1
|
Shi LL, Xiong P, Yang M, Ardicli O, Schneider SR, Funch AB, Kiykim A, Lopez J, Akdis CA, Akdis M. Role of IgG4 Antibodies in Human Health and Disease. Cells 2025; 14:639. [PMID: 40358163 PMCID: PMC12071442 DOI: 10.3390/cells14090639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/08/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune tolerance, particularly in the context of allergen-specific immunotherapy (AIT), where they can mediate tolerance to environmental antigens, inhibit IgE-dependent mast cell degranulation, and compete with IgE for allergen binding. This helps in attenuating allergic symptoms and is associated with increased levels of allergen-specific IgG4. However, in disease scenarios, the role of IgG4 is complex. IgG4 lacks complement fixation and, thus, shows a reduced ability to activate immune effector pathways, it was initially thought to be protective against autoimmune diseases. However, emerging evidence suggests that it can contribute to pathology. For instance, IgG4 autoantibodies against specific antigens can aggravate conditions in certain autoimmune disorders. In some cancers, it may play a role in immune evasion, with higher levels correlating with poor patient survival, albeit in others, its exact function remains elusive. Overall, understanding the precise role of IgG4 in various physiological and pathological conditions is crucial for developing targeted therapeutic strategies and improving patient outcomes.
Collapse
Affiliation(s)
- Li-li Shi
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Peng Xiong
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Minglin Yang
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
| | - Ozge Ardicli
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
- Division of Food Processing, Milk and Dairy Products Technology Program, Karacabey Vocational School, Bursa Uludag University, Bursa 16700, Turkey
| | - Stephan Raphael Schneider
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
| | - Anders Boutrup Funch
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Ayca Kiykim
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
- Department of Pediatrics, Division of Pediatric Allergy and Immunology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey
| | - Juan Lopez
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (L.-l.S.); (P.X.); (O.A.); (S.R.S.); (A.B.F.); (A.K.); (J.L.); (C.A.A.)
| |
Collapse
|
2
|
Zhang M, Liu W, Dai H, Jiang H, Zhao Q, Liu W, Rui H, Liu B. Heterogeneity of Renal Endothelial Cells, Interact with Neighboring Cells, and Endothelial Injury in Chronic Kidney Disease: Mechanisms and Therapeutic Implications. Int J Med Sci 2025; 22:2103-2118. [PMID: 40303495 PMCID: PMC12035827 DOI: 10.7150/ijms.108299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/04/2025] [Indexed: 05/02/2025] Open
Abstract
Chronic kidney disease (CKD) is closely associated with endothelial dysfunction, leading to symptoms such as albuminuria, edema, and coagulopathy. Recent advancements in single-cell sequencing have deepened our understanding of the heterogeneity of renal endothelial cells, which is significantly influenced by their microenvironment. Understanding the influence of neighboring cells on endothelial heterogeneity is essential for elucidating the mechanisms underlying vascular dysfunction and CKD progression. This review explores the latest research on renal endothelial cell heterogeneity and their interactions with neighboring cells. We further discuss the mechanisms of endothelial injury in CKD, including alterations to the endothelial glycocalyx, inflammation, oxidative stress, and dysfunction of the glomerular filtration barrier. Renal endothelial injury contributes to complications, including cardiovascular disease, diabetic nephropathy, and impaired vascular function. Therapeutic strategies encompass antihypertensive, hypoglycemic, and lipid-lowering treatments, supplemented by emerging approaches such as anti-inflammatory therapies, gene therapy, and lifestyle modifications. Through reviewing the relationship between endothelial injury and CKD progression, we emphasize potential strategies to enhance prognosis and mitigate disease progression.
