- Department of Otorhinolaryngology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoichi Miyazaki
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Department of Internal Medicine, Division of Nephrology and Hypertension, The Jikei University School of Medicine, Tokyo, Japan
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Hayashi R, Yamazaki S, Mutoh N, Hashimoto T, Ohshima H, Tani-Ishii N. Influence of IgA nephropathy on the progression of pulpitis and apical periodontitis in HIGA mice. J Oral Biosci 2024; 66:98-104. [PMID: 37979655 DOI: 10.1016/j.job.2023.11.003] [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] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 11/20/2023]
Abstract
OBJECTIVES Immunoglobulin (Ig)A nephropathy has been associated with oral infections such as periodontitis, but its pathogenesis is not fully understood; no treatments exist. This study analyzes the influence of IgA nephropathy, an autoimmune disease, on the pathogenesis of pulpitis and apical periodontitis. METHODS Two groups of mice were used in pulp infection experiments: high serum IgA nephropathy model mice (HIGA) and control mice (BALB/c). Histologic analyses of the pulp and apical periodontal tissues were performed on days 3, 5, 7, 14, and 28 following oral bacterial infection. The dynamics of odontoblasts, apoptotic cells, and IgA expression were analyzed using anti-Nestin, TUNEL, and anti-IgA staining, respectively. RESULTS Inflammatory cells infiltrated the exposed pulp at day three in both groups and by 14 days, these cells had infiltrated from the pulp to the apical periodontal tissue. The area of necrotic pulp tissue increased significantly in the control group at seven days. Odontoblasts decreased from day three onwards and disappeared by 28 days in both groups. The number of apoptotic cells in the pulp and apical periodontal tissues was significantly higher in the experimental group at day 28. The experimental group exhibited a significant increase in IgA production in the pulp after 14 days. Bone resorption in the apical periodontal tissue was significantly decreased in the experimental group at day 28. CONCLUSIONS The results of this study suggest that IgA nephropathy may modulate the inflammatory response and sustain long-term biological defense responses in pulpitis and apical periodontitis in HIGA mice.
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Affiliation(s)
- Reona Hayashi
- Department of Pulp Biology and Endodontics, Kanagawa Dental University, Japan
| | - Shiori Yamazaki
- Department of Pulp Biology and Endodontics, Kanagawa Dental University, Japan
| | - Noriko Mutoh
- Department of Pulp Biology and Endodontics, Kanagawa Dental University, Japan
| | - Tatsuo Hashimoto
- Department of Internal Medicine, Graduate School of Dentistry, Kanagawa Dental University, Japan
| | - Hayato Ohshima
- Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Japan
| | - Nobuyuki Tani-Ishii
- Department of Pulp Biology and Endodontics, Kanagawa Dental University, Japan.
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11
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Liu F, Chen H, Cao C, Liang Y, Zhou Y. The role of toll-like receptors (TLRs) and their therapeutic applications in glomerulonephritis. Int Urol Nephrol 2023; 55:2845-2856. [PMID: 37060433 DOI: 10.1007/s11255-023-03592-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
One of the most important features of innate immunity is the presence of a special group of pattern recognition receptors (PRRs) called toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), resulting in a quick and effective immune response to them. Glomerulonephritis (GN) is one of the most important categories of renal disorders characterized by destructive responses of the immune system to the glomerulus. To date, the association of TLRs as important innate immune system members with GN has been one of the topics that attracted the attention of researchers in this field. However, the exact role of these receptors in the immunopathogenesis of GN has not yet been fully discussed. Therefore, this study aims to overview the role of TLRs in GN and the possibility of using them as a potential therapeutic target.
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Affiliation(s)
- Feiyan Liu
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Huimin Chen
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Caixia Cao
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Yanlin Liang
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Ying Zhou
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China.
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12
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Lee M, Suzuki H, Ogiwara K, Aoki R, Kato R, Nakayama M, Fukao Y, Nihei Y, Kano T, Makita Y, Muto M, Yamada K, Suzuki Y. The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy. Kidney Int 2023; 104:943-955. [PMID: 37648155 DOI: 10.1016/j.kint.2023.08.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 07/26/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023]
Abstract
The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.
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Affiliation(s)
- Mingfeng Lee
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan; Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan.
| | - Kei Ogiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ryosuke Aoki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Rina Kato
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Maiko Nakayama
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Fukao
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yoshihito Nihei
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshiki Kano
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yuko Makita
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masahiro Muto
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Koshi Yamada
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
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Song J, Ke B, Tu W, Fang X. Roles of interferon regulatory factor 4 in the AKI-CKD transition, glomerular diseases and kidney allograft rejection. Ren Fail 2023; 45:2259228. [PMID: 37755331 PMCID: PMC10538460 DOI: 10.1080/0886022x.2023.2259228] [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: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023] Open
Abstract
Interferon regulatory factor 4 (IRF4) is expressed in immune cells and is a member of the interferon regulatory factor family. Recently, it has been found that IRF4 plays important roles in the acute kidney injury (AKI)-chronic kidney disease (CKD) transition, glomerular diseases and kidney allograft rejection. In particular, the relationship between IRF4 and the AKI-CKD transition has attracted widespread attention. Furthermore, it was also found that the deficiency of IRF4 hindered the transition from AKI to CKD through the suppression of macrophage-to-fibroblast conversion, inhibition of M1-M2 macrophage polarization, and reduction in neutrophil inward flow. Additionally, an examination of the crucial role of IRF4 in glomerular disease was conducted. It was reported that inhibiting IRF4 could alleviate the progression of glomerular disease, and potential physiopathology mechanisms associated with IRF4 were postulated. Lastly, IRF4 was found to have detrimental effects on the development of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR).
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Affiliation(s)
- Jianling Song
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, P.R. China
| | - Ben Ke
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, P.R. China
| | - Weiping Tu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, P.R. China
| | - Xiangdong Fang
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, P.R. China
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14
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Si FL, Tang C, Lv JC, Shi SF, Zhou XJ, Liu LJ, Zhang H. Comparison between hydroxychloroquine and systemic corticosteroids in IgA nephropathy: a two-year follow-up study. BMC Nephrol 2023; 24:175. [PMID: 37322444 PMCID: PMC10268518 DOI: 10.1186/s12882-023-03238-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 06/09/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Hydroxychloroquine (HCQ) is recommended as a treatment for IgA nephropathy (IgAN) to control proteinuria. The long-term effects of HCQ compared to systemic corticosteroid therapy remain unclear. METHODS We conducted a retrospective case‒control study at Peking University First Hospital. Thirty-nine patients with IgAN who received HCQ for at least 24 months without corticosteroids (CSs) or other immunosuppressive agents were included. Thirty-nine matched patients who received systemic CS therapy were selected using propensity score matching. Clinical data over a 24-month period were compared. RESULTS In the HCQ group, the level of proteinuria decreased from 1.72 [1.44, 2.35] to 0.97 [0.51, 1.37] g/d (-50.5 [-74.0, -3.4] %, P < 0.001) at 24 months. A significant decline in proteinuria was also found in the CS group, but no significant differences were found between the HCQ group and CS group in the levels of proteinuria (0.97 [0.51, 1.37] vs. 0.53 [0.25, 1.81] g/d, P = 0.707) and change rates (-50.5% [-74.0%, -3.4%] vs. -63.7% [-78.5%, -24.2%], P = 0.385) at 24 months. In addition, the decline rates of eGFR between the HCQ and CS groups were comparable (-7.9% [-16.1%, 5.8%] vs. -6.6% [-14.9%, 5.3%], P = 0.758). More adverse events were observed in the CS group. CONCLUSIONS Long-term use of HCQ can maintain stable renal function with minimal side effects. In patients who cannot tolerate corticosteroids, HCQ might be an effective and safe supportive therapy for IgAN.
