|
1
|
Cheung CK, Alexander S, Reich HN, Selvaskandan H, Zhang H, Barratt J. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol 2025; 21:9-23. [PMID: 39232245 PMCID: PMC7616674 DOI: 10.1038/s41581-024-00885-3] [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] [Accepted: 07/31/2024] [Indexed: 09/06/2024]
Abstract
IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region - probably derived from the mucosal immune system - is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN.
Collapse
Affiliation(s)
- Chee Kay Cheung
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK.
| | | | - Heather N Reich
- Department of Medicine, Division of Nephrology, University of Toronto, University Health Network, Toronto, ON, Canada
| | - Haresh Selvaskandan
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, P. R. China
| | - Jonathan Barratt
- Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK.
| |
Collapse
|
|
2
|
Novak J, King RG, Yother J, Renfrow MB, Green TJ. O-glycosylation of IgA1 and the pathogenesis of an autoimmune disease IgA nephropathy. Glycobiology 2024; 34:cwae060. [PMID: 39095059 PMCID: PMC11442006 DOI: 10.1093/glycob/cwae060] [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: 06/11/2024] [Revised: 07/21/2024] [Accepted: 08/01/2024] [Indexed: 08/04/2024] Open
Abstract
IgA nephropathy is a kidney disease characterized by deposition of immune complexes containing abnormally O-glycosylated IgA1 in the glomeruli. Specifically, some O-glycans are missing galactose that is normally β1,3-linked to N-acetylgalactosamine of the core 1 glycans. These galactose-deficient IgA1 glycoforms are produced by IgA1-secreting cells due to a dysregulated expression and activity of several glycosyltransferases. Galactose-deficient IgA1 in the circulation of patients with IgA nephropathy is bound by IgG autoantibodies and the resultant immune complexes can contain additional proteins, such as complement C3. These complexes, if not removed from the circulation, can enter the glomerular mesangium, activate the resident mesangial cells, and induce glomerular injury. In this review, we briefly summarize clinical and pathological features of IgA nephropathy, review normal and aberrant IgA1 O-glycosylation pathways, and discuss the origins and potential significance of natural anti-glycan antibodies, namely those recognizing N-acetylgalactosamine. We also discuss the features of autoantibodies specific for galactose-deficient IgA1 and the characteristics of pathogenic immune complexes containing IgA1 and IgG. In IgA nephropathy, kidneys are injured by IgA1-containing immune complexes as innocent bystanders. Most patients with IgA nephropathy progress to kidney failure and require dialysis or transplantation. Moreover, most patients after transplantation experience a recurrent disease. Thus, a better understanding of the pathogenetic mechanisms is needed to develop new disease-specific treatments.
Collapse
Affiliation(s)
- Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294, United States
| | - R Glenn King
- Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294, United States
| | - Janet Yother
- Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294, United States
| | - Matthew B Renfrow
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 720 20th Street South, Birmingham, AL 35294, United States
| | - Todd J Green
- Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, AL 35294, United States
| |
Collapse
|
|
3
|
Gleeson PJ, Monteiro RC. The Role of Mucosal Immunity: What Can We Learn From Animal and Human Studies? Semin Nephrol 2024; 44:151566. [PMID: 40082160 DOI: 10.1016/j.semnephrol.2025.151566] [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: 03/16/2025]
Abstract
Immunoglobulin A (IgA) is a key actor in the mucosal immune system, which moderates interactions between the host and environmental factors such as food antigens and commensal microorganisms. The pathogenesis of IgA nephropathy (IgAN) involves a multistep process starting with deglycosylation of mucosally derived, polymeric IgA1 (dg-IgA1) that reaches the circulation. Modified O-glycans on dg-IgA1 are targeted by IgG-autoantibodies, leading to the formation of circulating immune complexes that deposit in the glomerular mesangium. Infections of mucosal surfaces trigger flares of primary IgAN, while inflammatory bowel disease and liver cirrhosis are important causes of secondary IgAN, supporting a mucosal source of nephritogenic IgA1. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T-cell-dependent or T-cell-independent B-cell differentiation into IgA-secreting plasma cells. Herein we review the literature concerning mucosal immune function and how it is altered in this disease. We discuss recent evidence supporting a causal role of gut microbiota dysbiosis in IgAN pathogenesis.
Collapse
Affiliation(s)
- Patrick J Gleeson
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Nephrology Department.
| | - Renato C Monteiro
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Immunology laboratory of Bichat hospital, Paris, France
| |
Collapse
|
|
4
|
Gleeson PJ, Benech N, Chemouny J, Metallinou E, Berthelot L, da Silva J, Bex-Coudrat J, Boedec E, Canesi F, Bounaix C, Morelle W, Moya-Nilges M, Kenny J, O'Mahony L, Saveanu L, Arnulf B, Sannier A, Daugas E, Vrtovsnik F, Lepage P, Sokol H, Monteiro RC. The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis. Sci Transl Med 2024; 16:eadl6149. [PMID: 38536935 DOI: 10.1126/scitranslmed.adl6149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 03/01/2024] [Indexed: 04/05/2024]
Abstract
Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila. IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1KI-CD89tg) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins-a risk locus for IgA nephropathy-inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.
Collapse
Affiliation(s)
- Patrick J Gleeson
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
- Department of Medicine, School of Microbiology, APC Microbiome Ireland, University College Cork, Cork T12 Y337 Ireland
- AP-HP, Nord/université de Paris, hôpital Bichat-Claude Bernard, Service de Néphrologie, Paris 75018, France
| | - Nicolas Benech
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, Paris 75012, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris 75012, France
- Hospices Civils de Lyon, Claude Bernard Lyon 1 University, CRCL, 69003 Lyon, France
| | - Jonathan Chemouny
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France
| | - Eleftheria Metallinou
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Laureline Berthelot
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Jennifer da Silva
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Julie Bex-Coudrat
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Erwan Boedec
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Fanny Canesi
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Carine Bounaix
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Willy Morelle
- Université Lille, Centre National de la Recherche Française, UMR 8576-Unité de Glycobiologie Structurale et Fonctionnelle-Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
| | - Maryse Moya-Nilges
- Unité Technologie et Service Bioimagerie Ultrastructurale (UTechS UBI), Institut Pasteur, 28 Rue Du Docteur Roux, 75015 Paris, France
| | - John Kenny
- Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork P61 C996 Ireland
- APC Microbiome Ireland, University College Cork, College Road, Cork, T12 YT20 Ireland
| | - Liam O'Mahony
- Department of Medicine, School of Microbiology, APC Microbiome Ireland, University College Cork, Cork T12 Y337 Ireland
| | - Loredana Saveanu
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
| | - Bertrand Arnulf
- AP-HP, Nord/université de Paris, hôpital Saint Louis, Service d'Immuno-Hématologie, Myosotis 4, 75010 Paris, France
| | - Aurélie Sannier
- AP-HP, Nord/université de Paris, hôpital Bichat-Claude Bernard, Service d'Anatomie-Pathologique, 75018 Paris, France
| | - Eric Daugas
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
- AP-HP, Nord/université de Paris, hôpital Bichat-Claude Bernard, Service de Néphrologie, Paris 75018, France
| | - François Vrtovsnik
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
- AP-HP, Nord/université de Paris, hôpital Bichat-Claude Bernard, Service de Néphrologie, Paris 75018, France
| | - Patricia Lepage
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France
| | - Harry Sokol
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, Paris 75012, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris 75012, France
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France
| | - Renato C Monteiro
- Université Paris Cité, INSERM UMR1149 and CNRS EMR8252, Centre de Recherche sur l'Inflammation, Inflamex Laboratory of Excellence, Paris 75018, France
- AP-HP, Nord/université de Paris, hôpital Bichat-Claude Bernard, Service d'Immunologie, 75018 Paris, France
| |
Collapse
|
|
5
|
Shahriari S, Damodara S, Selvaganapathy PR. Isoelectric trapping and discrimination of histones from plasma in a microfluidic device using dehydrated isoelectric gate. Mikrochim Acta 2024; 191:131. [PMID: 38351209 DOI: 10.1007/s00604-024-06223-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024]
Abstract
Histones are basic proteins with an isoelectric point around 11. It has been shown that the level of plasma circulating histones increases significantly during sepsis, and circulating free histones are associated with sepsis severity and mortality. It was found that the median plasma total free histone concentration of sepsis ICU non-survivors is higher compared to survivors. Therefore, histone concentration can serve as a prognostic indicator and there is a need for a simple, low-cost, and rapid method for measuring histone levels. In this work, we have developed a microfluidic device containing an isoelectric membrane made of dehydrated agarose gel of a specific pH embedded in a porous membrane for isoelectric trapping of histones rapidly. Although isoelectric gates have been used for trapping proteins before, they have to be introduced at the time of the experiment. Here, we show that isoelectric gates formed by gels loaded in a scaffold can be integrated directly into the fabrication process flow, dehydrated for storage, and rehydrated during the experiment and still function effectively to achieve isoelectric trapping. A low-cost and rapid microfabrication technique, xurography, was used for agarose integration and device fabrication. The integrated device was tested with samples containing buffered histone, histone in the presence of high-concentration bovine serum albumin (BSA), and histone spiked in blood plasma. The results show that the device can be used to distinguish between survivors and non-survivors of sepsis in less than 10 min, making it suitable as a point-of-care device for sepsis prognosis.