Collapse
Affiliation(s)
- Meiyu Zhang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wu Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Haoran Dai
- Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100310, China
| | - Hanxue Jiang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Qihan Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Wenbin Liu
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hongliang Rui
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Baoli Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| |
Collapse
|
3
|
Teisseyre M, Destere A, Cremoni M, Zorzi K, Brglez V, Benito S, Bailly L, Fernandez C, Seitz-Polski B. Artificial intelligence-based personalised rituximab treatment protocol in membranous nephropathy (iRITUX): protocol for a multicentre randomised control trial. BMJ Open 2025; 15:e093920. [PMID: 40180405 PMCID: PMC11966952 DOI: 10.1136/bmjopen-2024-093920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 03/05/2025] [Indexed: 04/05/2025] Open
Abstract
INTRODUCTION Membranous nephropathy is an autoimmune kidney disease and the most common cause of nephrotic syndrome in non-diabetic Caucasian adults. Rituximab is now recommended as first-line therapy for membranous nephropathy. However, Kidney Disease Improving Global Outcomes guidelines do not recommend any specific protocol. Rituximab bioavailability is reduced in patients with membranous nephropathy due to urinary drug loss. Underdosing of rituximab is associated with treatment failure. We have previously developed a machine learning algorithm to predict the risk of underdosing. We have retrospectively shown that patients with a high risk of underdosing required higher doses of rituximab to achieve remission. The aim of this prospective study is to evaluate the efficacy of algorithm-driven rituximab treatment in patients with membranous nephropathy compared to standard treatment. METHODS A multicentre, randomised, controlled, open-label, prospective superiority clinical trial will be conducted in 13 French hospitals. 130 consecutive patients with primary membranous nephropathy and active nephrotic syndrome will be randomised to either the standard protocol control group (two 1 g rituximab infusions on days 0 and 15) or the algorithm-driven rituximab treatment group. In the latter, the rituximab dose will depend on the algorithm-estimated risk of underdosing. Patients with an algorithm-estimated risk of underdosing ≤50% will receive 1 g of rituximab on days 0 and 15. Patients with an algorithm-estimated risk of underdosing between 51% and 75% will receive 1 g of rituximab on days 0, 15 and 30. Finally, patients with an estimated risk of underdosing >75% will receive 1 g of rituximab on days 0, 15, 30 and 45. The primary study outcome is the rate of clinical remission (complete or partial) at month 6 after treatment initiation. The secondary outcomes include clinical remission at month 12, immunological remission, proteinuria, albuminuria, serum creatinine, estimated glomerular filtration rate, phospholipase A2 receptor type 1 antibody titre, anti-rituximab antibody occurrence, lymphocyte count, serum rituximab level and related adverse events. ETHICS AND DISSEMINATION The trial received ethics approval from the local ethics boards. The results of this study will confirm whether algorithm-driven rituximab treatment is more effective in inducing remission than the standard regimen and thus may contribute to improving management of patients with membranous nephropathy. The results of our study will be submitted to a peer-review journal. TRIAL REGISTRATION NUMBER NCT06341205 trial number. Registered on 2 April 2024.
Collapse
Affiliation(s)
- Maxime Teisseyre
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Département de Néphrologie, Dialyse et Transplantation, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Laboratoire d'Immunologie, Unité de Thérapie Cellulaire et Génique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | - Alexandre Destere
- Département de Pharmacologie Clinique et de Pharmacovigilance, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Inria, CNRS, Laboratoire J.A. Dieudonné, Maasai team, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
| | - Marion Cremoni
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Département de Néphrologie, Dialyse et Transplantation, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Laboratoire d'Immunologie, Unité de Thérapie Cellulaire et Génique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | - Kévin Zorzi
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Département de Néphrologie, Dialyse et Transplantation, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | - Vesna Brglez
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Laboratoire d'Immunologie, Unité de Thérapie Cellulaire et Génique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | | | - Laurent Bailly
- Département de Santé Publique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | - Céline Fernandez
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Laboratoire d'Immunologie, Unité de Thérapie Cellulaire et Génique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| | - Barbara Seitz-Polski
- Institut de Recherche sur le Cancer et Vieillissement UMR7284 CNRS INSERM U1081, Université Côte d'Azur, Nice, Provence-Alpes-Côte d'Azur, France
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique et Glomérulonéphrite Extra-Membraneuse, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Département de Néphrologie, Dialyse et Transplantation, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
- Laboratoire d'Immunologie, Unité de Thérapie Cellulaire et Génique, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Nice, Provence-Alpes-Côte d'Azur, France
| |
Collapse
|
4
|
Xu Y, Li Y, Zhang Y, Li G. Urine complement analysis implies complement activation is involved in membranous nephropathy. Front Med (Lausanne) 2025; 12:1515928. [PMID: 40018357 PMCID: PMC11865186 DOI: 10.3389/fmed.2025.1515928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
Background The onset and progression of membranous nephropathy (MN) have been associated with complement activation, yet the overall characteristics of this activation in the kidneys remain unclear. In our study, we utilized urine proteomic data to investigate the features of complement activation. We examined the relationship between urine complement components and both clinicopathological features and clinical outcomes in patients with MN. Methods Differential expression proteins (DEPs) analysis was performed using proteomic data from urine samples collected from 50 patients with MN, 50 patients with IgA nephropathies (IgAN), and 72 healthy controls (HC). Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were carried out on the DEPs identified in MN. We further investigated the differentially expressed urinary complement proteins in MN patients, exploring their relationships with clinicopathological features and clinical remission. Next, 11 representative complements were selected for validation. Immunohistochemistry and immunofluorescence techniques were employed to compare the expression of CD59 and C5b-9 in renal tissues from MN patients, with analyses conducted on both the clinical remission group and the no remission group (n = 6 in each group). Results Total 1,427 differentially expressed proteins were identified between the MN and HC groups. KEGG pathway analysis showed significant enrichment of these DEPs in the complement-activated pathway within the MN group. Additionally, a correlation was found between proteinuria and the levels of 27 urinary complement proteins. Notably, Collectin12 (collec12) and C1s were positively correlated with tubular atrophy/interstitial fibrosis (TIF) and monocyte infiltration. Furthermore, urine CD59 emerged as a predictor of clinical remission. Lower deposition of C5b-9 in renal tissue and higher expression of CD59 were detected in clinical remission group than non-remission group. Conclusion In patients with MN, abnormal levels of complement components in urine are commonly observed. Currently, the use of complement inhibitors has brought new hope for the treatment of MN. The factor B inhibitor LNP023 and the factor D inhibitor BCX9930 are undergoing clinical trials for the treatment of MN. Our study indicates that complement abnormalities could serve as clinical biomarkers for tracking the progression of MN, predicting clinical remission, and guiding targeted complement therapy for those affected.