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Affiliation(s)
- Feng-Lei Si
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Chen Tang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ji-Cheng Lv
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Su-Fang Shi
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li-Jun Liu
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China.
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
- Renal Division, Key Laboratory of Renal Disease, Peking University First Hospital, Peking University Institute of Nephrology, Ministry of Health of China, Beijing, 100034, PR China.
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China
- Key Laboratory of Renal Disease, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Health of China, Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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15
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Cai J, Gao D, Liu D, Liu Z. Telitacicept for autoimmune nephropathy. Front Immunol 2023; 14:1169084. [PMID: 37342346 PMCID: PMC10277628 DOI: 10.3389/fimmu.2023.1169084] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
B cells and the humoral immunity are important players in the pathogenesis of autoimmune diseases. BAFF (also known as BLYS) and a proliferation-inducing ligand APRIL are required for the maintenance of the B-cell pool and humoral immunity. BAFF and APRIL can promote B-cell differentiation, maturation, and plasma cell antibody secretion. BAFF/APRIL overexpression has been identified in several autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, IgA nephropathy, etc. Telitacicept, a novel fully human TACI-Fc fusion protein that binds both BAFF and APRIL, was approved in China in March 2021 for the treatment of systemic lupus erythematosus at a recommended dose of 160 mg/w subcutaneously and is in clinical trials for the treatment of multiple indications in other autoimmune diseases. In this review, we explored telitacicept's mechanism of action and clinical data. In addition, the immune features of autoimmune nephropathy were discussed, emphasizing lupus nephritis, IgA nephropathy, and membranous nephropathy.
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Affiliation(s)
- Jingjing Cai
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dan Gao
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
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16
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Mucha K, Pac M, Pączek L. Omics are Getting Us Closer to Understanding IgA Nephropathy. Arch Immunol Ther Exp (Warsz) 2023; 71:12. [PMID: 37060455 PMCID: PMC10105675 DOI: 10.1007/s00005-023-00677-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 03/02/2023] [Indexed: 04/16/2023]
Abstract
During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.
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Affiliation(s)
- Krzysztof Mucha
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
| | - Michał Pac
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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17
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Du Y, Cheng T, Liu C, Zhu T, Guo C, Li S, Rao X, Li J. IgA Nephropathy: Current Understanding and Perspectives on Pathogenesis and Targeted Treatment. Diagnostics (Basel) 2023; 13:diagnostics13020303. [PMID: 36673113 PMCID: PMC9857562 DOI: 10.3390/diagnostics13020303] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/19/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with varied clinical and histopathological features between individuals, particularly across races. As an autoimmune disease, IgAN arises from consequences of increased circulating levels of galactose-deficient IgA1 and mesangial deposition of IgA-containing immune complexes, which are recognized as key events in the widely accepted "multi-hit" pathogenesis of IgAN. The emerging evidence further provides insights into the role of genes, environment, mucosal immunity and complement system. These developments are paralleled by the increasing availability of diagnostic tools, potential biomarkers and therapeutic agents. In this review, we summarize current evidence and outline novel findings in the prognosis, clinical trials and translational research from the updated perspectives of IgAN pathogenesis.
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18
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Nihei Y, Suzuki H, Suzuki Y. Current understanding of IgA antibodies in the pathogenesis of IgA nephropathy. Front Immunol 2023; 14:1165394. [PMID: 37114051 PMCID: PMC10126238 DOI: 10.3389/fimmu.2023.1165394] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/27/2023] [Indexed: 04/29/2023] Open
Abstract
Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region-a hallmark of IgAN-and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.
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Affiliation(s)
- Yoshihito Nihei
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- Department of Nephrology, Juntendo University Urayasu Hospital, Chiba, Japan
- *Correspondence: Yusuke Suzuki, ; Hitoshi Suzuki,
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- *Correspondence: Yusuke Suzuki, ; Hitoshi Suzuki,
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Mucosal Immune System Dysregulation in the Pathogenesis of IgA Nephropathy. Biomedicines 2022; 10:biomedicines10123027. [PMID: 36551783 PMCID: PMC9775168 DOI: 10.3390/biomedicines10123027] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN.
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The Importance of Toll-like Receptor 9 Expression on Monocytes and Dendritic Cells in the Context of Epstein–Barr Virus Infection in the Immunopathogenesis of Primary Glomerulonephritis. Int J Mol Sci 2022; 23:ijms231911796. [PMID: 36233099 PMCID: PMC9570264 DOI: 10.3390/ijms231911796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/24/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Toll-like receptor 9 (TLR9) is activated by unmethylated cytosine-phosphate-guanosine (CpG) dinucleotides found in the genomes of pathogens such as Epstein–Barr virus (EBV). The aim of this study was to determine the role of TLR9 in the immunopathogenesis of IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) in the context of Epstein–Barr virus (EBV) infection. For this purpose, the frequency of TLR9-positive monocytes and dendritic cells (DCs, i.e., BDCA-1; myeloid dendritic cells, and BDCA-2; plasmocytoid dendritic cells) was studied, and a quantitative analysis of the concentration of TLR9 in the serum of patients diagnosed with IgAN and MPGN was undertaken. Higher frequencies of TLR9-positive DCs and monocytes in IgAN and MPGN patients were observed as compared with the control group. Patients diagnosed with GN exhibited a higher percentage of BDCA-1+CD19− and BDCA-2+CD123+ DCs than patients in the control group. Moreover, serum TLR9 concentration was shown to be significantly correlated with EBV DNA copy number/µg DNA, IgG, IgM, serum albumin, total protein in 24-h urine collection test and the frequency of BDCA-2+CD123+ DCs in peripheral blood. Our findings confirm that TLR9 may be involved in the development of IgAN and MPGN.
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21
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Zhou W, Chen MM, Liu HL, Si ZL, Wu WH, Jiang H, Wang LX, Vaziri ND, An XF, Su K, Chen C, Tan NH, Zhang ZH. Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho. Acta Pharmacol Sin 2022; 43:2609-2623. [PMID: 35347248 PMCID: PMC9525601 DOI: 10.1038/s41401-022-00898-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 03/06/2022] [Indexed: 02/07/2023]
Abstract
Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-β1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 μM. In primary mouse renal tubular cells, we showed that DHA (10 μM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/β-catenin and TGF-β/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.
