T-cell epitope of α3 chain of type IV collagen induces severe glomerulonephritis

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

doi:10.1046/j.1523-1755.2003.00227.x

Cited by 48 publications

(64 citation statements)

References 38 publications

(597 reference statements)

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“…None of the peptides induced clinical signs of EAG and neither focal necrotizing nor crescentic GN was seen by histology. Our findings are in line with the results reported in the HLA-DRB1*15:01 transgenic mouse model, but the findings in mice contrast to the results obtained in WKY rats, where a single immunization with an immunodominant peptide is sufficient to induce crescentic GN (21,(26)(27)(28). Immune responses launch dose-dependently.…”

Section: Discussionsupporting

confidence: 92%

“…These epitopes differed from those recently described in a human HLA-DRB1*15:01-restricted transgenic mouse model of anti-GBM disease and from T cell epitopes identified in HLA-DR15 + patients with Goodpasture's disease (7,21). Interestingly, P05 includes the dominant epitope found in the WKY rat EAG model (26)(27)(28).…”

Section: Discussionmentioning

confidence: 59%

“…Compared to the immunizations with complete m-a3IV-NC1, we used a 50-fold peptide dose (∼1 nmol versus ∼50 nmol). It was comparable to the dose used in the transgenic mouse study, and related to the body weight it was higher than the ones used in the WKY rat studies (21,(26)(27)(28). It is interesting that the extreme susceptibility of WKY rats for EAG is dependent on non-MHC genes and in particular the Fcgr3 has been shown to be relevant in the context of crescentic GN (29,30).…”

Section: Discussionmentioning

confidence: 75%

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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: 92%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 75%

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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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“…Studies in Wky rats have demonstrated the capacity of recombinant ␣3(IV)NC1 to elicit nephri-togenic responses (59) and the ability of transferred Th1 cell lines to induce crescentic disease in the absence of glomerular antibody deposition (60), confirming the primary role of autoreactive T cells in this model of autoimmune crescentic GN. Peptide mapping has defined a potent T cell epitope pCol (28 -40) that induced severe glomerulonephritis in rats (61).…”

Section: T Cells In Autoimmune Anti-gbm Gnmentioning

confidence: 99%

T Cells in Crescentic Glomerulonephritis

Tipping

Holdsworth

2006

Journal of the American Society of Nephrology

159

149

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G lomerulonephritis (GN) is not a single disease but shows a variety of histologic patterns, clinical features, and outcomes that indicate multiple pathogenic mechanisms. A pivotal role for adaptive immune responses in initiation of GN has been demonstrated in experimental models, but across the spectrum of human GN, direct evidence of immune pathogenesis is more variable. The strongest case that adaptive immune responses drive nephritogenic events in glomeruli in humans has been mounted in crescentic GN, and evidence for involvement of autoimmunity, either organspecific autoimmunity to glomerular antigens (e.g., anti-glomerular basement membrane [anti-GBM] GN) or systemic autoimmunity to nonglomerular antigens (e.g., ANCA-associated crescentic GN, lupus nephritis) now is emerging for many forms of human crescentic GN. CD4 ϩ T cells play a central role in adaptive immunity. T cell-independent responses are uncommon. They usually are associated with simple carbohydrate-rich antigens and do not show extensive Ig isotype switching or strong affinity maturation. The known antigens that drive crescentic GN show strong evidence of CD4 ϩ T cell dependence and do not have the characteristics of T-independent antigens. The evidence from glomerular pathology also suggests a prominent role for local CD4 ϩ T cell-driven Th1-type responses in crescentic GN with delayed-type hypersensitivity (DTH)-like cellular effectors (T cells and macrophages) as well as Th1 Ig isotypes in glomeruli.The relative contributions of cellular and humoral CD4 ϩ T cell-driven effectors, particularly in ANCA-associated GN, remains controversial, but it is clear that the nephritogenic immune responses are CD4 ϩ T cell-driven.

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“…Direct evidence comes from the passive transfer studies showing that in the absence of anti-GBM antibodies, the antigen-specific CD4 + T cells per se could initiate kidney injury (18). Subsequent studies have successfully identified a 13-mer peptide, pCol (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), that could induce autoantibodies against the peptide itself, autoreactive CD4 + T cell proliferation, and severe crescentic GN in Wistar Kyoto rats (19). Moreover, this pathogenic linear epitope could also trigger a diversified anti-GBM antibody response through intramolecular and intermolecular B cell epitope spreading (20).…”

Section: Introductionmentioning

confidence: 99%

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

Jia

Cui²,

Yang³

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Linear epitopes on the Goodpasture autoantigen involved in human anti-glomerular basement membrane (GBM) disease are not fully defined. This study investigated the linear epitopes recognized by circulating antibodies in anti-GBM patients, aiming to identify the potential nephrogenic linear epitopes and their clinical significance.Design, setting, participants, & measurements Sixty-eight patients with anti-GBM disease were enrolled. Twentyfour overlapping linear peptides were synthesized across the whole sequence of the human Goodpasture autoantigen. ELISA detected circulating antibodies against linear epitopes. Their associations with clinical features were further analyzed.Results Antibodies against linear peptides were detected in sera from 55 patients (80.9%). Three major epitopes with high frequencies were identified: P14 (41%), P16 (36.8%), and P18 (57%). P14, a formerly defined T cell epitope, was a mutual B cell epitope. Antibodies against P14 were frequently detected in patients with positive antineutrophil cytoplasmic antibodies (39.3% versus 12.5%; P=0.01). Patients with anti-P16 antibodies presented with higher serum creatinine on diagnosis (665.56227.2 versus 443.76296.8 mmol/L; P=0.001) and worse renal outcome during follow-up (hazard ratio, 2.10; 95% confidence interval, 1.10-3.90; P=0.02). The level of anti-P18 antibodies positively correlated with the percentage of crescents in glomeruli (r=0.54; P=0.008). Recognition of P22 was an independent predictor for patient death (hazard ratio, 3.02; 95% confidence interval, 1.20-7.57; P=0.02).Conclusions Antibodies against linear epitopes on the Goodpasture autoantigen could be detected in human anti-GBM disease and were associated with kidney injury. P14 was a mutual T and B cell epitope, implying its nephrogenic role in disease initiation.

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T-cell epitope of α3 chain of type IV collagen induces severe glomerulonephritis

Abstract: Our study not only demonstrated that a single T-cell epitope of Col4alpha3NC1 is sufficient to induce severe glomerulonephritis, but also provides a unique model for studying T-cell-mediated mechanisms in anti-GBM glomerulonephritis pathogenesis.

Cited by 48 publications

References 38 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 Cells in Crescentic Glomerulonephritis

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

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