Collapse
Affiliation(s)
- Yingxue Xu
- Department of Nephrology and Nephrology Institute, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Li
- Department of Nephrology and Nephrology Institute, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yong Zhang
- Department of Nephrology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China
| | - Guisen Li
- Department of Nephrology and Nephrology Institute, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| |
Collapse
|
5
|
Wang G, Yang L, Xu X, Guo W, Sun L, Wang Y, Cheng W, Ye N, Kong L, Zhao X, Cheng H. SARS-CoV-2 Protein Deposition Enhances Renal Complement Activation and Aggravates Kidney Injury in Membranous Nephropathy After COVID-19. Kidney Int Rep 2024; 9:3145-3155. [PMID: 39534192 PMCID: PMC11551107 DOI: 10.1016/j.ekir.2024.08.006] [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: 02/02/2024] [Revised: 07/22/2024] [Accepted: 08/05/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction COVID-19 has been reported to be associated with the occurrence and recurrence of membranous nephropathy (MN). The clinicopathological characteristics and complement system activation of MN after COVID-19 are unclear. Methods A total of 38 patients with biopsy-proven MN who developed new-onset proteinuria after COVID-19 were enrolled in this study. One hundred patients with primary MN diagnosed before the COVID-19 pandemic were the control. Renal immunohistochemical staining for SARS-CoV-2 nucleocapsid protein was performed in 38 patients with MN after COVID-19. Serum membrane attack complex (MAC) was detected by enzyme-linked immunosorbent assay. Glomerular staining for the complement proteins in different pathways were detected by immunohistochemistry. Results Thirteen of 38 patients had positive staining for SARS-CoV-2 nucleocapsid protein. Compared with the control patients, the clinical manifestations were more severe in patients after COVID-19. Patients with positive SARS-CoV-2 staining had a higher proportion of nephrotic syndrome, lower level of serum albumin, and greater severity of renal interstitial fibrosis than those of patients with negative SARS-CoV-2 staining. Serum MAC level and renal MAC staining intensity of MN after COVID-19 were significantly higher than those of the control patients. MAC expression in MN patients with positive SARS-CoV-2 staining was stronger than that in both control patients and MN after COVID-19 with negative SARS-CoV-2 staining. The expression trend of factor H was consistent with that of MAC. Conclusion Excessive activation of the complement system aggravated symptoms in MN after COVID-19. Therapeutic strategy targeting the complement system may need to be considered.
Collapse
Affiliation(s)
- Guoqin Wang
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lei Yang
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xiaoyi Xu
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Weiyi Guo
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lijun Sun
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yanyan Wang
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Wenrong Cheng
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Nan Ye
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lingqiang Kong
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xiaoyi Zhao
- Division of Nephrology, Affiliated Hospital of Chifeng University, Neimenggu, China
| | - Hong Cheng
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
6
|
Jiang S, Jiang D, Lian Z, Huang X, Li T, Zhang Y. THSD7A as a Promising Biomarker for Membranous Nephrosis. Mol Biotechnol 2024; 66:3117-3135. [PMID: 37884765 DOI: 10.1007/s12033-023-00934-5] [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: 07/10/2023] [Accepted: 10/05/2023] [Indexed: 10/28/2023]
Abstract
Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome. The disease exhibits heterogeneous outcomes with approximately 30% of cases progressing to end-stage renal disease. Traditionally, the standard approach of diagnosing MN involves performing a kidney biopsy. Nevertheless, kidney biopsy is an invasive procedure that poses risks for the patient including bleeding and pain, and bears greater costs for the health system. The clinical management of MN has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) in 2014 on the podocyte surface. At present, serum anti-PLA2R antibody detection and glomerular PLA2R antigen staining have been used for clinical diagnosis and prognosis, but the related detection of THSD7A has not been widely used in clinical practice. Here, we summarized the emerging knowledge regarding the roles THSD7A plays in MN and its clinical implications as diagnostic, prognostic, and therapeutic response as well as Methods for detecting serum THSD7A antibodies.