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Affiliation(s)
- Wei Zhou
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Min-Min Chen
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hui-Ling Liu
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Zi-Lin Si
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Wen-Hui Wu
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hong Jiang
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Lin-Xiao Wang
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - Xiao-Fei An
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ke Su
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Cheng Chen
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ning-Hua Tan
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Zhi-Hao Zhang
- State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Groza Y, Jemelkova J, Kafkova LR, Maly P, Raska M. IL-6 and its role in IgA nephropathy development. Cytokine Growth Factor Rev 2022; 66:1-14. [PMID: 35527168 DOI: 10.1016/j.cytogfr.2022.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 04/05/2022] [Indexed: 02/07/2023]
Abstract
IL-6 is considered one of the well characterized cytokines exhibiting homeostatic, pro- and anti-inflammatory activities, depending on the receptor variant and the induced intracellular cis- or trans-signaling responses. IL-6-activated pathways are involved in the regulation of cell proliferation, survival, differentiation, and cell metabolism changes. Deviations in IL-6 levels or abnormal response to IL-6 signaling are associated with several autoimmune diseases including IgA nephropathy (IgAN), one of most frequent primary glomerulonephritis worldwide. IgAN is associated with increased plasma concentration of IL-6 and increased plasma concentration of aberrantly galactosylated IgA1 immunoglobulin (Gd-IgA1). Gd-IgA1 is specifically recognized by autoantibodies, leading to the formation of circulating immune complexes (CIC) with nephritogenic potential, since CIC deposited in the glomerular mesangium induce mesangial cells proliferation and glomerular injury. Infection of the upper respiratory or digestive tract enhances IL-6 production and in IgAN patients is often followed by the macroscopic hematuria. This review recapitulates general aspects of IL-6 signaling and summarizes experimental evidences about IL-6 involvement in the etiopathogenesis of IgA nephropathy through the production of Gd-IgA1 and regulation of mesangial cell proliferation.
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Affiliation(s)
- Yaroslava Groza
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Jana Jemelkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic
| | - Leona Raskova Kafkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
| | - Petr Maly
- Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic.
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Bagchi S, Bhowmik D, Singh G, Agarwal SK. Hydroxychloroquine reduces proteinuria in Indian patients with IgA nephropathy. Kidney Int Rep 2022; 7:1443-1444. [PMID: 35685311 PMCID: PMC9171695 DOI: 10.1016/j.ekir.2022.04.086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/12/2022] [Accepted: 04/18/2022] [Indexed: 11/27/2022] Open
Affiliation(s)
- Soumita Bagchi
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
- Correspondence: Soumita Bagchi, Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India.
| | - Dipankar Bhowmik
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Geetika Singh
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Sanjay Kumar Agarwal
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
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24
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Is There a Role for Gut Microbiome Dysbiosis in IgA Nephropathy? Microorganisms 2022; 10:microorganisms10040683. [PMID: 35456735 PMCID: PMC9031807 DOI: 10.3390/microorganisms10040683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 02/06/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.
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25
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Hotta O, Ieiri N, Nagai M, Tanaka A, Harabuchi Y. Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions ( Glomerular vasculitis) in Immunoglobulin A Nephropathy. Int J Mol Sci 2022; 23:727. [PMID: 35054911 PMCID: PMC8775943 DOI: 10.3390/ijms23020727] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer's ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the glomerular vasculitis may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of glomerular vasculitis in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called "epipharynx-kidney axis" may provide an important focus for future research.
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Affiliation(s)
- Osamu Hotta
- Division of Internal Medicine, Hotta Osamu Clinic (HOC), Sendai 984-0013, Miyagi, Japan;
| | - Norio Ieiri
- Division of Internal Medicine, Hotta Osamu Clinic (HOC), Sendai 984-0013, Miyagi, Japan;
| | - Masaaki Nagai
- Division of Nephrology, Narita Memorial Hospital, Toyohashi 441-8029, Aichi, Japan;
| | | | - Yasuaki Harabuchi
- Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 078-8510, Japan;
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26
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Gholaminejad A, Roointan A, Gheisari Y. Transmembrane signaling molecules play a key role in the pathogenesis of IgA nephropathy: a weighted gene co-expression network analysis study. BMC Immunol 2021; 22:73. [PMID: 34861820 PMCID: PMC8642929 DOI: 10.1186/s12865-021-00468-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 11/19/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritis and a serious health concern worldwide; though still the underlying molecular mechanisms of IgAN are yet to be known and there is no efficient treatment for this disease. The main goal of this study was to explore the IgAN underlying pathogenic pathways, plus identifying the disease correlated modules and genes using the weighted gene co-expression network analysis (WGCNA) algorithm. RESULTS GSE104948 dataset (the expression data from glomerular tissue of IgAN patients) was analyzed and the identified differentially expressed genes (DEGs) were introduced to the WGCNA algorithm for building co-expression modules. Genes were classified into six co-expression modules. Genes of the disease's most correlated module were mainly enriched in the immune system, cell-cell communication and transmembrane cell signaling pathways. The PPI network was constructed by genes in all the modules and after hub-gene identification and validation steps, 11 genes, mostly transmembrane proteins (CD44, TLR1, TLR2, GNG11, CSF1R, TYROBP, ITGB2, PECAM1), as well as DNMT1, CYBB and PSMB9 were identified as potentially key players in the pathogenesis of IgAN. In the constructed regulatory network, hsa-miR-129-2-3p, hsa-miR-34a-5p and hsa-miR-27a-3p, as well as STAT3 were spotted as top molecules orchestrating the regulation of the hub genes. CONCLUSIONS The excavated hub genes from the hearts of co-expressed modules and the PPI network were mostly transmembrane signaling molecules. These genes and their upstream regulators could deepen our understanding of IgAN and be considered as potential targets for hindering its progression.
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Affiliation(s)
- Alieh Gholaminejad
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Hezar Jerib Avenue, 81746-73461, Isfahan, Iran
| | - Amir Roointan
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Hezar Jerib Avenue, 81746-73461, Isfahan, Iran.
| | - Yousof Gheisari
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Hezar Jerib Avenue, 81746-73461, Isfahan, Iran
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27
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Nagasawa Y, Nomura R, Misaki T, Ito S, Naka S, Wato K, Okunaka M, Watabe M, Fushimi K, Tsuzuki K, Matsumoto-Nakano M, Nakano K. Relationship between IgA Nephropathy and Porphyromonas gingivalis; Red Complex of Periodontopathic Bacterial Species. Int J Mol Sci 2021; 22:13022. [PMID: 34884826 PMCID: PMC8657970 DOI: 10.3390/ijms222313022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/22/2021] [Accepted: 11/27/2021] [Indexed: 12/30/2022] Open
Abstract
IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.