Collapse
Affiliation(s)
- Shadi Shahriari
- Department of Mechanical Engineering, McMaster University, Hamilton, ON, Canada
| | - Sreekant Damodara
- Department of Mechanical Engineering, McMaster University, Hamilton, ON, Canada
| | - P Ravi Selvaganapathy
- Department of Mechanical Engineering, McMaster University, Hamilton, ON, Canada.
- School of Biomedical Engineering, McMaster University, Hamilton, ON, Canada.
| |
Collapse
|
|
6
|
Zhong Z, Li Z, Li Y, Jiang L, Kong Q, Chen W, Feng S. RhoA vesicle trafficking-mediated transglutaminase 2 membrane translocation promotes IgA1 mesangial deposition in IgA nephropathy. JCI Insight 2023; 8:e160374. [PMID: 37811653 PMCID: PMC10619437 DOI: 10.1172/jci.insight.160374] [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: 03/28/2022] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not fully understood. In this study, we found that inhibition of TGase2 activity could dramatically decrease the amount of polymeric IgA1 (pIgA1) isolated from patients with IgAN that interacts with human mesangial cells (HMC). TGase2 was expressed both in the cytosol and on the membrane of HMC. Upon treatment with pIgA1, there were more TGase2 recruited to the membrane. Using a cell model of mesangial deposition of pIgA1, we identified 253 potential TGase2-associated proteins in the cytosolic fraction and observed a higher concentration of cellular vesicles and increased expression of Ras homolog family member A (RhoA) in HMC after pIgA1 stimulation. Both the amount of pIgA1 deposited on HMC and membrane TGase2 level were decreased by inhibition of the vesicle trafficking pathway. Mechanistically, TGase2 was found to be coprecipitated with RhoA in the cellular vesicles. Membrane TGase2 expression was greatly increased by overexpression of RhoA, while it was reduced by knockdown of RhoA. Our in vitro approach demonstrated that TGase2 was transported from the cytosol to the membrane through a RhoA-mediated vesicle-trafficking pathway that can facilitate pIgA1 interaction with mesangium in IgAN.
Collapse
Affiliation(s)
- Zhong Zhong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Zhijian Li
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yanjie Li
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Lanping Jiang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Qingyu Kong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Shaozhen Feng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| |
Collapse
|
|
7
|
Huang J, Qiu Y, Lücke F, Su J, Grundmeier G, Keller A. Multiprotein Adsorption from Human Serum at Gold and Oxidized Iron Surfaces Studied by Atomic Force Microscopy and Polarization-Modulation Infrared Reflection Absorption Spectroscopy. Molecules 2023; 28:6060. [PMID: 37630312 PMCID: PMC10459451 DOI: 10.3390/molecules28166060] [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: 07/20/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Multiprotein adsorption from complex body fluids represents a highly important and complicated phenomenon in medicine. In this work, multiprotein adsorption from diluted human serum at gold and oxidized iron surfaces is investigated at different serum concentrations and pH values. Adsorption-induced changes in surface topography and the total amount of adsorbed proteins are quantified by atomic force microscopy (AFM) and polarization-modulation infrared reflection absorption spectroscopy (PM-IRRAS), respectively. For both surfaces, stronger protein adsorption is observed at pH 6 compared to pH 7 and pH 8. PM-IRRAS furthermore provides some qualitative insights into the pH-dependent alterations in the composition of the adsorbed multiprotein films. Changes in the amide II/amide I band area ratio and in particular side-chain IR absorption suggest that the increased adsorption at pH 6 is accompanied by a change in protein film composition. Presumably, this is mostly driven by the adsorption of human serum albumin, which at pH 6 adsorbs more readily and thereby replaces other proteins with lower surface affinities in the resulting multiprotein film.
Collapse
Affiliation(s)
| | | | | | | | | | - Adrian Keller
- Technical and Macromolecular Chemistry, Paderborn University, Warburger Str. 100, 33098 Paderborn, Germany; (J.H.); (Y.Q.); (F.L.); (J.S.); (G.G.)
| |
Collapse
|
|
8
|
Tamura H. IgA nephropathy associated with Crohn's disease. World J Methodol 2023; 13:67-78. [PMID: 37456980 PMCID: PMC10348078 DOI: 10.5662/wjm.v13.i3.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/16/2023] [Accepted: 05/12/2023] [Indexed: 06/20/2023] Open
Abstract
The relationship between IgA nephropathy (IgAN) and Crohn’s disease was reported. IgAN is the most common primary glomerulonephritis and one of the leading causes of chronic kidney disease and end-stage renal failure, and up to 50% of cases progressed to end-stage renal disease within 25 years after IgAN diagnosis. However, specific and effective therapeutic strategies are still lacking. In this review, we discuss the possibility of the mechanism involved in IgAN associated with Crohn’s disease based on the findings of basic and clinical studies. Although the etiology of IgAN associated with Crohn’s disease is not permanent and various factors are thought to be involved, the stabilization of the disease condition of Crohn’s disease is believed to help treat IgAN.
Collapse
Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
| |
Collapse
|
|
9
|
Mestecky J, Julian BA, Raska M. IgA Nephropathy: Pleiotropic impact of Epstein-Barr virus infection on immunopathogenesis and racial incidence of the disease. Front Immunol 2023; 14:1085922. [PMID: 36865536 PMCID: PMC9973316 DOI: 10.3389/fimmu.2023.1085922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/25/2023] [Indexed: 02/09/2023] Open
Abstract
IgA nephropathy (IgAN) is an autoimmune disease in which poorly galactosylated IgA1 is the antigen recognized by naturally occurring anti-glycan antibodies, leading to formation of nephritogenic circulating immune complexes. Incidence of IgAN displays geographical and racial disparity: common in Europe, North America, Australia, and east Asia, uncommon in African Americans, many Asian and South American countries, Australian Aborigines, and rare in central Africa. In analyses of sera and cells from White IgAN patients, healthy controls, and African Americans, IgAN patients exhibited substantial enrichment for IgA-expressing B cells infected with Epstein-Barr virus (EBV), leading to enhanced production of poorly galactosylated IgA1. Disparities in incidence of IgAN may reflect a previously disregarded difference in the maturation of the IgA system as related to the timing of EBV infection. Compared with populations with higher incidences of IgAN, African Americans, African Blacks, and Australian Aborigines are more frequently infected with EBV during the first 1-2 years of life at the time of naturally occurring IgA deficiency when IgA cells are less numerous than in late childhood or adolescence. Therefore, in very young children EBV enters "non-IgA" cells. Ensuing immune responses prevent infection of IgA B cells during later exposure to EBV at older ages. Our data implicate EBV-infected cells as the source of poorly galactosylated IgA1 in circulating immune complexes and glomerular deposits in patients with IgAN. Thus, temporal differences in EBV primo-infection as related to naturally delayed maturation of the IgA system may contribute to geographic and racial variations in incidence of IgAN.
Collapse
Affiliation(s)
- Jiri Mestecky
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Laboratory of Cellular and Molecular Immunology Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Bruce A. Julian
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Milan Raska
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czechia
| |
Collapse
|
|
10
|
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.
Collapse
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,
| |
Collapse
|
|
11
|
Luvizotto MJ, Menezes-Silva L, Woronik V, Monteiro RC, Câmara NOS. Gut-kidney axis in IgA nephropathy: Role on mesangial cell metabolism and inflammation. Front Cell Dev Biol 2022; 10:993716. [PMID: 36467425 PMCID: PMC9715425 DOI: 10.3389/fcell.2022.993716] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/07/2022] [Indexed: 11/15/2023] Open
Abstract
IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a "gut-kidney axis" is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.
Collapse
Affiliation(s)
- Mateus Justi Luvizotto
- Department of Nephrology, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Luísa Menezes-Silva
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Viktoria Woronik
- Department of Nephrology, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Renato C. Monteiro
- Centre de Recherche sur l’Inflammation, INSERM and CNRS, Université Paris Cité, Paris, France
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| |
Collapse
|
|
12
|
Matsumoto Y, Aryal RP, Heimburg-Molinaro J, Park SS, Wever WJ, Lehoux S, Stavenhagen K, van Wijk JAE, Van Die I, Chapman AB, Chaikof EL, Cummings RD. Identification and characterization of circulating immune complexes in IgA nephropathy. SCIENCE ADVANCES 2022; 8:eabm8783. [PMID: 36306365 PMCID: PMC9616497 DOI: 10.1126/sciadv.abm8783] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 09/12/2022] [Indexed: 05/14/2023]
Abstract
The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.
Collapse
Affiliation(s)
- Yasuyuki Matsumoto
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Rajindra P. Aryal
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jamie Heimburg-Molinaro
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Simon S. Park
- Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Walter J. Wever
- Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Sylvain Lehoux
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Kathrin Stavenhagen
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Joanna A. E. van Wijk
- Department of Pediatric Nephrology, Amsterdam University Medical Centre, location VUmc, Amsterdam, Netherlands
| | - Irma Van Die
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Arlene B. Chapman
- Department of Medicine, Section of Nephrology, University of Chicago School of Medicine, Chicago, IL, USA
| | - Elliot L. Chaikof
- Department of Surgery, Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Wyss Institute of Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Richard D. Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
13
|
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.