Collapse
Affiliation(s)
- Shuiqing Jiang
- Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University, Fuzhou, 350117, Fujian, China.
| | - Dehua Jiang
- Kangrun Biotech LTD, Guangzhou, 511400, Guangdong, China
| | - Zhiyuan Lian
- Kangrun Biotech LTD, Guangzhou, 511400, Guangdong, China
| | - Xiaohong Huang
- Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University, Fuzhou, 350117, Fujian, China
| | - Ting Li
- Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University, Fuzhou, 350117, Fujian, China
| | - Yinan Zhang
- Fujian Key Laboratory of Developmental and Neural Biology, College of Life Science, Fujian Normal University, Fuzhou, 350117, Fujian, China
| |
Collapse
|
7
|
Zhang Q, Bin S, Budge K, Petrosyan A, Villani V, Aguiari P, Vink C, Wetzels J, Soloyan H, La Manna G, Podestà MA, Molinari P, Sedrakyan S, Lemley KV, De Filippo RE, Perin L, Cravedi P, Da Sacco S. C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy. JCI Insight 2024; 9:e172976. [PMID: 38227377 PMCID: PMC11143932 DOI: 10.1172/jci.insight.172976] [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: 06/09/2023] [Accepted: 01/11/2024] [Indexed: 01/17/2024] Open
Abstract
The deposition of antipodocyte autoantibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN.
Collapse
Affiliation(s)
- Qi Zhang
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
| | - Sofia Bin
- Translational Transplant Research Center and Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Kelly Budge
- Translational Transplant Research Center and Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Astgik Petrosyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Valentina Villani
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
| | - Paola Aguiari
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
| | - Coralien Vink
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jack Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hasmik Soloyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Manuel Alfredo Podestà
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paolo Molinari
- Translational Transplant Research Center and Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sargis Sedrakyan
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Kevin V. Lemley
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Roger E. De Filippo
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Paolo Cravedi
- Translational Transplant Research Center and Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stefano Da Sacco
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Saban Research Institute, Division of Urology, Children’s Hospital Los Angeles (CHLA), Los Angeles, California, USA
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| |
Collapse
|
8
|
Dong Z, Geng Y, Zhang P, Tang J, Cao Z, Zheng H, Guo J, Zhang C, Liu B, Liu WJ. Identification of molecular mechanism and key biomarkers in membranous nephropathy by bioinformatics analysis. Am J Transl Res 2022; 14:5833-5847. [PMID: 36105034 PMCID: PMC9452341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 07/20/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES Membranous nephropathy (MN) is an autoimmune nephropathy. The incidence of MN is increasing gradually in recent years. Previous studies focused on antibody production, complement activation and podocyte injury in MN. However, the etiology and underlying mechanism of MN remain to be further studied. METHODS GSE104948 and GSE108109 of glomerular expression profile were downloaded from Gene Expression Omnibus (GEO) database, GSE47184, GSE99325, GSE104954, GSE108112, GSE133288 of renal tubule expression profile, and GSE73953 of peripheral blood mononuclear cells (PBMCs) expression profile. After data integration by Networkanalyst, differentially expressed genes (DEGs) between MN and healthy samples were obtained. DEGs were enriched in gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG), and protein-protein interaction (PPI) networks of these genes were constructed through Metascape, etc. We further understood the function of hub genes through gene set enrichment analysis (GSEA). The diagnostic value of DEGs in MN was evaluated by receiver operating characteristic (ROC) analysis. RESULTS A total of 3 genes (TP53, HDAC5, and SLC2A3) were screened out. Among them, the up-regulated TP53 expression may be closely related to MN renal pathological changes. However, the expression of MN podocyte target antigen was not significantly different from that of healthy controls. In addition, the changes of Wnt signaling pathway in PBMCs and the effects of SLC2A3 on the differentiation of M2 monocyte need further study. CONCLUSION It is difficult to unify a specific mechanism for the changes of glomerulus, renal tubules and PBMCs in MN patients. This may be related to the pathogenesis, pathology and immune characteristics of MN. MN podocyte target antigen may not be the root cause of the disease, but a stage result in the pathogenesis process.