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Affiliation(s)
- Yasuyuki Nagasawa
- Department of Internal Medicine, Division of Kidney and Dialysis, Hyogo College of Medicine, Nishinomiya 663-8501, Hyogo, Japan
| | - Ryota Nomura
- Department of Pediatric Dentistry, Division of Oral infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (K.N.)
| | - Taro Misaki
- Division of Nephrology, Seirei Hamamatsu General Hospital, Shizuoka 430-8558, Hamamatsu, Japan;
- Department of Nursing, Faculty of Nursing, Seirei Christopher University, Shizuoka 433-8558, Hamamatsu, Japan
| | - Seigo Ito
- Department of Internal medicine, Japan Self-Defense Gifu Hospital, Gifu 502-0817, Kakamigahara, Japan;
| | - Shuhei Naka
- Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Okayama, Japan; (S.N.); (M.M.-N.)
| | - Kaoruko Wato
- Department of Pediatric Dentistry, Division of Oral infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (K.N.)
| | - Mieko Okunaka
- Department of Otolaryngology, Meiwa Hospital, Nishinomiya 663-8186, Hyogo, Japan; (M.O.); (M.W.); (K.F.)
| | - Maiko Watabe
- Department of Otolaryngology, Meiwa Hospital, Nishinomiya 663-8186, Hyogo, Japan; (M.O.); (M.W.); (K.F.)
| | - Katsuya Fushimi
- Department of Otolaryngology, Meiwa Hospital, Nishinomiya 663-8186, Hyogo, Japan; (M.O.); (M.W.); (K.F.)
- Department of Otorhinolaryngology, Head and Neck Surgery, Hyogo College of Medicine, Nishinomiya 663-8501, Hyogo, Japan;
| | - Kenzo Tsuzuki
- Department of Otorhinolaryngology, Head and Neck Surgery, Hyogo College of Medicine, Nishinomiya 663-8501, Hyogo, Japan;
| | - Michiyo Matsumoto-Nakano
- Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Okayama, Japan; (S.N.); (M.M.-N.)
| | - Kazuhiko Nakano
- Department of Pediatric Dentistry, Division of Oral infection and Disease Control, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (K.W.); (K.N.)
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28
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Gross hematuria after SARS-CoV-2 vaccination: questionnaire survey in Japan. Clin Exp Nephrol 2021; 26:316-322. [PMID: 34773533 PMCID: PMC8590432 DOI: 10.1007/s10157-021-02157-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/04/2021] [Indexed: 11/25/2022]
Abstract
Background Recent clinical reports indicate a correlation between gross hematuria after the coronavirus 2019 (COVID-19) vaccination in patients with glomerulonephritis, especially immunoglobulin A nephropathy (IgAN). Furthermore, healthcare workers in Japan were initially vaccinated with an mRNA vaccine from February 17, 2021, and some of them experienced gross hematuria after receiving the vaccination. Methods We conducted a web-based survey of the councilor members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between gross hematuria and COVID-19 vaccination. Results In the first survey, 27 cases (female: 22, 81.5%) of gross hematuria were reported after receiving a COVID-19 vaccination. Of them, 19 (70.4%) patients were already diagnosed with IgAN at the occurrence of gross hematuria. Proteinuria appeared in eight of the 14 (57.1%) cases with no proteinuria before vaccination and hematuria in five of the seven (71.4%) cases with no hematuria before vaccination. The second survey revealed that a renal biopsy was performed after vaccination in four cases, all of whom were diagnosed with IgAN. Only one case showed a slightly increased serum creatinine level, and no patients progressed to severe renal dysfunction. Conclusion This study clarified the clinical features of gross hematuria after a COVID-19 vaccination. Because there was no obvious progression to severe renal dysfunction, safety of the COVID-19 vaccination is warranted at least in the protocol of inoculation twice. Supplementary Information The online version contains supplementary material available at 10.1007/s10157-021-02157-x.
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29
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Lauriero G, Abbad L, Vacca M, Celano G, Chemouny JM, Calasso M, Berthelot L, Gesualdo L, De Angelis M, Monteiro RC. Fecal Microbiota Transplantation Modulates Renal Phenotype in the Humanized Mouse Model of IgA Nephropathy. Front Immunol 2021; 12:694787. [PMID: 34712223 PMCID: PMC8546224 DOI: 10.3389/fimmu.2021.694787] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 09/03/2021] [Indexed: 01/22/2023] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. Several observations suggest that gut microbiota could be implicated in IgAN pathophysiology. Aiming at exploring whether microbiota modulation is able to influence disease outcome, we performed fecal microbiota transplantation (FMT) from healthy controls (HC-sbjs), non-progressor (NP-pts) and progressor (P-pts) IgAN patients to antibiotic-treated humanized IgAN mice (α1KI-CD89Tg), by oral gavage. FMT was able to modulate renal phenotype and inflammation. On one hand, the microbiota from P-pts was able to induce an increase of serum BAFF and galactose deficient-IgA1 levels and a decrease of CD89 cell surface expression on blood CD11b+ cells which was associated with soluble CD89 and IgA1 mesangial deposits. On the other hand, the microbiota from HC-sbjs was able to induce a reduction of albuminuria immediately after gavage, an increased cell surface expression of CD89 on blood CD11b+ cells and a decreased expression of KC chemokine in kidney. Higher serum BAFF levels were found in mice subjected to FMT from IgAN patients. The main bacterial phyla composition and volatile organic compounds profile significantly differed in mouse gut microbiota. Microbiota modulation by FMT influences IgAN phenotype opening new avenues for therapeutic approaches in IgAN.
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Affiliation(s)
- Gabriella Lauriero
- Center for Research on Inflammation, Inflamex Laboratory of Excellence, Paris University, Paris, France.,INSERM U1149, Paris, France.,CNRS ERL8252, Paris, France.,Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Lilia Abbad
- Center for Research on Inflammation, Inflamex Laboratory of Excellence, Paris University, Paris, France.,INSERM U1149, Paris, France.,CNRS ERL8252, Paris, France
| | - Mirco Vacca
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Celano
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Jonathan M Chemouny
- Center for Research on Inflammation, Inflamex Laboratory of Excellence, Paris University, Paris, France.,INSERM U1149, Paris, France.,CNRS ERL8252, Paris, France
| | - Maria Calasso
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Laureline Berthelot
- Center for Research on Inflammation, Inflamex Laboratory of Excellence, Paris University, Paris, France
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy
| | - Renato C Monteiro
- Center for Research on Inflammation, Inflamex Laboratory of Excellence, Paris University, Paris, France.,INSERM U1149, Paris, France.,CNRS ERL8252, Paris, France
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30
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Suzuki H, Novak J. IgA glycosylation and immune complex formation in IgAN. Semin Immunopathol 2021; 43:669-678. [PMID: 34570260 DOI: 10.1007/s00281-021-00883-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/24/2021] [Indexed: 12/17/2022]
Abstract
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. This disease, discovered in 1968, is characterized by IgA-IgG glomerular immunodeposits with a mesangial pattern. It is thought that these immunodeposits originate from the immune complexes formed in the circulation. It is hypothesized that the pathogenesis of IgAN is driven by aberrant glycoforms of IgA1 (galactose-deficient IgA1, Gd-IgA1). Gd-IgA1, in genetically susceptible individuals, represents the initiating factor for the formation of circulating immune complexes due to its recognition by IgG autoantibodies and the subsequent formation of pathogenic IgA1-IgG immune complexes. Complement activation through alternative and/or lectin pathways is likely playing an important role in the pathogenic properties of these complexes and may further upregulate local inflammatory responses and glomerular injury.
