CD4+ T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis

Wu, Jean; Hicks, John; Borillo, Jason; Glass, William F.; Lou, Yahuan

doi:10.1172/jci200213876

Cited by 81 publications

(183 citation statements)

References 32 publications

(18 reference statements)

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“…Although the renal CD3 cell count and its strong correlation with the percentage of glomerular crescents hint at a causal relationship, transfer experiments are necessary to prove this point. Indeed, T cell transfers in WKY rats or in HLA-DRB1*15:01 transgenic mice have also suggested a direct participation of T cells in the emergence of crescentic GN (20,21). Our results also support studies in the EAG and the nephrotoxic nephritis model, which suggest a role of both Th1 and Th17 cells in the development of crescentic GN (15,(20)(21)(22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 86%

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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: 86%

“…Our results as well as T cell transfer assays in mouse and rat EAG suggest that T cells may be the principal mediators of crescent formation and subsequent/associated tubulointerstitial damage (15,20,21). However, we failed to detect crescentic GN in P71-immunized mice despite the induction of P71-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 55%

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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“…In rodent models of anti-GBM nephritis, nearly half of the rats immunized with rCol43NC1 developed severe glomerulonephritis and lacked IgG deposition in the kidneys (Wu et al, 2001). rCol43NC1-specific T cells have been identified as having a direct pathogenic role in initiating glomerular injury in the absence of autoantibodies (Wu et al, 2002). The therapeutic intervention by the depletion of CD8 + cells using monoclonal antibodies could block crescent formation and glomerulonephritis development in the models without significantly affecting the circulating levels of antibodies (Reynolds et al, 2002;Kawasaki et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…In rodent models, 3(IV)NC1-specific CD4 + T cells alone are sufficient to induce glomerular injury in the absence of autoantibodies against GBM, revealing a direct pathogenic role (Wu et al, 2002). The disease cannot be induced in CD4 + and CD8 + T cell knockout mice (Tipping et al, 1998) and is inhibited by CD28-B7 and CD154-CD40 co-stimulatory blockades (Reynolds et al, 2000(Reynolds et al, , 2004 as well as anti-CD8 monoclonal antibodies (Reynolds et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

Jia²,

Li³

et al. 2016

Sci. China Life Sci.

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“…Disregard of the cause, binding of immunoglobulins to the GBM activates the complement system and a cascade of proteases, which results in disruption of the glomerular filtration barrier followed by proteinuria and formation of glomerular crescent. The cell-mediated immunoreactivity by CD4+ and CD8+ T cells is soon followed by migration of macrophages and neutrophils into the glomerulus causing further inflammation and increased proteinuria which lead to interstitial nephritis (Kitching et al, 2002;Remuzzi and Bertani, 1998;Timoshanko et al, 2001;Wu et al, 2001Wu et al, , 2002.…”

Section: Goodpasture's Syndromementioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

539

476

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Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated α-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter-and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

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CD4+ T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis

Cited by 81 publications

References 32 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

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

Mammalian collagen IV

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