Collapse
Affiliation(s)
- Zhaocheng Dong
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Yunling Geng
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Pingna Zhang
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Jingyi Tang
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Zijing Cao
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Huijuan Zheng
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Jing Guo
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Chao Zhang
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| | - Baoli Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical UniversityBeijing, China
| | - Wei Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China
- Renal Research Institution of Beijing University of Chinese Medicine, Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese MedicineBeijing, China
| |
Collapse
|
9
|
Salvadori M, Tsalouchos A. New antigens involved in membranous nephropathy beyond phospholipase A2 receptor. World J Nephrol 2022; 11:115-126. [PMID: 36161266 PMCID: PMC9353762 DOI: 10.5527/wjn.v11.i4.115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/24/2022] [Accepted: 07/08/2022] [Indexed: 02/06/2023] Open
Abstract
When the physiopathology of membranous nephropathy was first described, almost 30% of cases were recognized to be secondary to well-known diseases such as autoimmune diseases, tumors or infections. The remaining 70% cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown. The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these "so called" primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases. Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens. Finally, using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples, these new antigens were detected on the glomerular membrane, and the related antibodies were detected in serum samples. The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases, tumors and infections. This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies. The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata, Florence 50012, Tuscany, Italy
| |
Collapse
|
10
|
Saleem M, Shaikh S, Hu Z, Pozzi N, Java A. Post-Transplant Thrombotic Microangiopathy due to a Pathogenic Mutation in Complement Factor I in a Patient With Membranous Nephropathy: Case Report and Review of Literature. Front Immunol 2022; 13:909503. [PMID: 35720299 PMCID: PMC9204634 DOI: 10.3389/fimmu.2022.909503] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ injury occurring due to endothelial cell damage and microthrombi formation in small vessels. TMA is primary when a genetic or acquired defect is identified, as in atypical hemolytic uremic syndrome (aHUS) or secondary when occurring in the context of another disease process such as infection, autoimmune disease, malignancy or drugs. Differentiating between a primary complement-mediated process and one triggered by secondary factors is critical to initiate timely treatment but can be challenging for clinicians, especially after a kidney transplant due to presence of multiple confounding factors. Similarly, primary membranous nephropathy is an immune-mediated glomerular disease associated with circulating autoantibodies (directed against the M-type phospholipase A2 receptor (PLA2R) in 70% cases) while secondary membranous nephropathy is associated with infections, drugs, cancer, or other autoimmune diseases. Complement activation has also been proposed as a possible mechanism in the etiopathogenesis of primary membranous nephropathy; however, despite complement being a potentially common link, aHUS and primary membranous nephropathy have not been reported together. Herein we describe a case of aHUS due to a pathogenic mutation in complement factor I that developed after a kidney transplant in a patient with an underlying diagnosis of PLA2R antibody associated-membranous nephropathy. We highlight how a systematic and comprehensive analysis helped to define the etiology of aHUS, establish mechanism of disease, and facilitated timely treatment with eculizumab that led to recovery of his kidney function. Nonetheless, ongoing anti-complement therapy did not prevent recurrence of membranous nephropathy in the allograft. To our knowledge, this is the first report of a patient with primary membranous nephropathy and aHUS after a kidney transplant.
Collapse
Affiliation(s)
- Maryam Saleem
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Sana Shaikh
- Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Zheng Hu
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Nicola Pozzi
- Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Anuja Java
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| |
Collapse
|
11
|
Teisseyre M, Cremoni M, Boyer-Suavet S, Ruetsch C, Graça D, Esnault VLM, Brglez V, Seitz-Polski B. Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy. Front Immunol 2022; 13:859419. [PMID: 35603210 PMCID: PMC9114510 DOI: 10.3389/fimmu.2022.859419] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/22/2022] [Indexed: 02/06/2023] Open
Abstract
Primary membranous nephropathy (pMN) is an auto-immune disease characterized by auto-antibodies targeting podocyte antigens resulting in activation of complement and damage to the glomerular basement membrane. pMN is the most common cause of nephrotic syndrome in adults without diabetes. Despite a very heterogeneous course of the disease, the treatment of pMN has for many years been based on uniform management of all patients regardless of the severity of the disease. The identification of prognostic markers has radically changed the vision of pMN and allowed KDIGO guidelines to evolve in 2021 towards a more personalized management based on the assessment of the risk of progressive loss of kidney function. The recognition of pMN as an antibody-mediated autoimmune disease has rationalized the use immunosuppressive drugs such as rituximab. Rituximab is now a first line immunosuppressive therapy for patients with pMN with proven safety and efficacy achieving remission in 60-80% of patients. For the remaining 20-40% of patients, several mechanisms may explain rituximab resistance: (i) decreased rituximab bioavailability; (ii) immunization against rituximab; and (iii) chronic glomerular damage. The treatment of patients with rituximab-refractory pMN remains controversial and challenging. In this review, we provide an overview of recent advances in the management of pMN (according to the KDIGO 2021 guidelines), in the understanding of the pathophysiology of rituximab resistance, and in the management of rituximab-refractory pMN. We propose a treatment decision aid based on immunomonitoring to identify failures related to underdosing or immunization against rituximab to overcome treatment resistance.
Collapse
Affiliation(s)
- Maxime Teisseyre
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
| | - Marion Cremoni
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
| | - Sonia Boyer-Suavet
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
| | - Caroline Ruetsch
- Laboratoire d’Immunologie, CHU de Nice, Université Côte d’Azur, Nice, France
| | - Daisy Graça
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
| | - Vincent L. M. Esnault
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Service de Néphrologie-Dialyse-Transplantation, CHU de Nice, Université Côte d’Azur, Nice, France
| | - Vesna Brglez
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
| | - Barbara Seitz-Polski
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
- Laboratoire d’Immunologie, CHU de Nice, Université Côte d’Azur, Nice, France
- Service de Néphrologie-Dialyse-Transplantation, CHU de Nice, Université Côte d’Azur, Nice, France
| |
Collapse
|
12
|
Lin DW, Chang CC, Hsu YC, Lin CL. New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid. Int J Mol Sci 2022; 23:3525. [PMID: 35408886 PMCID: PMC8998908 DOI: 10.3390/ijms23073525] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/23/2022] Open
Abstract
Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.