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Affiliation(s)
- Hitoshi Suzuki
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan.
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, BBRB 761A, AL, 35294, Birmingham, USA.
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Abstract
IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia and the Western world. In most patients, it follows an asymptomatic to oligosymptomatic course and GFR loss, if any, is slow. The mainstay of therapy therefore is optimized supportive care, i.e., measures that lower blood pressure, reduce proteinuria, minimize lifestyle risk factors, and otherwise help to reduce non-specific insults to the kidneys. The value of immunosuppression has become controversial and if at all, systemic high-dose corticosteroid therapy should be considered for a few months taking into account patient characteristics that would caution against or preclude such therapy. In addition, adverse events related to corticosteroid therapy markedly increase as GFR declines. Beyond corticosteroids, there is little evidence that any additional immunosuppression is helpful, with the exception of mycophenolate mofetil in patients of Asian descent. A considerable number of clinical trials ranging from enteric coated budesonide to blockade of B-cell function to complement inhibitors are currently ongoing and will hopefully allow a more targeted therapy of high-risk patients with progressive IgAN in the future.
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Aloise DDA, Coura-Vital W, Carneiro M, Rodrigues MV, Toscano GADS, da Silva RB, Silva-Portela RDCB, Fontes-Dantas FL, Agnez-Lima LF, Vitor RWA, Andrade-Neto VFD. Association between ocular toxoplasmosis and APEX1 and MYD88 polymorphism. Acta Trop 2021; 221:106006. [PMID: 34118207 DOI: 10.1016/j.actatropica.2021.106006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/30/2021] [Accepted: 06/01/2021] [Indexed: 10/21/2022]
Abstract
Ocular toxoplasmosis (OT) is the most common form of posterior uveitis, and in some countries, it is the most frequent cause of visual impairment. Studies demonstrate that the polymorphism in genes involved with the immune response can be related both to the occurrence and to the recurrence of OT. Thus, the present study aimed to analyze the association between OT and the polymorphism of the APEX1 (rs1130409) and MyD88 (rs7744) genes. The studied sample consisted of 48 volunteers with OT and 96 asymptomatic volunteers, but positive for anti - T. gondii IgG (control group). Blood collection was performed for serological analysis (ELISA) and DNA extraction. Genotyping of the polymorphism was performed using real-time PCR. To analyze the association between gene polymorphism and OT, logistic regression was performed. The results showed no association between the MYD88 gene polymorphism and the development of OT. However, a significant association was found between OT and APEX1 gene polymorphism, indicating that individuals expressing polymorphic (GG) or heterozygous (GT) alleles are more likely to develop the disease (P-value = 0.02 and 0.03 respectively). These results suggest that APEX1 (rs1130409) polymorphism is a risk factor for the occurrence of ocular toxoplasmosis in the studied population.
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Suzuki Y, Monteiro RC, Coppo R, Suzuki H. The Phenotypic Difference of IgA Nephropathy and its Race/Gender-dependent Molecular Mechanisms. KIDNEY360 2021; 2:1339-1348. [PMID: 35369654 PMCID: PMC8676395 DOI: 10.34067/kid.0002972021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
IgA nephropathy (IgAn), defined by the pre dominant de position of IgA in the glomerular mesangium, is the most common form of GN throughout the world. However, its incidence, sex distribution, clinical presentation, and progression and pathogenic initiating factors are largely variable and do not fit such a simple definition. To assess the heterogeneity of this disease, we recently conducted a clinical survey on the presentation and clinical management of patients with IgAn in Europe and Japan. This clinical survey highlights similarities and differences in patients from different cont inents. The survey revealed obvious differences between nations in the frequency of gastrointestinal complications, including inflammatory bowel diseases (IBD) and celiac disease, which were more frequent in European patients. Such findings are compatible with susceptibility loci related to intestinal immunity and IBD in recent genome wide association studies (GWAS) on IgAn. However, most of the molecules in these mucosal-related loci fulfill the immunologic function not only of gut-associated lymphoid tissue (GALT), but also nasopharyngeal/bronchial-associated lymphoid tissues (NALT/BALT). Indeed, a similar frequency of macrohematuria coinciding with upper respiratory infection, a hallmark manifestation of this disease, was found in the survey, emphasizing the pathogenic roles of these molecules in the NALT/BALT of patients with IgAn. Recent experimental and clinical studies including GWAS on multiple common infections and IBD indicate immune crosstalk between GALT and NALT/BALT, and some related mediators, such as TNF superfamily ligands (APRIL/BAFF). This review explains the epidemiologic heterogeneity of this disease with the clinical survey, and discusses race and sex-dependent molecular mechanisms.
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Affiliation(s)
- Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Renato C. Monteiro
- Faculty of Medicine, University of Paris, Paris, France
- Center for Research on Inflammation, Paris, France
- Inflamex Laboratory of Excellence, Paris, France
- Immunology Department, Bichat Hospital, Assistance Publique de Paris, Paris, France
| | | | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Are there animal models of IgA nephropathy? Semin Immunopathol 2021; 43:639-648. [PMID: 34230994 DOI: 10.1007/s00281-021-00878-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 12/18/2022]
Abstract
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Up to 40% of IgAN patients develop end-stage kidney disease after 15-20 years. Despite the poor prognosis associated with this multifactorial disease, no clear treatment strategy has been identified, primarily due to the lack of understanding of its pathogenesis. Clinical observations indicate that aberrant IgAN immune systems, rather than intrinsic renal abnormalities, may be involved in its pathogenesis. Moreover, nephritogenic IgA and its related immune complexes are considered to be produced not only in the mucosa, but also in systemic immune sites, such as the bone marrow; however, there are numerous challenges to understanding this dynamic and complex immune axis in humans. Thus, several investigators have used experimental animal models. Although there are inter-strain differences in IgA molecules and immune responses between humans and rodents, animal models remain a powerful tool for investigating IgAN's pathogenesis, and the subsequent development of effective treatments. Here, we introduced some classical models of IgAN with or without genetic manipulation and recent translational approaches with some promising models. This includes humanized mouse models expressing human IgA1 and human IgA Fc receptor (CD89) that develops spontaneously the disease. Pre-clinical studies targeting IgA1 are discussed. Together, animal models are very useful tools to study pathophysiology and to validate new therapeutic approaches for IgAN.