Collapse
|
|
14
|
Delapierre A, Terrier B, Pillebout E, Baudart P, Jourde-Chiche N, Lioger B, Martis N, Moulis G, Rivière E, Le Gouellec N, Raffray L, Urbanski G, Sanges S, Maurier F, Deroux A, Mekinian A, Monteiro R, Marcelli C, Guillevin L, Maillot F, Lucas B, Aouba A, Audemard-Verger A. Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement. Clin Rheumatol 2022; 41:1483-1491. [PMID: 35041109 DOI: 10.1007/s10067-021-05937-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 09/01/2021] [Accepted: 09/21/2021] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile. METHODS We analyzed clinical and biological data from a nationwide study that included adult IgAV patients. Presentation and outcomes of patients with or without joint involvement were compared at baseline and during follow-up. Plasma cytokine measurements of IgAV patients included in a prospective study were also analyzed using multiplex assays. RESULTS Among 260 patients, 62% had joint involvement. Among them, rheumatological manifestations included arthralgia (100%) or arthritis (16%), mostly involving the knees and ankles. In multivariate analysis, patients with joint involvement, compared to those without, were younger (p = 0.002; OR 0.87; 95% CI 0.80-0.95) and showed more frequent gastrointestinal tract involvement (p = 0.012; OR = 2.08; 95% CI 1.18-3.67). However, no difference in terms of clinical response, relapse, end-stage renal disease, or death was observed between groups. Among 13 cytokines measured, plasma interleukin (IL)-1β level was higher in patients with joint involvement compared to those without (mean ± SEM IL-1β, 3.5 ± 1.2 vs. 0.47 ± 0.1 pg/ml; p = 0.024) or healthy controls (vs. 1.2 ± 0.5 pg/ml; p = 0.076). CONCLUSION Joint involvement is frequent in adult IgAV and is associated with more frequent gastrointestinal involvement. Increased plasma IL-1β levels raise the question of targeting this cytokine in patients with chronic and/or refractory joint involvement. Key Points • Joint involvement in adult IgAV is a frequent manifestation. • Joint involvement is associated with more frequent gastrointestinal manifestations. • Interleukin-1β (IL-1β) might orchestrate joint inflammation in adult IgAV. • IL-1β might be a therapeutic target in patients with chronic and/or refractory joint involvement.
Collapse
Affiliation(s)
- Alice Delapierre
- Department of Rheumatology, Normandie UNIV, UNICAEN, CHU de Caen Normandie, 14 000, Caen, France
| | - Benjamin Terrier
- Université Paris Descartes, Paris, France.,Department of Internal Medicine, Hôpital Cochin, Paris, France.,National Referral Center for Systemic and Autoimmune Diseases, Hôpital Cochin, Paris, France
| | - Evangéline Pillebout
- Department of Nephrology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Pauline Baudart
- Department of Rheumatology, Normandie UNIV, UNICAEN, CHU de Caen Normandie, 14 000, Caen, France
| | - Noémie Jourde-Chiche
- Aix-Marseille Univ, C2VN, INSERM, INRA, Centre de Néphrologie Et Transplantation Rénale, CHU de La Conception, AP-HM, Marseille, France
| | - Bertrand Lioger
- Department of Internal Medicine, Hôpital Saint Louis, APHP, Paris, France
| | - Nihal Martis
- Department of Internal Medicine, CHU, Nice, France
| | | | | | - Noémie Le Gouellec
- Department of Internal Medicine and Nephrology, Valenciennes, CH, France
| | - Loïc Raffray
- Department of Internal Medicine, CHU, La Réunion, France
| | | | - Sébastien Sanges
- Département de Médecine Interne Et Immunologie Clinique, CHU Lille, 59000, Lille, France.,Univ. Lille, INSERM, U995 - LIRIC - Lille Inflammation Research International Center, Lille, France
| | | | - Alban Deroux
- Department of Internal Medicine, CHU de Grenoble, Grenoble, France
| | - Arsène Mekinian
- Department of Internal Medicine, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Renato Monteiro
- Center of Research On Inflammation INSERM U1149, CNRS ERL8252, Paris Diderot University, Paris, France
| | - Christian Marcelli
- Department of Rheumatology, Normandie UNIV, UNICAEN, CHU de Caen Normandie, 14 000, Caen, France
| | - Loïc Guillevin
- Université Paris Descartes, Paris, France.,Department of Internal Medicine, Hôpital Cochin, Paris, France.,National Referral Center for Systemic and Autoimmune Diseases, Hôpital Cochin, Paris, France
| | - Francois Maillot
- Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France.,University of Tours, Tours, France
| | - Bruno Lucas
- Paris Descartes University, Cochin Institute, CNRS UMR8104, INSERM U1016, Paris, France
| | - Achille Aouba
- Department of Internal Medicine and Clinical Immunology, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000, Caen, France
| | - Alexandra Audemard-Verger
- Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France. .,University of Tours, Tours, France.
| | | |
Collapse
|
|
15
|
Nagasawa Y, Misaki T, Ito S, Naka S, Wato K, Nomura R, Matsumoto-Nakano M, Nakano K. Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis. Int J Mol Sci 2022; 23:725. [PMID: 35054910 PMCID: PMC8775524 DOI: 10.3390/ijms23020725] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 12/23/2022] Open
Abstract
A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.
Collapse
Affiliation(s)
- Yasuyuki Nagasawa
- Department of General Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Hyogo, Japan
| | - Taro Misaki
- Division of Nephrology, Seirei Hamamatsu General Hospital, Hamamatsu 430-8558, Shizuoka, Japan;
- Department of Nursing, Faculty of Nursing, Seirei Christopher University, Hamamatsu 433-8558, Shizuoka, Japan
| | - Seigo Ito
- Department of Internal Medicine, Japan Self-Defense Gifu Hospital, Kakamigahara 502-0817, Gifu, 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.); (R.N.); (K.N.)
| | - 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.); (R.N.); (K.N.)
| | - 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.); (R.N.); (K.N.)
| |
Collapse
|
|
16
|
Haniuda K, Gommerman JL, Reich HN. The microbiome and IgA nephropathy. Semin Immunopathol 2021; 43:649-656. [PMID: 34664087 DOI: 10.1007/s00281-021-00893-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022]
Abstract
The immunopathogenic mechanisms underlying immunoglobulin A nephropathy (IgAN) are poorly understood, yet it is one of the most common causes of kidney failure globally. The commonly referenced syndrome of synpharyngitic gross hematuria as a presenting feature of IgAN has led to a logical association between infections and development of IgAN, however no pathogenic organism has been clearly linked to IgAN. Advances in sequencing technology have enabled more detailed characterization of host microbial communities, and highlighted the interrelationship between microbiota and immune responses in health and disease. This review will summarize current thinking on the relationship between microbiota and development of IgAN with a focus on recent studies relating aberrant mucosal IgA-biased immune responses to microbiota and how this may be related to the immunopathogenesis of IgAN.
Collapse
Affiliation(s)
- Kei Haniuda
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | | | - Heather N Reich
- Division of Nephrology, Department of Medicine, University of Toronto and University Health Network, Toronto, ON, Canada.
| |
Collapse
|
|
17
|
Is complement the main accomplice in IgA nephropathy? From initial observations to potential complement-targeted therapies. Mol Immunol 2021; 140:1-11. [PMID: 34601376 DOI: 10.1016/j.molimm.2021.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/01/2021] [Accepted: 09/17/2021] [Indexed: 12/22/2022]
Abstract
IgA Nephropathy (IgAN) is the main cause of primary glomerulonephritis, globally. This disease is associated with a wide range of clinical presentations, variable prognosis and a spectrum of histological findings. More than fifty years after its first description, this heterogeneity continues to complicate efforts to understand the pathogenesis. Nevertheless, involvement of the complement system in IgAN was identified early on. Dysfunction of the immunoglobulin A (IgA) system, the principal offender in this disease, including modification of isoforms and glycoforms of IgA1, the nature of immune complexes and autoantibodies to galactose deficient IgA1 might all be responsible for complement activation in IgAN. However, the specific mechanisms engaging complement are still under examination. Research in this domain should allow for identification of patients that may benefit from complement-targeted therapy, in the foreseeable future.
Collapse
|
|
18
|
Adhikari J, Rizwan M, Koh D, Keasberry NA, Ahmed MU. Electrochemical Study of Dimensional Specific Carbon Nanomaterials Modified Glassy Carbon Electrode for Highly Sensitive Label-free Detection of Immunoglobulin A. CURR ANAL CHEM 2020. [DOI: 10.2174/1573411015666190925152124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Immunoglobulin A (IgA) accounts for 15% of total protein production per
day and plays a crucial role in the first-line immune defence. Recently, IgA has been established as a
vital clinical biomarker for nephropathy, allergic asthma, celiac disease (CD), pneumonia, and asthma
as well as some neurological disorders. In this work, we have studied several carbon nanomaterials
(CNMs) having different dimensions (D): carbon nano-onions (CNOs) - 0D, single-walled carbon
nanotubes (SWCNTs) - 1D, and graphene nanoplatelets (GNPs) - 2D, on glassy carbon electrode
(GCE) to identify which CNMs (CNOs/SWCNTs/GNPs) work best to fabricate IgA based electrochemical
immunosensor.