Collapse
Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi 60069, Taiwan;
| | - Cheng-Chih Chang
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan;
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Division of Chinese Materia Medica Development, National Research Institute of Chinese Medicine, Taipei 613016, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 613016, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833253, Taiwan
| |
Collapse
|
13
|
Zhao Y, Cai M, Jiang Z, Dong B, Yan Y, Wang Y, Zuo L. Association of serum mannose-binding lectin, anti-phospholipase A2 receptor antibody and renal outcomes in idiopathic membranous nephropathy and atypical membranous nephropathy: a single center retrospective cohort study. Ren Fail 2022; 44:428-433. [PMID: 35272568 PMCID: PMC8920381 DOI: 10.1080/0886022x.2022.2048016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Objectives Idiopathic membranous nephropathy (iMN) is a major cause of nephrotic syndrome. Atypical membranous nephropathy (aMN) is a new type of nephropathy in China, characterized by a ‘full-house’ on immunofluorescent examination, that is IgG, IgA, IgM, C3, C1q positive, but without clinical evidence of a secondary cause. Phospholipase A2 receptor (PLA2R) was the major target antigens in iMN patients. Activation of the mannose-binding lectin (MBL) pathway plays a vital role in the development of MN. Our objective was to investigate the role of PLA2R and MBL in the pathogenesis of iMN and aMN. Methods We conducted a retrospective observational study using propensity score matching by age, gender, and eGFR. All clinical, laboratory data, and follow-up data of the patients were collected. Serum levels of anti-PLA2R antibodies and MBL were tested. Results Finally, 30 iMN patients and 30 aMN patients were included, and 20 healthy controls were retrospectively collected in this study. The 24 h proteinuria level was higher and serum albumin was lower in anti-PLA2R (+) patients than in anti-PLA2R (−) patients in both iMN and aMN groups. In aMN patients, MBL levels were significantly higher in anti-PLA2R (+) patients than in anti-PLA2R (−) patients (p = .045). The serum level of anti-PLA2R positively correlated with no-remission in both iMN and aMN groups. Conclusions The complement lectin pathway has an association with the development of MN, especially in patients with positive anti-PLA2R antibodies. Serum MBL cannot differentiate between the two diseases. Serum MBL levels are not associated with clinical manifestations, nor with prognosis.
Collapse
Affiliation(s)
- Yuchao Zhao
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Meishun Cai
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Zhenbin Jiang
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Bao Dong
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Yu Yan
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Yina Wang
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| | - Li Zuo
- Department of Nephrology, Peking University People's Hospital, Beijing, China
| |
Collapse
|
14
|
Vivarelli M, van de Kar N, Labbadia R, Diomedi-Camassei F, Thurman JM. A clinical approach to children with C3 glomerulopathy. Pediatr Nephrol 2022; 37:521-535. [PMID: 34002292 DOI: 10.1007/s00467-021-05088-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/28/2021] [Accepted: 04/20/2021] [Indexed: 11/28/2022]
Abstract
C3 glomerulopathy is a relatively new clinical entity that represents a challenge both to diagnose and to treat. As new therapeutic agents that act as complement inhibitors become available, many with an oral formulation, a better understanding of this disease and of the underlying complement dysregulation driving it has become increasingly useful to optimize patient care. Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. Complement inhibitors are being studied in adult and adolescent clinical trials for these indications. This review summarizes current knowledge and future perspectives on every aspect of the diagnosis and management of C3 glomerulopathy and elucidates current understanding of the role of complement in this condition and in other glomerular diseases in children. An overview of ongoing trials involving therapeutic agents targeting complement in glomerular diseases is also provided.
Collapse
Affiliation(s)
- Marina Vivarelli
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy.
| | - Nicole van de Kar
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Raffaella Labbadia
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy
| | | | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| |
Collapse
|
15
|
Wendt R, Siwy J, He T, Latosinska A, Wiech T, Zipfel PF, Tserga A, Vlahou A, Rupprecht H, Catanese L, Mischak H, Beige J. Molecular Mapping of Urinary Complement Peptides in Kidney Diseases. Proteomes 2021; 9:proteomes9040049. [PMID: 34941814 PMCID: PMC8709096 DOI: 10.3390/proteomes9040049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 02/07/2023] Open
Abstract
Defective complement activation has been associated with various types of kidney disease. This led to the hypothesis that specific urine complement fragments may be associated with kidney disease etiologies, and disease progression may be reflected by changes in these complement fragments. We investigated the occurrence of complement fragments in urine, their association with kidney function and disease etiology in 16,027 subjects, using mass spectrometry based peptidomics data from the Human Urinary Proteome/Peptidome Database. Twenty-three different urinary peptides originating from complement proteins C3, C4 and factor B (CFB) could be identified. Most C3-derived peptides showed inverse association with estimated glomerular filtration rate (eGFR), while the majority of peptides derived from CFB demonstrated positive association with eGFR. Several peptides derived from the complement proteins C3, C4 and CFB were found significantly associated with specific kidney disease etiologies. These peptides may depict disease-specific complement activation and could serve as non-invasive biomarkers to support development of complement interventions through assessing complement activity for patients’ stratification and monitoring of drug impact. Further investigation of these complement peptides may provide additional insight into disease pathophysiology and could possibly guide therapeutic decisions, especially when targeting complement factors.
