The Fine Specificity and Cytokine Profile of T-Helper Cells Responsive to the α3 Chain of Type IV Collagen in Goodpasture’s Disease

Cairns, Lindsay S.; Phelps, R.G.; Bowie, Laura; Hall, Andrew M.; Saweirs, Walaa W M; Rees, Andrew J.; Barker, Robert N.

doi:10.1097/01.asn.0000091588.80007.0e

Cited by 70 publications

(112 citation statements)

References 35 publications

(173 reference statements)

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“…Three major linear epitopes were identified with high frequencies of recognition: P14, P16, and P18. Second, a mutual T and B cell epitope, P14, was revealed in patients with anti-GBM disease, which was not only a target antigen of circulating antibodies found in this study but was also a formerly defined T cell epitope in Goodpasture patients (22). Third, the frequencies and levels of antibodies against linear epitopes were found, for the first time, to be associated with the severity of kidney injury of anti-GBM patients.…”

Section: Discussionsupporting

confidence: 52%

“…P14, amino acid residues 129-150, was formerly defined as a T cell epitope that could stimulate peripheral CD4 + T cell proliferation in Goodpasture patients (22). Previous studies have demonstrated that P14 contained the core sequence with highest predicted binding affinity with HLA-DR15 (25,26), which was proven to be the genetic marker for susceptibility to anti-GBM disease.…”

Section: Discussionmentioning

confidence: 99%

“…High frequencies of recognition were found for three linear peptides: P14 (41.2%), P16 (36.8%), and P18 (57.4%) ( Table 1, Figure 1). Among them, P14 contained the immunodominant region E B (7) and was proven to be one of the T cell epitopes in patients with Goodpasture disease (22). The recognition for other linear peptides was lower, ranging from 1.5% to 22.1%.…”

Section: Frequencies Of Serum Antibodies Recognizing Each Linear Peptidementioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Frequencies Of Serum Antibodies Recognizing Each Linear Peptidementioning

confidence: 99%

See 1 more Smart Citation

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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“…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%

“…Diagnosis is based on the detection of circulating autoantibodies and their deposition along the GBMs (3,4). The major autoantigen is the noncollagenous domain 1 of the a3-chain of type IV collagen (a3IV-NC1), which is targeted by both Abs and T cells (5)(6)(7). The role of the T cells in the initiation and progression of crescentic GN is still incompletely understood (8,9).…”

mentioning

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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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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Regulatory T cells in renal disease

et al. 2018

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The kidney is vulnerable to injury, both acute and chronic from a variety of immune and metabolic insults, all of which at least to some degree involve inflammation. Regulatory T cells modulate systemic autoimmune and allogenic responses in glomerulonephritis and transplantation. Intrarenal regulatory T cells (Tregs), including those recruited to the kidney, have suppressive effects on both adaptive and innate immune cells, and probably also intrinsic kidney cells. Evidence from autoimmune glomerulonephritis implicates antigen‐specific Tregs in HLA‐mediated dominant protection, while in several human renal diseases Tregs are abnormal in number or phenotype. Experimentally, Tregs can protect the kidney from injury in a variety of renal diseases. Mechanisms of Treg recruitment to the kidney include via the chemokine receptors CCR6 and CXCR3 and potentially, at least in innate injury TLR9. The effects of Tregs may be context dependent, with evidence for roles for immunoregulatory roles both for endogenous Tbet‐expressing Tregs and STAT‐3‐expressing Tregs in experimental glomerulonephritis. Most experimental work and some of the ongoing human trials in renal transplantation have focussed on unfractionated thymically derived Tregs (tTregs). However, induced Tregs (iTregs), type 1 regulatory T (Tr1) cells and in particular antigen‐specific Tregs also have therapeutic potential not only in renal transplantation, but also in other kidney diseases.

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The Fine Specificity and Cytokine Profile of T-Helper Cells Responsive to the α3 Chain of Type IV Collagen in Goodpasture’s Disease

Cited by 70 publications

References 35 publications

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

Antibodies against Linear Epitopes on the Goodpasture Autoantigen and Kidney Injury

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

Regulatory T cells in renal disease

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