Methods:
Different CNMs (CNOs, SWCNTs, GNPs) were tested for high electric current on GCE
using square wave voltammetry (SWV), and among them, GNPs modified GCE platform
(GNPs/GCE) showcased the highest electric current. Therefore, GNPs/GCE was utilized for the development
of highly sensitive label-free electrochemical immunosensor for the detection of Immunoglobulin
A using SWV.
Results:
Despite the simple fabrication strategies employed, the fabricated sensor demonstrated a
low limit of detection of 50 fg mL-1 with an extensive linear range of detection from 50 fg mL-1 to
0.1 μg mL-1.
Conclusion:
Fabricated immunosensor represented high stability, repeatability, specificity and resistance
to most common interferences as well as great potential to analyse the real sample.
Collapse
Affiliation(s)
- Juthi Adhikari
- Faculty of Science, Biosensors and Biotechnology Laboratory, Chemical Science Programme, Universiti Brunei Darussalam. Jalan Tungku Link, Gadong, BE 1410, Brunei, Brunei Darussalam
| | - Mohammad Rizwan
- Faculty of Science, Biosensors and Biotechnology Laboratory, Chemical Science Programme, Universiti Brunei Darussalam. Jalan Tungku Link, Gadong, BE 1410, Brunei, Brunei Darussalam
| | - David Koh
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong, BE 1410, Brunei Darussalam
| | - Natasha Ann Keasberry
- Faculty of Science, Biosensors and Biotechnology Laboratory, Chemical Science Programme, Universiti Brunei Darussalam. Jalan Tungku Link, Gadong, BE 1410, Brunei, Brunei Darussalam
| | - Minhaz Uddin Ahmed
- Faculty of Science, Biosensors and Biotechnology Laboratory, Chemical Science Programme, Universiti Brunei Darussalam. Jalan Tungku Link, Gadong, BE 1410, Brunei, Brunei Darussalam
| |
Collapse
|
|
19
|
Serum Soluble CD89-IgA Complexes Are Elevated in IgA Nephropathy without Immunosuppressant History. DISEASE MARKERS 2020; 2020:8393075. [PMID: 32076466 PMCID: PMC7017530 DOI: 10.1155/2020/8393075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023]
Abstract
Purpose CD89 (FcαRI), the receptor of IgA, can shed from cells to form complexes with IgA in serum and is supposed to participate in the pathogenesis of IgA nephropathy (IgAN). There are contradictory results on their utility in clinical practice. This study is aimed at investigating whether sCD89-IgA complexes can help in the diagnosis or evaluation of the disease. Methods A sandwich ELISA was established using anti-CD89 as a capture antibody and HRP-conjugated anti-IgA as a detection antibody. This method was used to measure serum levels of sCD89-IgA complexes in IgAN patients without immunosuppressant history and healthy subjects. Correlations between serum levels of sCD89-IgA complexes and disease severity were analyzed. Results Serum sCD89-IgA complexes increased with age (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (P < 0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals ( Conclusions Serum sCD89-IgA complexes can guide diagnosis of IgAN in patients without immunosuppressant history, but provide limited help in clinicopathologic prediction.
Collapse
|
|
20
|
Adhikari J, Keasberry NA, Mahadi AH, Yoshikawa H, Tamiya E, Ahmed MU. An ultra-sensitive label-free electrochemiluminescence CKMB immunosensor using a novel nanocomposite-modified printed electrode. RSC Adv 2019; 9:34283-34292. [PMID: 35529968 PMCID: PMC9074035 DOI: 10.1039/c9ra05016g] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/08/2019] [Indexed: 11/23/2022] Open
Abstract
This study presents a novel and ultrasensitive electrochemiluminescence approach for the quantitative assessment of creatine kinase MB (CK-MB). Both carbon, carbon nano-onions (CNOs) and metal-based nanoparticles, such as gold nanoparticles (AuNPs) and iron oxide (Fe3O4), were combined to generate a unique nanocomposite for the detection of CKMB. The immunosensor construction involved the deposition of the nanocomposite on the working electrode, followed by the incubation of an antibody and a blocking agent. Tris(2,2'-bipyridyl)-ruthenium(ii) chloride ([Ru(bpy)3]2+Cl) was used as a luminophore, where tri-n-propylamine (TPrA) was selected as the co-reactant due to its aqueous immobility and luminescence properties. The analytical performance was demonstrated by cyclic voltammetry on ECL. The characterization of each absorbed layer was performed by cyclic voltammetry (CV) and chronocoulometry (CC) techniques in both EC and ECL. For further characterization of iron oxide, gold nanoparticles and carbon nano-onions, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD) were performed. The proposed immunosensor showcases a wide linear range (10 ng mL-1 to 50 fg mL-1), with an extremely low limit of detection (5 fg mL-1). This CKMB immunosensor also exhibits remarkable selectivity, reproducibility, stability and resistance capability towards common interferences available in human serum. In addition, the immunosensor holds great potential to work with real serum samples for clinical diagnosis.
Collapse
Affiliation(s)
- Juthi Adhikari
- Biosensors and Biotechnology Laboratory, Chemical Science Programme, Faculty of Science, Universiti Brunei Darussalam Jalan Tungku Link, Gadong BE 1410 Brunei Darussalam
| | - Natasha Ann Keasberry
- Biosensors and Biotechnology Laboratory, Chemical Science Programme, Faculty of Science, Universiti Brunei Darussalam Jalan Tungku Link, Gadong BE 1410 Brunei Darussalam
| | - Abdul Hanif Mahadi
- Centre for Advanced Material and Energy Sciences, Universiti Brunei Darussalam Tungku Link, Gadong BE1410 Brunei Darussalam
| | - Hiroyuki Yoshikawa
- Nanobioengineering Laboratory, Department of Applied Physics, Graduate School of Engineering, Osaka University 2-1 Yamada-oka, Suita Osaka 565-0871 Japan
| | - Eiichi Tamiya
- Nanobioengineering Laboratory, Department of Applied Physics, Graduate School of Engineering, Osaka University 2-1 Yamada-oka, Suita Osaka 565-0871 Japan
- AIST PhotoBIO-OIL, Osaka University Suita Osaka 565-0871 Japan
| | - Minhaz Uddin Ahmed
- Biosensors and Biotechnology Laboratory, Chemical Science Programme, Faculty of Science, Universiti Brunei Darussalam Jalan Tungku Link, Gadong BE 1410 Brunei Darussalam
| |
Collapse
|
|
21
|
Serum Levels of Joining Chain-Containing IgA1 Are Not Elevated in Patients with IgA Nephropathy. DISEASE MARKERS 2019; 2019:9802839. [PMID: 31354895 PMCID: PMC6636472 DOI: 10.1155/2019/9802839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 03/05/2019] [Accepted: 05/06/2019] [Indexed: 01/21/2023]
Abstract
Background It has been suggested that mesangial IgA deposits are dimeric or polymeric in IgA nephropathy (IgAN). However, evidence concerning the molecular form of serum IgA in IgAN is controversial. And there is no direct evidence that the serum levels of joining chain- (J chain-) containing IgA (J-IgA) are elevated in IgAN. In this study, we aimed to measure serum J-IgA and glomerular J chain deposition with anti-J chain monoclonal antibody in IgAN. Methods BALB/c mice were immunized with human J chain-GST recombinant peptide to obtain anti-J chain monoclonal antibody. The levels of serum total IgA and J-IgA were measured by sandwich enzyme-linked immunosorbent assay in 115 patients with IgAN and 117 healthy volunteers. J chain deposition in kidney specimens was analyzed by immunohistochemistry staining. Results Serum levels of total IgA1 were elevated in IgAN patients compared to healthy subjects. However, serum levels of IgA, J-IgA, and J chain-containing IgA1 (J-IgA1), the J-IgA to total IgA ratio, and the J-IgA1 to total IgA1 ratio were not significantly different between IgAN patients and healthy subjects. Western blot analysis and gel filtration analysis using purified IgA1 also showed that the proportion of J chain-containing polymeric IgA1 was lower in IgAN patients compared to healthy subjects. No correlation was found between serum J-IgA or J-IgA1 and clinical features in IgAN. Immunohistochemistry analysis showed that glomerular J chain was positive in 12 IgAN patients (57.1%). The values of the J-IgA to IgA ratio and J-IgA1 to IgA ratio were significantly higher in IgAN patients with glomerular J chain deposition than those without. However, the serum levels of J-IgA and J-IgA1 and the J-IgA1 to IgA1 ratio were not significantly higher in two subgroups. Conclusions Although serum levels of total IgA1 were elevated in IgAN, the serum levels of J-IgA1 were not elevated. And serum J-IgA, serum J-IgA1, and J chain deposition were not correlated with disease severity in IgAN.