Collapse
Affiliation(s)
- Ralph Wendt
- Department of Nephrology and Kuratorium for Dialysis and Transplantation (KfH) Renal Unit, Hospital St. Georg, 04129 Leipzig, Germany;
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (T.H.); (A.L.); (H.M.)
| | - Tianlin He
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (T.H.); (A.L.); (H.M.)
| | - Agnieszka Latosinska
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (T.H.); (A.L.); (H.M.)
| | - Thorsten Wiech
- Nephropathology Section, Institute of Pathology, University Medical Center, 20246 Hamburg, Germany;
| | - Peter F. Zipfel
- Institute of Microbiology, Friedrich-Schiller-University, 07743 Jena, Germany;
- Department of Infection Biology, Leibniz Institute for Natural Product Researach and Infection Biology, 07745 Jena, Germany
| | - Aggeliki Tserga
- Biomedical Research Foundation, Academy of Athens, Department of Biotechnology, 11527 Athens, Greece; (A.T.); (A.V.)
| | - Antonia Vlahou
- Biomedical Research Foundation, Academy of Athens, Department of Biotechnology, 11527 Athens, Greece; (A.T.); (A.V.)
| | - Harald Rupprecht
- Department of Nephrology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany; (H.R.); (L.C.)
| | - Lorenzo Catanese
- Department of Nephrology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany; (H.R.); (L.C.)
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (T.H.); (A.L.); (H.M.)
| | - Joachim Beige
- Department of Nephrology and Kuratorium for Dialysis and Transplantation (KfH) Renal Unit, Hospital St. Georg, 04129 Leipzig, Germany;
- Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06108 Halle (Saale), Germany
- Correspondence: ; Tel.: +49-341-909-4896
| |
Collapse
|
16
|
Teisseyre M, Cremoni M, Boyer-Suavet S, Crepin T, Benzaken S, Zorzi K, Esnault V, Brglez V, Seitz-Polski B. Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy. Front Immunol 2021; 12:738788. [PMID: 34721403 PMCID: PMC8548826 DOI: 10.3389/fimmu.2021.738788] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/21/2021] [Indexed: 11/25/2022] Open
Abstract
Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%–80% of cases. For the remaining 20%–40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.
Collapse
Affiliation(s)
- Maxime Teisseyre
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France
| | - Marion Cremoni
- Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France
| | - Sonia Boyer-Suavet
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Thomas Crepin
- Centre Hospitalier Regional Universitaire de Besancon (CHU Besancon), Department of Nephrology, Dialysis, and Renal Transplantation, Besancon, France
| | - Sylvia Benzaken
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France
| | - Kévin Zorzi
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Vincent Esnault
- Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France
| | - Vesna Brglez
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Barbara Seitz-Polski
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire de Nice (CHU de Nice), Université Côte d'Azur, Nice, France.,Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| |
Collapse
|
17
|
Le Quintrec M, Teisseyre M, Bec N, Delmont E, Szwarc I, Perrochia H, Machet MC, Chauvin A, Mavroudakis N, Taieb G, Lanfranco L, Rigothier C, José B, Concetta C, Geneste C, Pernin V, Larroque C, Devaux J, Beyze A. Contactin-1 is a novel target antigen in membranous nephropathy associated with chronic inflammatory demyelinating polyneuropathy. Kidney Int 2021; 100:1240-1249. [PMID: 34600965 DOI: 10.1016/j.kint.2021.08.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/31/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022]
Abstract
Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound contactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-contactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated.