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35
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An Update on the Current State of Management and Clinical Trials for IgA Nephropathy. J Clin Med 2021; 10:jcm10112493. [PMID: 34200024 PMCID: PMC8200196 DOI: 10.3390/jcm10112493] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 12/31/2022] Open
Abstract
IgA nephropathy remains the most common primary glomerular disease worldwide. It affects children and adults of all ages, and is a leading cause of end-stage kidney disease, making it a considerable public health issue in many countries. Despite being initially described over 50 years ago, there are still no disease specific treatments, with current management for most patients being focused on lifestyle measures and renin-angiotensin-aldosterone system blockade. However, significant advances in the understanding of its pathogenesis have been made particularly over the past decade, leading to great interest in developing new therapeutic strategies, and a significant rise in the number of interventional clinical trials being performed. In this review, we will summarise the current state of management of IgAN, and then describe major areas of interest where new therapies are at their most advanced stages of development, that include the gut mucosal immune system, B cell signalling, the complement system and non-immune modulators. Finally, we describe clinical trials that are taking place in each area and explore future directions for translational research.
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36
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IgA Vasculitis and IgA Nephropathy: Same Disease? J Clin Med 2021; 10:jcm10112310. [PMID: 34070665 PMCID: PMC8197792 DOI: 10.3390/jcm10112310] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022] Open
Abstract
Many authors suggested that IgA Vasculitis (IgAV) and IgA Nephropathy (IgAN) would be two clinical manifestations of the same disease; in particular, that IgAV would be the systemic form of the IgAN. A limited number of studies have included sufficient children or adults with IgAN or IgAV (with or without nephropathy) and followed long enough to conclude on differences or similarities in terms of clinical, biological or histological presentation, physiopathology, genetics or prognosis. All therapeutic trials available on IgAN excluded patients with vasculitis. IgAV and IgAN could represent different extremities of a continuous spectrum of the same disease. Due to skin rash, patients with IgAV are diagnosed precociously. Conversely, because of the absence of any clinical signs, a renal biopsy is practiced for patients with an IgAN to confirm nephropathy at any time of the evolution of the disease, which could explain the frequent chronic lesions at diagnosis. Nevertheless, the question that remains unsolved is why do patients with IgAN not have skin lesions and some patients with IgAV not have nephropathy? Larger clinical studies are needed, including both diseases, with a common histological classification, and stratified on age and genetic background to assess renal prognosis and therapeutic strategies.
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Kano T, Suzuki H, Makita Y, Fukao Y, Suzuki Y. Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy. Kidney Int 2021; 100:364-376. [PMID: 33961870 DOI: 10.1016/j.kint.2021.04.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 03/31/2021] [Accepted: 04/08/2021] [Indexed: 12/15/2022]
Abstract
Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgAN-onset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.
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Affiliation(s)
- Toshiki Kano
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
| | - Yuko Makita
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Fukao
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
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Gholaminejad A, Gheisari Y, Jalali S, Roointan A. Comprehensive analysis of IgA nephropathy expression profiles: identification of potential biomarkers and therapeutic agents. BMC Nephrol 2021; 22:137. [PMID: 33874912 PMCID: PMC8054414 DOI: 10.1186/s12882-021-02356-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/12/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND IgA nephropathy (IgAN) is a kidney disease recognized by the presence of IgA antibody depositions in kidneys. The underlying mechanisms of this complicated disease are remained to be explored and still, there is an urgent need for the discovery of noninvasive biomarkers for its diagnosis. In this investigation, an integrative approach was applied to mRNA and miRNA expression profiles in PBMCs to discover a gene signature and novel potential targets/biomarkers in IgAN. METHODS Datasets were selected from gene expression omnibus database. After quality control checking, two datasets were analyzed by Limma to identify differentially expressed genes/miRNAs (DEGs and DEmiRs). Following identification of DEmiR-target genes and data integration, intersecting mRNAs were subjected to different bioinformatic analyses. The intersecting mRNAs, DEmiRs, related transcription factors (from TRRUST database), and long-non coding RNAs (from LncTarD database) were used for the construction of a multilayer regulatory network via Cytoscape. RESULT "GSE25590" (miRNA) and "GSE73953" (mRNA) datasets were analyzed and after integration, 628 intersecting mRNAs were identified. The mRNAs were mainly associated with "Innate immune system", "Apoptosis", as well as "NGF signaling" pathways. A multilayer regulatory network was constructed and several hub-DEGs (Tp53, STAT3, Jun, etc.), DEmiRs (miR-124, let-7b, etc.), TFs (NF-kB, etc.), and lncRNAs (HOTAIR, etc.) were introduced as potential factors in the pathogenesis of IgAN. CONCLUSION Integration of two different expression datasets and construction of a multilayer regulatory network not only provided a deeper insight into the pathogenesis of IgAN, but also introduced several key molecules as potential therapeutic target/non-invasive biomarkers.
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Affiliation(s)
- Alieh Gholaminejad
- Regenerative medicine research center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yousof Gheisari
- Regenerative medicine research center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sedigheh Jalali
- Department of Pediatrics, The University of Melbourne, Melbourne, Australia
| | - Amir Roointan
- Regenerative medicine research center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Yamaguchi H, Goto S, Takahashi N, Tsuchida M, Watanabe H, Yamamoto S, Kaneko Y, Higashi K, Mori H, Nakamura Y, Horii A, Kurokawa K, Narita I. Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy. Nephrol Dial Transplant 2021; 36:75-86. [PMID: 33099625 PMCID: PMC7771982 DOI: 10.1093/ndt/gfaa223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. METHODS Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. RESULTS Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. CONCLUSIONS These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.