Collapse
|
|
22
|
Wehbi B, Oblet C, Boyer F, Huard A, Druilhe A, Paraf F, Cogné E, Moreau J, El Makhour Y, Badran B, Van Egmond M, Cogné M, Aldigier JC. Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation. J Am Soc Nephrol 2019; 30:1238-1249. [PMID: 31227634 DOI: 10.1681/asn.2018111089] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/10/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits. METHODS To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans. RESULTS We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition. CONCLUSIONS In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
Collapse
Affiliation(s)
- Batoul Wehbi
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France.,Biochemistry Department, Cancer Biology and Molecular Immunology Laboratory, Lebanese University Section I, Beirut, Lebanon
| | - Christelle Oblet
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France
| | - François Boyer
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France
| | - Arnaud Huard
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France
| | - Anne Druilhe
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France
| | - François Paraf
- Anatomy-Histopathology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France
| | - Etienne Cogné
- Nephrology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France
| | - Jeanne Moreau
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France
| | - Yolla El Makhour
- Life and Earth Sciences Department, Environmental Health Research Laboratory, Lebanese University Section V, Nabatieh, Lebanon; and
| | - Bassam Badran
- Biochemistry Department, Cancer Biology and Molecular Immunology Laboratory, Lebanese University Section I, Beirut, Lebanon
| | - Marjolein Van Egmond
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Michel Cogné
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France;
| | - Jean-Claude Aldigier
- Immunology Department, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Santé et de la Recherche Médicale 1262, Limoges University, Limoges, France;
| |
Collapse
|
|
23
|
Guo N, Liu S, Bow LM, Cui X, Zhang L, Xu S, Lu S, Tian J. The protective effect and mechanism of rapamycin in the rat model of IgA nephropathy. Ren Fail 2019; 41:334-339. [PMID: 31057050 PMCID: PMC6507862 DOI: 10.1080/0886022x.2019.1577257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background: The pathogenesis of the development of IgA nephropathy has not been clear up to now. At present, some studies revealed that the mTOR pathway may participate in IgA nephropathy; however, the mechanism has not been systematically studied. In this study, we established an IgAN rat model to investigate the protective effects of rapamycin as a new type of immunosuppressant, as well as its therapeutic mechanisms. Methods: After the establishment of IgA nephropathy model, rats were treated with different concentrations of rapamycin, and the protective effect of different concentrations of rapamycin on renal function of the rats was observed. The deposition of IgA was observed by immunofluorescence. The kidney expression of Akt and p70S6k proteins in mTOR pathway was examined using the western blot assay after rapamycin treatment. Results: Morphology and immunofluorescence confirmed that the rat model of IgA nephropathy was successfully established. In particular, the level of proteinuria decreased with the increase of the dose of rapamycin, as well as the deposition of IgA in glomeruli. Moreover, the western blot analysis indicated that the expression of p70S6K in the downstream of mTOR pathway decreased and the upstream protein AKT of the mTOR pathway was overexpressed in the rats model. Conclusion: We found that rapamycin has protective effects in the IgA nephropathy rat model in a dose-dependent manner. In addition, the result of western blot assay suggested that rapamycin may display its therapeutic effects through interfering the AKT-mTOR-p70S6K signaling pathway.
Collapse
Affiliation(s)
- Ning Guo
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Shengli Liu
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Laurine M Bow
- b Transplant Immunology Laboratory , Hartford Hospital , Hartford , CT , USA.,c Department of Transplantation Surgery , Yale University School of Medicine , New Haven , CT , USA
| | - Xianquan Cui
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Luwei Zhang
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Shihao Xu
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Sai Lu
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| | - Jun Tian
- a Department of Organ Transplantation, Qilu Hospital , Shandong University , Jinan , China
| |
Collapse
|
|
24
|
Monteiro RC. Recent advances in the physiopathology of IgA nephropathy. Nephrol Ther 2018; 14 Suppl 1:S1-S8. [PMID: 29606255 DOI: 10.1016/j.nephro.2018.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 02/01/2018] [Indexed: 01/01/2023]
Abstract
Immunoglobulin A nephropathy or Berger's disease is the most common type of primary glomerulonephritis, which is characterized by IgA1-containing immune-deposits in the glomerular mesangium. Microscopic haematuria and proteinuria are the most common presentations. Mesangial cell proliferation with IgA deposition is found on renal biopsy. Mechanims of the disease implicate at least four key molecules have been implicated in immune complex formation: galactose-deficient IgA1, autoantibodies anti-galactose-deficient-IgA1, soluble CD89 (Fc receptor for IgA) and the CD71 mesangial IgA receptor (transferrin receptor). These factors associated with environmental factors (antigens, food and microbiota) are correlated with disease progression and recurrence after transplantation. This review exploits recent data on the role of these molecular players of the disease, which may improve future therapeutic management of immunoglobulin A nephropathy.
Collapse
Affiliation(s)
- Renato C Monteiro
- Inserm U1149 centre de recherche sur l'inflammation, 16, rue Henri-Huchard, 75018 Paris, France; CNRS ERL8252, 16, rue Henri-Huchard, 75018 Paris, France; Laboratoire d'excellence Inflamex, faculté de médecine Bichat, université Paris-Diderot, 16, rue Henri-Huchard, 75018 Paris, France; Service d'immunologie, DHU Fire, hôpital Bichat, 16, rue Henri-Huchard, 75018 Paris, France.
| |
Collapse
|
|
25
|
Luo YD, Zhang QL, Yao SJ, Lin DQ. Evaluation of adsorption selectivity of immunoglobulins M, A and G and purification of immunoglobulin M with mixed-mode resins. J Chromatogr A 2018; 1533:77-86. [DOI: 10.1016/j.chroma.2017.12.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/07/2017] [Accepted: 12/08/2017] [Indexed: 12/13/2022]
|
|
26
|
Abstract
IgA nephropathy is the most common form of primary glomerulonephritis worldwide and an important cause of chronic kidney disease and end-stage kidney failure. Its pathophysiology remains in part unsolved but it is recognized as an immune complex disease. Recent years have brought progress in the field through the discovery of several genetic susceptibility loci and the formulation of the multi-hit pathogenesis model. Presentation, clinical course and histology can be extremely variable, making any histological classification still difficult. Indeed, most therapeutic studies until now include patients based only on the severity of clinical criteria but the new classification of Oxford should change that. Only the management of patients with nephropathy with minimal change glomerular lesions and nephrotic syndrome, or extra-capillary glomerulonephritis and rapidly progressive renal failure, is consensual: Corticosteroids alone for the first and associated with immunosuppressive drugs for the latter. The recent Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guideline is still controversial, especially in light of the last clinical studies. Corticosteroid therapy can be discussed in patients with proteinuria greater than 1 g/day without renal failure. All IgA nephropathy patients should benefit from the global management of chronic glomerular disease, including a renin-angiotensin system blocker in the presence of hypertension or proteinuria.
Collapse
Affiliation(s)
- Evangéline Pillebout
- Service de néphrologie, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France.
| | - Jérôme Vérine
- Service d'anatomie pathologique, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France
| |
Collapse
|
|
27
|
Molecular Insights into the Pathogenesis of IgA Nephropathy. Trends Mol Med 2015; 21:762-775. [DOI: 10.1016/j.molmed.2015.10.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 10/17/2015] [Accepted: 10/19/2015] [Indexed: 01/04/2023]
|
|
28
|
Lechner SM, Papista C, Chemouny JM, Berthelot L, Monteiro RC. Role of IgA receptors in the pathogenesis of IgA nephropathy. J Nephrol 2015; 29:5-11. [PMID: 26572664 DOI: 10.1007/s40620-015-0246-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 10/29/2015] [Indexed: 11/28/2022]
Abstract
Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end-stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd-IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcαRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment.
