Murine Membranous Nephropathy: Immunization with α3(IV) Collagen Fragment Induces Subepithelial Immune Complexes and FcγR-Independent Nephrotic Syndrome

Malekpour, Mahdi; Luo, Weijia; Ge, Lite; Olaru, Florina; Wang, Xuping; Bah, Maimouna; Sado, Yoshikazu; Heidet, Laurence; Kleinau, Sandra; Fogo, Agnes B.; Borza, Dorin-Bogdan

doi:10.4049/jimmunol.1103368

Cited by 25 publications

(36 citation statements)

References 63 publications

(67 reference statements)

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“…Although two immunizations were sufficient to induce membranous glomerulopathy, additional immunizations were required to transform the phenotype toward a focal necrotizing or even crescentic GN without notable differences in the a3IV-NC1-specific Ab response. This result is in accordance with a recent study from Zhang et al (17) in which DBA/1 mice received two immunizations with human a3IV-NC1. In contrast to the typically linear deposition of Abs in human anti-GBM GN, DBA/1 mice develop a membranous phenotype after immunization with mouse or human a3IV-NC1 (14,15,17).…”

Section: Discussionsupporting

confidence: 93%

“…In contrast to the typically linear deposition of Abs in human anti-GBM GN, DBA/1 mice develop a membranous phenotype after immunization with mouse or human a3IV-NC1 (14,15,17). Therefore, a solid Ab response appears to be sufficient to induce membranous glomerulopathy, which is mediated by immune complex deposition as well as in situ formation (17).…”

Section: Discussionmentioning

confidence: 99%

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Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Hopfer

Hünemörder

Treder

et al. 2015

The Journal of Immunology

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Mouse experimental autoimmune glomerulonephritis, a model of human antiglomerular basement membrane disease, depends on both Ab and T cell responses to the Goodpasture Ag noncollagenous domain 1 of the α3-chain of type IV collagen (α3IV-NC1). The aim of our study was to further characterize the T cell–mediated immune response. Repeated immunization with mouse α3IV-NC1 caused fatal glomerulonephritis in DBA/1 mice. Although two immunizations were sufficient to generate high α3IV-NC1–specific IgG titers, Ab and complement deposition along the glomerular basement membranes, and a nephrotic syndrome, two additional immunizations were needed to induce a necrotizing/crescentic glomerulonephritis. Ten days after the first immunization, α3IV-NC1–specific CD4+ cells producing TNF-α, IFN-γ, or IL-17A were detected in the spleen. With the emergence of necrotizing/crescentic glomerulonephritis, ∼0.15% of renal CD4+ cells were specific for α3IV-NC1. Using peptides spanning the whole α3IV-NC1 domain, three immunodominant T cell epitopes were identified. Immunization with these peptides did not lead to clinical signs of experimental autoimmune glomerulonephritis or necrotizing/crescentic glomerulonephritis. However, mice immunized with one of the peptides (STVKAGDLEKIISRC) developed circulating Abs against mouse α3IV-NC1 first detected at 8 wk, and 50% of the mice showed mild proteinuria at 18–24 wk due to membranous glomerulopathy. Taken together, our results suggest that autoreactive T cells are able to induce the formation of pathologic autoantibodies. The quality and quantity of α3IV-NC1–specific Ab and T cell responses are critical for the phenotype of the glomerulonephritis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Hopfer

Hünemörder

Treder

et al. 2015

The Journal of Immunology

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“…Blood and spot urine were collected as described. 15,33 Mice were euthanized at 14 weeks after immunization. Blood and kidneys were collected for further analyses.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…For IgG imaging studies, DBA/1J mice immunized with a3NC1, as described, 15 were euthanized 8 weeks later. To model the glomerular deposition of anti-GBM IgG autoantibodies, DBA/1 mice were injected intravenously with mouse IgG anti-a3NC1 mAb 8D1 (200 mg in sterile PBS) and euthanized the next day.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…At 14 weeks after a3NC1 immunization, kidneys examined by light microscopy showed mild glomerular pathology, with few crescents and relatively little inflammation (Figure 2A), similar to a3NC1-immunized DBA/1 mice with comparable albuminuria. 14,15 Electron microscopy showed extensive subepithelial IC deposits surrounded by an expanded GBM and effacement of podocyte foot processes in a3NC1-immunized B6 Because the clinical presentation, morphology, and effector mechanisms depend on where ICs are localized in the capillary wall, we compared IgG distribution in a3NC1-immunized mice and mice injected with anti-a3NC1 antibodies modeling anti-GBM autoantibodies. The distribution and relative abundance of mouse IgG, as imaged by immunoperoxidase immunoelectron microscopy and stochastic optical reconstruction microscopy (STORM), a method for superresolution fluorescence microscopy, were concordant.…”

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confidence: 99%

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Neonatal Fc Receptor Promotes Immune Complex–Mediated Glomerular Disease

Olaru

Luo

Suleiman³

et al. 2014

Journal of the American Society of Nephrology

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The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the a3 chain of type IV collagen (a3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with a3NC1 developed no albuminuria and had lower levels of serum IgG anti-a3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-a3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.

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A Review on Drug‐Induced Nephrotoxicity: Pathophysiological Mechanisms, Drug Classes, Clinical Management, and Recent Advances in Mathematical Modeling and Simulation Approaches

Mody

Ramakrishnan

Chaar

et al. 2020

Clinical Pharm in Drug Dev

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A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited. Thus, drug-induced nephrotoxicity remains a major clinical challenge. Prior knowledge of risk factors associated with special patient populations and specific classes of drugs, combined with early diagnosis, therapeutic drug monitoring with dose adjustments, as well as timely prospective treatments are essential to prevent and manage them better. Most incident drug-induced renal toxicity is reversible only if diagnosed at an early stage and treated promptly. Hence, diagnosis at an early stage is the need of the hour to counter it. Significant recent advances in the identification of novel early biomarkers of nephrotoxicity are not beyond limitations. In such a scenario, mathematical modeling and simulation (M&S) approaches may help to better understand and predict toxicities in a clinical setting. This review summarizes pathophysiological mechanisms of drug-induced nephrotoxicity, classes of nephrotoxic drugs, management, prevention, and diagnosis in clinics. Finally, it also highlights some of the recent advancements in mathematical M&S approaches that could be used to better understand and predict drug-induced nephrotoxicity.

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Murine Membranous Nephropathy: Immunization with α3(IV) Collagen Fragment Induces Subepithelial Immune Complexes and FcγR-Independent Nephrotic Syndrome

Cited by 25 publications

References 63 publications

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

Neonatal Fc Receptor Promotes Immune Complex–Mediated Glomerular Disease

A Review on Drug‐Induced Nephrotoxicity: Pathophysiological Mechanisms, Drug Classes, Clinical Management, and Recent Advances in Mathematical Modeling and Simulation Approaches

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