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Affiliation(s)
- Hiroki Yamaguchi
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shin Goto
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Nao Takahashi
- Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masafumi Tsuchida
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hirofumi Watanabe
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Suguru Yamamoto
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yoshikatsu Kaneko
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koichi Higashi
- Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan
| | - Hiroshi Mori
- Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan
| | | | - Arata Horii
- Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Ken Kurokawa
- Genome Evolution Laboratory, National Institute of Genetics, Mishima, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Sallustio F, Curci C, Chaoul N, Fontò G, Lauriero G, Picerno A, Divella C, Di Leo V, De Angelis M, Ben Mkaddem S, Macchia L, Gallone A, Monteiro RC, Pesce F, Gesualdo L. High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients. Nephrol Dial Transplant 2021; 36:452-464. [PMID: 33200215 PMCID: PMC7898021 DOI: 10.1093/ndt/gfaa264] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Indexed: 12/12/2022] Open
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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Affiliation(s)
- Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari “Aldo
Moro”, Bari, Italy
| | - Claudia Curci
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University
of Bari “Aldo Moro”, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Nada Chaoul
- Allergology Unit, Department of Emergency and Organ Transplantation, University
“Aldo Moro”, Bari, Italy
| | - Giulia Fontò
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Gabriella Lauriero
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Angela Picerno
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Chiara Divella
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Vincenzo Di Leo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo
Moro, Bari, Italy
| | - Sanae Ben Mkaddem
- Faculty of Medicine, Center for Research on Inflammation, Paris Diderot
University, INSERM U1149, ELR8252 CNRS, Paris, France
| | - Luigi Macchia
- Allergology Unit, Department of Emergency and Organ Transplantation, University
“Aldo Moro”, Bari, Italy
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University
of Bari “Aldo Moro”, Bari, Italy
| | - Renato C Monteiro
- Faculty of Medicine, Center for Research on Inflammation, Paris Diderot
University, INSERM U1149, ELR8252 CNRS, Paris, France
| | - Francesco Pesce
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and
Organ Transplantation, University “Aldo Moro”, Bari, Italy
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Wei M, Meng S, Shi S, Liu L, Zhou X, Lv J, Zhu L, Zhang H. Monozygotic Twins Discordant for Immunoglobulin A Nephropathy Display Differences in DNA Methylation and Gene Expression. KIDNEY DISEASES 2020; 7:200-209. [PMID: 34179115 DOI: 10.1159/000512169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/07/2020] [Indexed: 12/23/2022]
Abstract
Introduction Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. It involves both genetic and environmental factors, among which DNA methylation, the most studied epigenetic modification, was shown to play a role. Here, we assessed genome-wide DNA methylation and gene expression profiles in 2 pairs of IgAN-discordant monozygotic (MZ) twins, in order to characterize methylation changes and their potential influences on gene expression in IgAN. Methods Genome-wide DNA methylation and gene expression profiles were evaluated in peripheral blood mononuclear cells obtained from 2 IgAN-discordant MZ twins. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected, and an integrated analysis was performed. Finally, functional enrichment analysis was done for DMR-associated genes and DEGs. Results Totally 521 DMRs were detected for 2 IgAN-discordant MZ twins. Among them, 9 DMRs were found to be mapped to genes that differentially expressed in 2 MZ twins, indicating the potential regulatory mechanisms of expression for these 9 genes (MNDA, DYSF, IL1R2, TLR6, TREML2, TREM1, IL32, S1PR5, and ADGRE3) in IgAN. Biological process analysis of them showed that they were mostly involved in the immune system process. Functional enrichment analysis of DEGs and DMR-associated genes both identified multiple pathways relevant to inflammatory and immune responses. And DMR-associated genes were significantly enriched in terms related to T-cell function. Conclusions Our findings indicate that changes in DNA methylation patterns were involved in the pathogenesis of IgAN. Nine target genes detected in our study may provide new ideas for the exploration of molecular mechanisms of IgAN.
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Affiliation(s)
- Min Wei
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Sijun Meng
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Sufang Shi
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Lijun Liu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xujie Zhou
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jicheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Zhu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Institute of Nephrology, Peking University, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,State Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Ren Q, Cheng L, Yi J, Ma L, Pan J, Gou SJ, Fu P. Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases. Curr Med Chem 2020; 27:5829-5854. [PMID: 31161985 DOI: 10.2174/0929867325666190603110907] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/15/2019] [Accepted: 05/13/2019] [Indexed: 02/08/2023]
Abstract
Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.
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Affiliation(s)
- Qian Ren
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lu Cheng
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Yi
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Pan
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shen-Ju Gou
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
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43
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Park JI, Kim TY, Oh B, Cho H, Kim JE, Yoo SH, Lee JP, Kim YS, Chun J, Kim BS, Lee H. Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases. Sci Rep 2020; 10:16206. [PMID: 33004860 PMCID: PMC7530979 DOI: 10.1038/s41598-020-73035-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 08/24/2020] [Indexed: 12/28/2022] Open
Abstract
Immunoglobulin A nephropathy (IgAN) involves repeated events of gross haematuria with concurrent upper airway infections. The mucosal immune system, especially the tonsil, is considered the initial site of inflammation, although the role of the tonsillar microbiota has not been established in IgAN. In this study, we compared the tonsillar microbiota of patients with IgAN (n = 21) and other glomerular diseases (n = 36) as well as, healthy controls (n = 23) from three medical centres in Korea. The microbiota was analysed from tonsil swabs using the Illumina MiSeq system based on 16S rRNA gene. Tonsillar bacterial diversity was higher in IgAN than in other glomerular diseases, although it did not differ from that of healthy controls. Principal coordinates analysis revealed differences between the tonsillar microbiota of IgAN and both healthy and disease controls. The proportions of Rahnella, Ruminococcus_g2, and Clostridium_g21 were significantly higher in patients with IgAN than in healthy controls (corrected p < 0.05). The relative abundances of several taxa were correlated with the estimated glomerular filtration rate, blood urea nitrogen, haemoglobin, and serum albumin levels. Based on our findings, tonsillar microbiota may be associated with clinical features and possible immunologic pathogenesis of IgAN.
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Affiliation(s)
- Ji In Park
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Tae-Yoon Kim
- Department of Life Science, Multidisciplinary Genome Institute, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, Republic of Korea.,Illumina, Inc, Seoul, Republic of Korea
| | - Bumjo Oh
- Department of Family Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
| | - Hyunjeong Cho
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Ji Eun Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.,Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Seong Ho Yoo
- Department of Forensic Medicine and Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Jongsik Chun
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - Bong-Soo Kim
- Department of Life Science, Multidisciplinary Genome Institute, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, Republic of Korea.
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea.
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Mertowski S, Lipa P, Morawska I, Niedźwiedzka-Rystwej P, Bębnowska D, Hrynkiewicz R, Grywalska E, Roliński J, Załuska W. Toll-Like Receptor as a Potential Biomarker in Renal Diseases. Int J Mol Sci 2020; 21:ijms21186712. [PMID: 32933213 PMCID: PMC7554805 DOI: 10.3390/ijms21186712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/08/2023] Open
Abstract
One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups to be established based on the type of disease, thereby predicting response to treatment or disease relapse. Advances in understanding the pathogenesis of diseases, such as membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA (immunoglobulin A) nephropathy, and diabetic nephropathy, along with the progressive development and standardization of plasma and urine proteomics techniques, have facilitated the identification of an increasing number of molecules that may be useful for these purposes. The growing number of studies on the role of TLR (toll-like receptor) receptors in the pathogenesis of kidney disease forces contemporary researchers to reflect on these molecules, which may soon join the group of renal biomarkers and become a helpful tool in the diagnosis of glomerulopathy. In this article, we conducted a thorough review of the literature on the role of TLRs in the pathogenesis of glomerulopathy. The role of TLR receptors as potential marker molecules for the development of neoplastic diseases is emphasized more and more often, as prognostic factors in diseases on several epidemiological backgrounds.
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Affiliation(s)
- Sebastian Mertowski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Paulina Lipa
- Department of Genetics and Microbiology, Institute of Microbiology and Biotechnology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19 St., 20-033 Lublin, Poland;
| | - Izabela Morawska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
| | - Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Dominika Bębnowska
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (D.B.); (R.H.)
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
- Correspondence: (S.M.); (P.N.-R.); (E.G.)
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (I.M.); (J.R.)