Collapse
Affiliation(s)
- Sebastian M Lechner
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1149 Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Inflamex Laboratory of Excellence Site Xavier Bichat, Paris, France.,CNRS ERL8252, Paris, France
| | - Christina Papista
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1149 Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Inflamex Laboratory of Excellence Site Xavier Bichat, Paris, France.,CNRS ERL8252, Paris, France
| | - Jonathan M Chemouny
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1149 Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Inflamex Laboratory of Excellence Site Xavier Bichat, Paris, France.,CNRS ERL8252, Paris, France
| | - Laureline Berthelot
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1149 Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Inflamex Laboratory of Excellence Site Xavier Bichat, Paris, France.,CNRS ERL8252, Paris, France
| | - Renato C Monteiro
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1149 Centre de Recherche sur l'Inflammation, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,Inflamex Laboratory of Excellence Site Xavier Bichat, Paris, France. .,CNRS ERL8252, Paris, France. .,Service d'Immunologie, Assistance Publique de Paris, DHU Fire, Hôpital Bichat, Paris, France.
| |
Collapse
|
|
29
|
Yamaji K, Suzuki Y, Suzuki H, Satake K, Horikoshi S, Novak J, Tomino Y. The kinetics of glomerular deposition of nephritogenic IgA. PLoS One 2014; 9:e113005. [PMID: 25409466 PMCID: PMC4237359 DOI: 10.1371/journal.pone.0113005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 10/17/2014] [Indexed: 11/18/2022] Open
Abstract
Whether IgA nephropathy is attributable to mesangial IgA is unclear as there is no correlation between intensity of deposits and extent of glomerular injury and no clear mechanism explaining how these mesangial deposits induce hematuria and subsequent proteinuria. This hinders the development of a specific therapy. Thus, precise events during deposition still remain clinical challenge to clarify. Since no study assessed induction of IgA nephropathy by nephritogenic IgA, we analyzed sequential events involving nephritogenic IgA from IgA nephropathy-prone mice by real-time imaging systems. Immunofluorescence and electron microscopy showed that serum IgA from susceptible mice had strong affinity to mesangial, subepithelial, and subendothelial lesions, with effacement/actin aggregation in podocytes and arcade formation in endothelial cells. The deposits disappeared 24-h after single IgA injection. The data were supported by a fluorescence molecular tomography system and real-time and 3D in vivo imaging. In vivo imaging showed that IgA from the susceptible mice began depositing along the glomerular capillary from 1 min and accumulated until 2-h on the first stick in a focal and segmental manner. The findings indicate that glomerular IgA depositions in IgAN may be expressed under the balance between deposition and clearance. Since nephritogenic IgA showed mesangial as well as focal and segmental deposition along the capillary with acute cellular activation, all glomerular cellular elements are a plausible target for injury such as hematuria.
Collapse
Affiliation(s)
- Kenji Yamaji
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Hitoshi Suzuki
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Kenji Satake
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Satoshi Horikoshi
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
30
|
Haslene-Hox H, Oveland E, Woie K, Salvesen HB, Tenstad O, Wiig H. Distribution volumes of macromolecules in human ovarian and endometrial cancers--effects of extracellular matrix structure. Am J Physiol Heart Circ Physiol 2014; 308:H18-28. [PMID: 25380817 DOI: 10.1152/ajpheart.00672.2014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Elements of the extracellular matrix (ECM), notably collagen and glucosaminoglycans, will restrict part of the space available for soluble macromolecules simply because the molecules cannot occupy the same space. This phenomenon may influence macromolecular drug uptake. To study the influence of steric and charge effects of the ECM on the distribution volumes of macromolecules in human healthy and malignant gynecologic tissues we used as probes 15 abundant plasma proteins quantified by high-resolution mass spectrometry. The available distribution volume (VA) of albumin was increased in ovarian carcinoma compared with healthy ovarian tissue. Furthermore, VA of plasma proteins between 40 and 190 kDa decreased with size for endometrial carcinoma and healthy ovarian tissue, but was independent of molecular weight for the ovarian carcinomas. An effect of charge on distribution volume was only found in healthy ovaries, which had lower hydration and high collagen content, indicating that a condensed interstitium increases the influence of negative charges. A number of earlier suggested biomarker candidates were detected in increased amounts in malignant tissue, e.g., stathmin and spindlin-1, showing that interstitial fluid, even when unfractionated, can be a valuable source for tissue-specific proteins. We demonstrate that the distribution of abundant plasma proteins in the interstitium can be elucidated by mass spectrometry methods and depends markedly on hydration and ECM structure. Our data can be used in modeling of drug uptake, and give indications on ECM components to be targeted to increase the uptake of macromolecular substances.
Collapse
Affiliation(s)
| | - Eystein Oveland
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Kathrine Woie
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; and
| | - Helga B Salvesen
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; and Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Olav Tenstad
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Helge Wiig
- Department of Biomedicine, University of Bergen, Bergen, Norway;
| |
Collapse
|
|
31
|
Satake K, Shimizu Y, Sasaki Y, Yanagawa H, Suzuki H, Suzuki Y, Horikoshi S, Honda S, Shibuya K, Shibuya A, Tomino Y. Serum under-O-glycosylated IgA1 level is not correlated with glomerular IgA deposition based upon heterogeneity in the composition of immune complexes in IgA nephropathy. BMC Nephrol 2014; 15:89. [PMID: 24928472 PMCID: PMC4064268 DOI: 10.1186/1471-2369-15-89] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Accepted: 06/09/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although serum under-O-glycosylated IgA1 in IgA nephropathy (IgAN) patients may deposit more preferentially in glomeruli than heavily-O-glycosylated IgA1, the relationship between the glomerular IgA deposition level and the O-glycan profiles of serum IgA1 remains obscure. METHODS Serum total under-O-glycosylated IgA1 levels were quantified in 32 IgAN patients by an enzyme-linked immunosorbent assay (ELISA) with Helix aspersa (HAA) lectin. Serum under-O-glycosylated polymeric IgA1 (pIgA1) was selectively measured by an original method using mouse Fcα/μ receptor (mFcα/μR) transfectant and flow cytometry (pIgA1 trap). The percentage area of IgA deposition in the whole glomeruli (Area-IgA) was quantified by image analysis on the immunofluorescence of biopsy specimens. Correlations were assessed between the Area-IgA and data from HAA-ELISA or pIgA1 trap. The relationships between clinical parameters and data from HAA-ELISA or pIgA1 trap were analyzed by data mining approach. RESULTS While the under-O-glycosylated IgA1 levels in IgAN patients were significantly higher than those in healthy controls when measured (p<0.05), there was no significant difference in under-O-glycosylated pIgA1. There was neither a correlation observed between the data from HAA-ELISA and pIgA1 trap (r2=0.09) in the IgAN patients (r2=0.005) nor was there a linear correlation between Area-IgA and data from HAA-ELISA or the pIgA1 trap (r2=0.005, 0.03, respectively). Contour plots of clinical parameters versus data from HAA-ELISA and the pIgA1 trap revealed that patients with a high score in each clinical parameter concentrated in specific areas, showing that patients with specific O-glycan profiles of IgA1 have similar clinical parameters. A decision tree analysis suggested that dominant immune complexes in glomeruli were consisted of: 1) IgA1-IgG and complements, 2) pIgA1 and complements, and 3) monomeric IgA1-IgA or aggregated monomeric IgA1. CONCLUSIONS Serum under-O-glycosylated IgA1 levels are not correlated with glomerular IgA deposition based upon heterogeneity in the composition of glomerular immune complexes in IgAN patients.
Collapse
Affiliation(s)
| | - Yoshio Shimizu
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Takahashi K, Raska M, Stuchlova Horynova M, Hall SD, Poulsen K, Kilian M, Hiki Y, Yuzawa Y, Moldoveanu Z, Julian BA, Renfrow MB, Novak J. Enzymatic sialylation of IgA1 O-glycans: implications for studies of IgA nephropathy. PLoS One 2014; 9:e99026. [PMID: 24918438 PMCID: PMC4053367 DOI: 10.1371/journal.pone.0099026] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 04/23/2014] [Indexed: 11/18/2022] Open
Abstract
Patients with IgA nephropathy (IgAN) have elevated circulating levels of IgA1 with some O-glycans consisting of galactose (Gal)-deficient N-acetylgalactosamine (GalNAc) with or without N-acetylneuraminic acid (NeuAc). We have analyzed O-glycosylation heterogeneity of naturally asialo-IgA1 (Ale) myeloma protein that mimics Gal-deficient IgA1 (Gd-IgA1) of patients with IgAN, except that IgA1 O-glycans of IgAN patients are frequently sialylated. Specifically, serum IgA1 of healthy controls has more α2,3-sialylated O-glycans (NeuAc attached to Gal) than α2,6-sialylated O-glycans (NeuAc attached to GalNAc). As IgA1-producing cells from IgAN patients have an increased activity of α2,6-sialyltransferase (ST6GalNAc), we hypothesize that such activity may promote premature sialylation of GalNAc and, thus, production of Gd-IgA1, as sialylation of GalNAc prevents subsequent Gal attachment. Distribution of NeuAc in IgA1 O-glycans may play an important role in the pathogenesis of IgAN. To better understand biological functions of NeuAc in IgA1, we established protocols for enzymatic sialylation leading to α2,3- or α2,6-sialylation of IgA1 O-glycans. Sialylation of Gal-deficient asialo-IgA1 (Ale) myeloma protein by an ST6GalNAc enzyme generated sialylated IgA1 that mimics the Gal-deficient IgA1 glycoforms in patients with IgAN, characterized by α2,6-sialylated Gal-deficient GalNAc. In contrast, sialylation of the same myeloma protein by an α2,3-sialyltransferase yielded IgA1 typical for healthy controls, characterized by α2,3-sialylated Gal. The GalNAc-specific lectin from Helix aspersa (HAA) is used to measure levels of Gd-IgA1. We assessed HAA binding to IgA1 sialylated at Gal or GalNAc. As expected, α2,6-sialylation of IgA1 markedly decreased reactivity with HAA. Notably, α2,3-sialylation also decreased reactivity with HAA. Neuraminidase treatment recovered the original HAA reactivity in both instances. These results suggest that binding of a GalNAc-specific lectin is modulated by sialylation of GalNAc as well as Gal in the clustered IgA1 O-glycans. Thus, enzymatic sialylation offers a useful model to test the role of NeuAc in reactivities of the clustered O-glycans with lectins.