Collapse
Affiliation(s)
- Moglie Le Quintrec
- University of Montpellier, Department of Nephrology, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France.
| | - Maxime Teisseyre
- University of Montpellier, Department of Nephrology, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| | - Nicole Bec
- IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| | - Emilien Delmont
- Aix Marseille University, Referral Center of Neuromuscular Disease, Immunology Laboratory la Conception, Marseille, France
| | - Ilan Szwarc
- University of Montpellier, Department of Nephrology, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France
| | - Hélène Perrochia
- University of Montpellier, Department of Pathology, CHU Montpellier, Hôpital Guy de Chauliac, Montpellier, France
| | | | - Anthony Chauvin
- IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| | - Nicolas Mavroudakis
- Referral Center of Neuromuscular Disease, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Guillaume Taieb
- University of Montpellier Department of Neurology, CHU Montpellier, Hôpital Gui de Chauliac, Montpellier, France; IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Luca Lanfranco
- Department of Nephrology, University of Brest, Brest, France
| | - Claire Rigothier
- Department of Nephrology, CHU Pellegrin, University of Bordeaux, Bordeaux, France
| | - Boucraut José
- Immunology Laboratory la Conception, Aix Marseille University, Marseille, France
| | | | - Clair Geneste
- Nephrology-Clinical Immunology, Tours University Hospital, Tours, Indre-et-Loire, France
| | - Vincent Pernin
- University of Montpellier, Department of Nephrology, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| | - Christian Larroque
- IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| | - Jérôme Devaux
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Anaïs Beyze
- University of Montpellier, Department of Nephrology, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; IRMB, University of Montpellier, INSERM U1183, CHU Montpellier, Montpellier, France
| |
Collapse
|
18
|
Tesar V, Hruskova Z. Autoantibodies in the Diagnosis, Monitoring, and Treatment of Membranous Nephropathy. Front Immunol 2021; 12:593288. [PMID: 33828546 PMCID: PMC8019786 DOI: 10.3389/fimmu.2021.593288] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 02/22/2021] [Indexed: 01/25/2023] Open
Abstract
The discovery of anti-podocyte antibodies in primary membranous nephropathy (MN) has revolutionized our approach toward the diagnosis and treatment of this disease. Evaluation of serum levels of anti-podocyte antibodies paved the way for non-invasive diagnosis and helped distinguish between primary and secondary MN although the relationship between anti-podocyte antibodies and cancer remains to be elucidated. Serum levels of anti-PLA2R antibodies directed against the major podocyte autoantigen are related to MN activity and the decrease in serum levels of anti-PLA2R antibodies in response to treatment (immunologic remission) also serves as an early indicator of the later putative proteinuric remission, enabling personalization of the treatment. The serum levels of anti-podocyte antibodies also enable the prediction of renal outcomes in terms of both remission and the risk of progression to end-stage renal disease. The positivity of anti-PLA2R antibodies before renal transplantation is associated with the risk of recurrence of MN. It remains to be established if all these relations observed in patients with anti-PLA2R antibodies are also valid for expanding spectrum of antibodies directed against recently discovered minor antigens (e.g., THSD7A, NELL-1, semaphorin 3B).
Collapse
Affiliation(s)
- Vladimir Tesar
- Department of Nephrology, 1st Faculty of Medicine, General University Hospital, Charles University, Prague, Czechia
| | | |
Collapse
|
19
|
Cantarelli C, Jarque M, Angeletti A, Manrique J, Hartzell S, O'Donnell T, Merritt E, Laserson U, Perin L, Donadei C, Anderson L, Fischman C, Chan E, Draibe J, Fulladosa X, Torras J, Riella LV, La Manna G, Fiaccadori E, Maggiore U, Bestard O, Cravedi P. A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti-Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients. Kidney Int Rep 2020; 5:1764-1776. [PMID: 33102969 PMCID: PMC7569696 DOI: 10.1016/j.ekir.2020.07.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/20/2022] Open
Abstract
Introduction Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited. Methods We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non–immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq). Results After adjusting for multiple testing, plasma cells and regulatory B cells (BREG) were significantly higher (P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels (P = 0.042) and were associated with disease activity. Ex vivo–expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies (P < 0.001) in MN patients. Tumor necrosis factor-α (TNF-α) was the only significantly increased cytokine in MN patients (P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire. Conclusion This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.
Collapse
Affiliation(s)
- Chiara Cantarelli
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Dipartimento di Medicina e Chirurgia Università di Parma, Unita' Operativa Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy
| | - Marta Jarque
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Biomedical Research Institute of Bellvitge, Barcelona, Spain
| | - Andrea Angeletti
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Joaquin Manrique
- Nephrology Service, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Susan Hartzell
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Timothy O'Donnell
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Elliot Merritt
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Uri Laserson
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Laura Perin
- Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Chiara Donadei
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Lisa Anderson
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Clara Fischman
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Emilie Chan
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Juliana Draibe
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Biomedical Research Institute of Bellvitge, Barcelona, Spain
| | - Xavier Fulladosa
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Biomedical Research Institute of Bellvitge, Barcelona, Spain
| | - Joan Torras
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Biomedical Research Institute of Bellvitge, Barcelona, Spain
| | - Leonardo V Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Gaetano La Manna
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Enrico Fiaccadori
- Dipartimento di Medicina e Chirurgia Università di Parma, Unita' Operativa Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy
| | - Umberto Maggiore
- Dipartimento di Medicina e Chirurgia Università di Parma, Unita' Operativa Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy
| | - Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Biomedical Research Institute of Bellvitge, Barcelona, Spain
| | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|