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 20-954 Lublin, Poland;
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Shirai Y, Miura K, Yabuuchi T, Nagasawa T, Ishizuka K, Takahashi K, Taneda S, Honda K, Yamaguchi Y, Suzuki H, Suzuki Y, Hattori M. Rapid progression to end-stage renal disease in a child with IgA-dominant infection-related glomerulonephritis associated with parvovirus B19. CEN Case Rep 2020; 9:423-430. [PMID: 32621069 DOI: 10.1007/s13730-020-00501-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 06/25/2020] [Indexed: 01/18/2023] Open
Abstract
Parvovirus B19 (PVB19) has been known to cause acute glomerulonephritis and nephrotic syndrome with various renal histologic patterns, such as endocapillary glomerulonephritis and collapsing glomerulopathy. Remission is achieved spontaneously or by treatment with steroid and/or immunosuppressants in most patients, except those with sickle cell anemia or two APOL1 risk alleles. In this study, we report the case of a previously healthy 5-year-old boy with infection-related glomerulonephritis (IRGN) associated with PVB19 that progressed to end-stage renal disease (ESRD). He presented with macrohematuria, nephrotic-range proteinuria, and progressive renal dysfunction despite treatment with methylprednisolone pulse therapy, plasmapheresis, and intravenous immunoglobulin. The kidney biopsy specimens exhibited endocapillary infiltration and mesangiolysis with cellular crescent formation. Immunofluorescence analysis revealed that IgA was dominantly positive in the glomeruli, with some co-localized with KM55, which is a specific monoclonal antibody for galactose-deficient IgA1 (Gd-IgA1). The intensity of the KM55 signal in the present patient was weaker than that in patients with IgA nephropathy. To our knowledge, this is the first report of IRGN associated with PVB19 that progressed to ESRD without any underlying diseases. Further investigations are needed to determine the significance of IgA and Gd-IgA1 deposition in IRGN associated with PVB19.
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Affiliation(s)
- Yoko Shirai
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kenichiro Miura
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Tomoo Yabuuchi
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Takeshi Nagasawa
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kiyonobu Ishizuka
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Kazuhiro Takahashi
- Department of Pediatrics, Teikyo University, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan
| | - Sekiko Taneda
- Department of Pathology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Kazuho Honda
- Department of Anatomy, School of Medicine, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, Japan
| | | | - Hitoshi Suzuki
- Department of Nephrology, Faculty of Medicine, Juntendo University, 3-1-3, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Faculty of Medicine, Juntendo University, 3-1-3, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Motoshi Hattori
- Department of Pediatric Nephrology, School of Medicine, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
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Hotta O, Oda T. The epipharynx-kidney axis triggers glomerular vasculitis in immunoglobulin A nephropathy. Immunol Res 2020; 67:304-309. [PMID: 31745821 DOI: 10.1007/s12026-019-09099-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Macroscopic hematuria concomitant with acute pharyngitis is a characteristic feature of immunoglobulin A nephropathy (IgAN). Although the underlying mechanism of worsening hematuria has not been fully elucidated, activation of the innate immune system of nasopharynx-associated lymphoid tissue is thought to play an important role. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. As latent but significant epipharyngitis presents in most IgAN patients, it is plausible that acute pharyngitis due to airway infection may contribute as a trigger of the epipharyngeal innate immune system, which is already upregulated in the chronically inflamed environment. The aim of this review was to discuss the mechanism of epipharynx-kidney axis involvement in glomerular vasculitis responsible for the worsening of hematuria in IgAN.
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Affiliation(s)
- Osamu Hotta
- Division of Internal Medicine, Hotta Osamu Clinic, Sendai, Japan.,Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takashi Oda
- Department of Nephrology and Blood Purification, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.
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47
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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: 53] [Impact Index Per Article: 10.6] [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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48
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Management and treatment of glomerular diseases (part 1): conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference. ACTA ACUST UNITED AC 2020. [DOI: 10.36485/1561-6274-2020-24-2-22-41] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline’s publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.
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49
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Floege J, Barbour SJ, Cattran DC, Hogan JJ, Nachman PH, Tang SCW, Wetzels JFM, Cheung M, Wheeler DC, Winkelmayer WC, Rovin BH. Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2020; 95:268-280. [PMID: 30665568 DOI: 10.1016/j.kint.2018.10.018] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 10/10/2018] [Accepted: 10/24/2018] [Indexed: 01/10/2023]
Abstract
The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.
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Affiliation(s)
- Jürgen Floege
- Division of Nephrology, Rheinisch-Westfälische Technische Hochschule University of Aachen, Aachen, Germany.
| | - Sean J Barbour
- British Columbia Provincial Renal Agency, Vancouver, British Columbia, Canada; Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Health Evaluation and Outcomes Research, St. Paul's Hospital, Vancouver, British Columbia, Canada
| | - Daniel C Cattran
- Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Jonathan J Hogan
- Division of Nephrology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Patrick H Nachman
- Division of Renal Diseases and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sydney C W Tang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Jack F M Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | - Wolfgang C Winkelmayer
- Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Brad H Rovin
- Division of Nephrology, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA.
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50
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Wang C, Deng H, Gong Y, You R, Chen M, Zhao MH. Effect of high mobility group box 1 on Toll-like receptor 9 in B cells in myeloperoxidase-ANCA-associated vasculitis. Autoimmunity 2019; 53:28-34. [PMID: 31790283 DOI: 10.1080/08916934.2019.1696777] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
High mobility group box 1 (HMGB1) played pathogenic role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Recent findings demonstrated that Toll-like receptor 9 (TLR9) was involved in B cell tolerance breaking of autoimmune disease, including AAV. Here, we investigated the effect of HMGB1 on TLR9 in B cells of AAV. In the present work, patients with myeloperoxidase (MPO)-AAV in active stage were recruited. Intracellular TLR9 expression in various B cell subpopulations of the whole blood was detected by flow cytometry and the correlation with clinical data was analysed. Our results showed that intracellular TLR9 expression in B cells, memory B cells and plasmablasts correlated with erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). In particular, TLR9 expression in plasma cells correlated with ESR, CRP, serum creatinine, eGFR, and Birmingham Vasculitis Activity Score. To further explore the effect of HMGB1 on B cell, peripheral blood mononuclear cells (PBMCs) from AAV patients were isolated. After stimulated with HMGB1, TLR9 expression in various B cell subpopulations and proliferation ratio of live B cells were analysed by flow cytometry. We found that TLR9 expression in plasma cells and the proliferation ratio of live B cells by HMGB1 stimulation were significantly upregulated compared with the control group. Therefore, TLR9 expression in plasma cells was associated with disease activity of MPO-AAV. HMGB1 could enhance TLR9 expression in plasma cells and B cell proliferation. These indicated a role of HMGB1 on TLR9 in B cells in MPO-AAV, which would provide potential clues for intervention strategies.
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Affiliation(s)
- Chen Wang
- Department of Medicine, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 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, Beijing, China
| | - Hui Deng
- Department of Medicine, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 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, Beijing, China
| | - Yan Gong
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, China
| | - Ran You
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, China
| | - Min Chen
- Department of Medicine, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 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, Beijing, China
| | - Ming-Hui Zhao
- Department of Medicine, Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, 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, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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