Collapse
Affiliation(s)
- Kazuo Takahashi
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Milan Raska
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University in Olomouc, Olomouc, Czech Republic
| | - Milada Stuchlova Horynova
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University in Olomouc, Olomouc, Czech Republic
| | - Stacy D. Hall
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Knud Poulsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Mogens Kilian
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Yoshiyuki Hiki
- Fujita Health University School of Health Sciences, Toyoake, Japan
| | - Yukio Yuzawa
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Zina Moldoveanu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Bruce A. Julian
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Matthew B. Renfrow
- UAB Biomedical FT-ICR MS Laboratory, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| |
Collapse
|
|
33
|
Narimatsu Y, Kuno A, Ito H, Kaji H, Kaneko S, Usui J, Yamagata K, Narimatsu H. IgA nephropathy caused by unusual polymerization of IgA1 with aberrant N-glycosylation in a patient with monoclonal immunoglobulin deposition disease. PLoS One 2014; 9:e91079. [PMID: 24651839 PMCID: PMC3961232 DOI: 10.1371/journal.pone.0091079] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 02/07/2014] [Indexed: 11/18/2022] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis characterized by the deposition of IgA immune complexes in the glomerular region. The cause of IgAN is unknown, but multiple mechanisms have been suggested. We previously reported a rare case of mesangioproliferative glomerulonephritis in a patient with monoclonal immunoglobulin deposition disease associated with monoclonal IgA1. In this study, we performed the detailed analyses of serum IgA1 from this patient in comparison with those from patients with mIgA plasma cell disorder without renal involvement and healthy volunteers. We found unusual polymerization of IgA1 with additional N-glycosylation distinctive in this patient, which was different from known etiologies. Glycan profiling of IgA1 by the lectin microarray revealed an intense signal for Wisteria floribunda agglutinin (WFA). This signal was reduced by disrupting the native conformation of IgA1, suggesting that the distinct glycan profile was reflecting the conformational alteration of IgA1, including the glycan conformation detected as additional N-glycans on both the heavy and light chains. This unusually polymerized state of IgA1 would cause an increase of the binding avidity for lectins. WFA specifically recognized highly polymerized and glycosylated IgA1. Our results of analysis in the rare case of a patient with monoclonal immunoglobulin deposition disease suggest that the formation of unusually polymerized IgA1 is caused by divergent mechanisms including multiple structural alterations of glycans, which contributes to IgA1 deposition and mesangium proliferation.
Collapse
Affiliation(s)
- Yoshiki Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Atsushi Kuno
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Hiromi Ito
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
- Department of Biochemistry, Life Sciences and Social Medicine, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hiroyuki Kaji
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Syuzo Kaneko
- Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Joichi Usui
- Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hisashi Narimatsu
- Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
- * E-mail:
| |
Collapse
|
|
34
|
New insights into the pathogenesis of IgA nephropathy. Semin Immunopathol 2014; 36:431-42. [PMID: 24442210 DOI: 10.1007/s00281-013-0411-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 11/26/2013] [Indexed: 01/10/2023]
Abstract
IgA nephropathy (IgAN) is the most common diagnosis amongst primary glomerular diseases in most countries where renal biopsies are regularly performed. Only a fraction of these patients is at high risk of losing glomerular filtration rate (GFR) in particular those with high grade proteinuria, uncontrolled hypertension or already impaired GFR at diagnosis, and those with renal scars in the renal biopsy. Genetic modifiers of IgAN onset and/or course are emerging. Spontaneous animal models of IgAN are problematic given considerable species differences between the rodent and human IgA system. However, new transgenic models help to better understand the pathogenesis. A key pathogenetic role appears to be played by underglycated IgA1 as well as autoantibodies to these IgA glycoforms and IgA receptors such as CD89 and transferrin receptor 1. Once IgA and/or IgA-containing immune complexes are deposited or formed in the mesangium, secondary effector mechanisms become important including complement activation, release of mesangial growth factors (in particular platelet-derived growth factor), and finally non-IgAN-specific events that culminate in glomerular and subsequently renal tubulointerstitial scaring. Here, we review these processes and describe potential novel therapeutic targets in IgAN.
Collapse
|
|
35
|
Ben Mkaddem S, Rossato E, Heming N, Monteiro RC. Anti-inflammatory role of the IgA Fc receptor (CD89): From autoimmunity to therapeutic perspectives. Autoimmun Rev 2013. [DOI: 10.1016/j.autrev.2012.10.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
|
|
36
|
Kolka R, Valdimarsson H, Bodvarsson M, Hardarson S, Jonsson T. Defective immunoglobulin A (IgA) glycosylation and IgA deposits in patients with IgA nephropathy. APMIS 2013; 121:890-7. [DOI: 10.1111/apm.12051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 12/14/2012] [Indexed: 11/29/2022]
|
|
37
|
Berthelot L, Monteiro RC. [Formation of IgA deposits in Berger's disease: what we learned from animal models]. Biol Aujourdhui 2013; 207:241-7. [PMID: 24594572 DOI: 10.1051/jbio/2013022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Indexed: 11/14/2022]
Abstract
Immunoglobulin A (IgA) nephropathy (N) is the most common form of primary glomerulonephritis in the world and one of the first cause of end-stage renal failure. IgAN is characterized by the accumulation in mesangial areas of immune complexes containing IgA1. While epidemiology and clinical studies of IgAN are well-established, the mechanism(s) underlying disease development is poorly understood. The pathogenesis of this disease involves the deposition of polymeric and undergalactosylated IgA1 in the mesangium. Quantitative and structural changes of IgA1 play a key role in the development of the disease, due to functional abnormalities of two IgA receptors: the FcαR (CD89) expressed by blood myeloid cells and the transferrin receptor (TfR1) on mesangial cells. Abnormal IgA induces release of soluble CD89, responsible for the formation of circulating IgA complexes. These complexes are trapped by the TfR1 that is overexpressed on mesangial cells in IgAN patients, inducing the expression of transglutaminase 2. This enzyme stabilises IgA deposits at the surface of mesangial cells. These cells are then activated, proliferate and produce proinflammatory cytokines, leading to the loss of renal function.
Collapse
Affiliation(s)
- Laureline Berthelot
- INSERM U699, Faculté Bichat, 16 rue Henri Huchard, 75018 Paris, France - Université Paris Diderot, Faculté de Médecine, Site Bichat, 16 rue Henri Huchard, 75890 Paris Cedex 18, France - Laboratoire d'Excellence Inflamex, Sorbonne Paris Cité, 75890 Paris Cedex 18, France
| | - Renato C Monteiro
- INSERM U699, Faculté Bichat, 16 rue Henri Huchard, 75018 Paris, France - Université Paris Diderot, Faculté de Médecine, Site Bichat, 16 rue Henri Huchard, 75890 Paris Cedex 18, France - Laboratoire d'Excellence Inflamex, Sorbonne Paris Cité, 75890 Paris Cedex 18, France
| |
Collapse
|
|
38
|
Berthelot L, Papista C, Maciel TT, Biarnes-Pelicot M, Tissandie E, Wang PHM, Tamouza H, Jamin A, Bex-Coudrat J, Gestin A, Boumediene A, Arcos-Fajardo M, England P, Pillebout E, Walker F, Daugas E, Vrtosvnik F, Flamant M, Benhamou M, Cogné M, Moura IC, Monteiro RC. Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. ACTA ACUST UNITED AC 2012; 209:793-806. [PMID: 22451718 PMCID: PMC3328362 DOI: 10.1084/jem.20112005] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Transglutaminase 2 is required for the development of IgA nephropathy. IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA–soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1–sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89–TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1–sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1–sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.
Collapse
Affiliation(s)
- Laureline Berthelot
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 699, Paris 75870, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Novak J, Julian BA, Mestecky J, Renfrow MB. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin Immunopathol 2012; 34:365-82. [PMID: 22434325 DOI: 10.1007/s00281-012-0306-z] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Accepted: 03/02/2012] [Indexed: 12/18/2022]
Abstract
IgA nephropathy, described in 1968 as IgA-IgG immune-complex disease, is an autoimmune disease. Galactose-deficient IgA1 is recognized by unique autoantibodies, resulting in the formation of pathogenic immune complexes that ultimately induce glomerular injury. Thus, formation of the galactose-deficient IgA1-containing immune complexes is a critical factor in the pathogenesis of IgA nephropathy. Studies of molecular defects of IgA1 can define new biomarkers specific for IgA nephropathy that can be developed into clinical assays to aid in the diagnosis, assessment of prognosis, and monitoring of disease progression.
Collapse
Affiliation(s)
- Jan Novak
- University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | | | | | | |
Collapse
|
|
40
|
Floege J. The Pathogenesis of IgA Nephropathy: What Is New and How Does It Change Therapeutic Approaches? Am J Kidney Dis 2011; 58:992-1004. [DOI: 10.1053/j.ajkd.2011.05.033] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 05/26/2011] [Indexed: 02/07/2023]
|
|
41
|
Levy M, Grünfeld JP, Lesavre P. Jean Berger 17 septembre 1930, Valdoie (90) - 22 mai 2011, Paris. Nephrol Ther 2011. [DOI: 10.1016/j.nephro.2011.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
42
|
Boumediene A, Oblet C, Oruc Z, Duchez S, Morelle W, Huynh A, Pourrat J, Aldigier JC, Cogné M. Gammopathy with IgA mesangial deposition provides a monoclonal model of IgA nephritogenicity and offers new insights into its molecular mechanisms. Nephrol Dial Transplant 2011; 26:3930-7. [DOI: 10.1093/ndt/gfr131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
43
|
Hilhorst M, van Paassen P, van Breda Vriesman P, Cohen Tervaert JW. Immune complexes in acute adult-onset Henoch-Schonlein nephritis. Nephrol Dial Transplant 2011; 26:3960-7. [PMID: 21441402 DOI: 10.1093/ndt/gfr149] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Adult-onset Henoch-Schönlein purpura nephritis (HSPN) and primary IgA (IgAN) nephropathy have been considered indistinguishable immunohistopathologically and are often considered as two extremes of one disease entity. We postulate that adult-onset Henoch-Schönlein can be distinguished histologically from primary IgAN and that both diseases differ in their immunopathological mechanisms. METHODS Twenty consecutive patients with adult-onset HSPN were studied. Serum was analysed for circulating IgA immune complexes; renal biopsies were analysed by light and electron microscopy (EM). As disease controls, 40 IgAN patients were studied. RESULTS Intracapillary leukocyte margination was seen in 15 of the 20 patients and cellular crescent formation in all renal biopsies of the HSPN patients. IgAN biopsies showed a few small crescents without intracapillary leukocytes. In 16 HSPN patients, EM was performed and in 10, no dense deposits were found. In all biopsies of IgAN patients, typical 'humps' were found. In 6 of 9 analysed HSPN patients, intermediate to large circulating immune complexes were found, whereas in 4 of 28 analysed patients with primary IgAN small circulating immune complexes were found. CONCLUSIONS We consider adult-onset HSPN distinguishable in histology and ultrastructure from primary IgAN. We believe adult-onset Henoch-Schönlein to be a circulating immune complex disease.
Collapse
Affiliation(s)
- Marc Hilhorst
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | | | | | | |
Collapse
|
|
44
|
Papista C, Berthelot L, Monteiro RC. Dysfunctions of the Iga system: a common link between intestinal and renal diseases. Cell Mol Immunol 2011; 8:126-34. [PMID: 21278767 DOI: 10.1038/cmi.2010.69] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Immunoglobulin A (Iga)-isotype antibodies play an important role in immunity owing to their structure, glycosylation, localization and receptor interactions. Dysfunctions in this system can lead to multiple types of pathology. This review describes the characteristics of Iga and discusses the involvement of abnormalities in the Iga system on the development of celiac disease and Iga nephropathy.
Collapse
|
|
45
|
|
|
46
|
Abstract
IgA nephropathy is the primitive glomerulonephritis the most frequently encountered worldwide. In about one case out of three, it is responsible for the progression from progressive renal failure to end-stage renal failure. The pathophysiological mechanisms of this disease which is mediated by immune complexes remain unclear. The presentation, clinical progression and optical microscope aspect of the renal biopsy may widely vary, making any histological classification very difficult. Most therapeutic studies include the patients only on clinical criteria of severity. The only consensual management is that of patients with a nephropathy and mild glomerular lesions and a nephritic syndrome, or with an extracapillar glomerulonephritis and a rapidly progressive renal failure; corticoids are indicated in former cases while corticoids must be combined with immunosuppressive agents in the latter ones. Corticotherapy may be considered in patients with a proteinuria higher than 1g/day without renal failure. In any patient with primitive IgA nephropathy, the overall management used for chronic glomerulopathy must be initiated, including, in case of arterial hypertension or proteinuria, the renin-angiotensin system blockade.
Collapse
|
|
47
|
Role of IgA and IgA fc receptors in inflammation. J Clin Immunol 2009; 30:1-9. [PMID: 19834792 DOI: 10.1007/s10875-009-9338-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Accepted: 09/24/2009] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Signals delivered by serum monomeric IgA (mIgA) are essential in controlling the immune system by preventing the development of autoimmunity and inflammation. However, IgA can also, when aggregated, be deleterious to the host, inducing inflammatory diseases. This Janus-like nature of IgA is mainly due to their heterogeneity in molecular forms and their interaction with IgA receptors. DISCUSSION While serum mIgA are mainly involved in FcalphaRI-mediated inhibition of immune responses, macromolecular serum IgA or circulating IgA immune complexes are often deleterious to the host by inducing sustained activation through IgA receptors including FcalphaRI and transferrin receptor. CONCLUSION FcalphaRI-mediated inhibitory function is able to suppress several inflammatory diseases in mice including asthma and glomerulonephritis. Intravenous mIgA (mIgAIV) and anti-FcalphaR monovalent antibodies represent thus promising tools for immunotherapy.
Collapse
|
|
48
|
Moura IC, Benhamou M, Launay P, Vrtovsnik F, Blank U, Monteiro RC. The glomerular response to IgA deposition in IgA nephropathy. Semin Nephrol 2008; 28:88-95. [PMID: 18222350 DOI: 10.1016/j.semnephrol.2007.10.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Compelling evidence points to a role for IgA receptors in the pathogenesis of IgA nephropathy. The soluble form of the type I IgA receptor (FcalphaRI or CD89) forms complexes with IgA that can be found in patients' serum and that initiate the disease in CD89 transgenic mice. A nonclassic IgA receptor, identified as the transferrin receptor (TfR), is highly expressed in patients' mesangium and colocalizes with IgA deposits. TfR preferentially binds polymeric IgA1 complexes, but not monomeric IgA1 or IgA2. The TfR-IgA1 interaction is dependent on carbohydrate moieties because hypoglycosylated IgA1 has superior binding to TfR than normally glycosylated IgA1. Polymeric IgA1 binding enhances mesangial cell TfR expression and results in cell proliferation and inflammatory and profibrogenic cytokine and chemokine production, suggesting a pivotal role in mesangial cell proliferation, matrix expansion, and recruitment of inflammatory cells. We propose that, as a second event, activation of the classic, FcRgamma-associated transmembrane FcalphaRI expressed on circulating myeloid leukocytes takes place. FcalphaRI/gamma2 cross-linking in human FcalphaRI transgenic animals promotes disease progression by enhancing leukocyte chemotaxis and cytokine production, and IgA immune complexes from IgA nephropathy patients induce FcalphaRI-dependent cell activation. This review therefore details the functional consequences of IgA/receptor interactions and discusses proposed mechanisms to explain the development and chronicity of the disease.
Collapse
|
|
49
|
Almogren A, Kerr MA. Irreversible aggregation of the Fc fragment derived from polymeric but not monomeric serum IgA1—Implications in IgA-mediated disease. Mol Immunol 2008; 45:87-94. [PMID: 17606293 DOI: 10.1016/j.molimm.2007.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 05/08/2007] [Accepted: 05/09/2007] [Indexed: 11/23/2022]
Abstract
IgA is by far the most abundant immunoglobulin in humans. It is found in serum and in secretions (SIgA). Unlike any other class of immunoglobulin, each form of IgA occurs naturally in different polymerisation states. In serum, the predominant form of IgA is IgA1 of which around 90% is monomeric and 10% is dimeric or polymeric. The proportion of dimeric/polymeric IgA increases in a number of important diseases, such as IgA nephropathy and in chronic liver disease. In both, there is evidence that further aggregation of dimeric/polymeric IgA is the cause of the characteristic tissue deposition. To investigate the effect of role of IgA polymerisation on the structure and function of IgA, we purified different molecular forms of IgA1 from myeloma serum (monomer, dimer and trimer) and SIgA1 from colostrum. Structural features of these different IgA1 forms were examined following proteolysis using Neisseria gonorrhoeae IgA1 type 2 protease and Streptococcus pneumoniae IgA1 protease. These IgA1 proteases cleave IgA1 at the hinge region and produce Fcalpha and Fab fragments. Western blot analysis demonstrated that the Fcalpha fragments of serum dimeric and trimeric but not monomeric IgA1 aggregated to form multimers resistant to disruption in SDS-PAGE under non-reducing conditions. Size exclusion chromatography under native conditions of cleaved serum dimeric IgA1 demonstrated that aggregation occurs because of structural changes in the IgA per se and was not an effect of the SDS-PAGE system. In the same assay, SIgA1 (dimeric) did not aggregate after digestion. The results suggest an important, previously unrecognised, property of dimeric/polymeric serum IgA1, which might explain its propensity to aggregate and deposit in tissues.
Collapse
Affiliation(s)
- Adel Almogren
- Department of Pathology, Immunology Unit, College of Medicine and King Khalid University Hospital, P.O. Box 2925, Riyadh 11461, Saudi Arabia
| | | |
Collapse
|
|
50
|
Oortwijn BD, Eijgenraam JW, Rastaldi MP, Roos A, Daha MR, van Kooten C. The Role of Secretory IgA and Complement in IgA Nephropathy. Semin Nephrol 2008; 28:58-65. [DOI: 10.1016/j.semnephrol.2007.10.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
|