The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN

Joshua Ooi, Janet Chang, Kim O'Sullivan, Vadim Pedchenko, Billy G Hudson, Arthur A Vandenbark, Lars Fugger, Stephen Roger Holdsworth, Arthur Richard Kitching

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*15:01. The target autoantigen in this disease is the noncollagenous domain of the alpha3 chain of type IV collagen, alpha3(IV)NC1, but critical early T cell epitopes presented by this human MHC class II molecule are unknown. Here, by immunizing HLA-DRB1*15:01 transgenic mice with whole recombinant alpha3(IV)NC1 and with overlapping alpha3(IV)NC1 peptides, we defined a HLA-DRB1*15:01-restricted alpha3(IV)NC1 T cell epitope (alpha3) with four critical residues. This peptide was not immunogenic in HLA-DRB1*01:01 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from alpha3(IV)NC1. CD4 T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for alpha3, transferred disease into naive HLA-DRB1*15:01 transgenic mice, evidenced by the development of necrotizing crescentic GN, albuminuria, renal impairment, and accumulation of CD4 T cells and macrophages in glomeruli. Because Fcgamma receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcgammaRIIb-deficient background. Immunization with either alpha3 or alpha3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcgammaRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcgammaRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01-restricted T cell epitope alpha3 can induce T cell responses and injury in anti-GBM GN.
Original languageEnglish
Pages (from-to)419 - 431
Number of pages13
JournalJournal of the American Society of Nephrology
Volume24
Issue number3
DOIs
Publication statusPublished - 2013

Cite this

@article{00d00736f1724763a7f529729c899293,
title = "The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN",
abstract = "Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*15:01. The target autoantigen in this disease is the noncollagenous domain of the alpha3 chain of type IV collagen, alpha3(IV)NC1, but critical early T cell epitopes presented by this human MHC class II molecule are unknown. Here, by immunizing HLA-DRB1*15:01 transgenic mice with whole recombinant alpha3(IV)NC1 and with overlapping alpha3(IV)NC1 peptides, we defined a HLA-DRB1*15:01-restricted alpha3(IV)NC1 T cell epitope (alpha3) with four critical residues. This peptide was not immunogenic in HLA-DRB1*01:01 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from alpha3(IV)NC1. CD4 T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for alpha3, transferred disease into naive HLA-DRB1*15:01 transgenic mice, evidenced by the development of necrotizing crescentic GN, albuminuria, renal impairment, and accumulation of CD4 T cells and macrophages in glomeruli. Because Fcgamma receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcgammaRIIb-deficient background. Immunization with either alpha3 or alpha3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcgammaRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcgammaRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01-restricted T cell epitope alpha3 can induce T cell responses and injury in anti-GBM GN.",
author = "Joshua Ooi and Janet Chang and Kim O'Sullivan and Vadim Pedchenko and Hudson, {Billy G} and Vandenbark, {Arthur A} and Lars Fugger and Holdsworth, {Stephen Roger} and Kitching, {Arthur Richard}",
year = "2013",
doi = "10.1681/ASN.2012070705",
language = "English",
volume = "24",
pages = "419 -- 431",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "3",

}

The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN. / Ooi, Joshua; Chang, Janet; O'Sullivan, Kim; Pedchenko, Vadim; Hudson, Billy G; Vandenbark, Arthur A; Fugger, Lars; Holdsworth, Stephen Roger; Kitching, Arthur Richard.

In: Journal of the American Society of Nephrology, Vol. 24, No. 3, 2013, p. 419 - 431.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN

AU - Ooi, Joshua

AU - Chang, Janet

AU - O'Sullivan, Kim

AU - Pedchenko, Vadim

AU - Hudson, Billy G

AU - Vandenbark, Arthur A

AU - Fugger, Lars

AU - Holdsworth, Stephen Roger

AU - Kitching, Arthur Richard

PY - 2013

Y1 - 2013

N2 - Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*15:01. The target autoantigen in this disease is the noncollagenous domain of the alpha3 chain of type IV collagen, alpha3(IV)NC1, but critical early T cell epitopes presented by this human MHC class II molecule are unknown. Here, by immunizing HLA-DRB1*15:01 transgenic mice with whole recombinant alpha3(IV)NC1 and with overlapping alpha3(IV)NC1 peptides, we defined a HLA-DRB1*15:01-restricted alpha3(IV)NC1 T cell epitope (alpha3) with four critical residues. This peptide was not immunogenic in HLA-DRB1*01:01 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from alpha3(IV)NC1. CD4 T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for alpha3, transferred disease into naive HLA-DRB1*15:01 transgenic mice, evidenced by the development of necrotizing crescentic GN, albuminuria, renal impairment, and accumulation of CD4 T cells and macrophages in glomeruli. Because Fcgamma receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcgammaRIIb-deficient background. Immunization with either alpha3 or alpha3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcgammaRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcgammaRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01-restricted T cell epitope alpha3 can induce T cell responses and injury in anti-GBM GN.

AB - Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*15:01. The target autoantigen in this disease is the noncollagenous domain of the alpha3 chain of type IV collagen, alpha3(IV)NC1, but critical early T cell epitopes presented by this human MHC class II molecule are unknown. Here, by immunizing HLA-DRB1*15:01 transgenic mice with whole recombinant alpha3(IV)NC1 and with overlapping alpha3(IV)NC1 peptides, we defined a HLA-DRB1*15:01-restricted alpha3(IV)NC1 T cell epitope (alpha3) with four critical residues. This peptide was not immunogenic in HLA-DRB1*01:01 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from alpha3(IV)NC1. CD4 T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for alpha3, transferred disease into naive HLA-DRB1*15:01 transgenic mice, evidenced by the development of necrotizing crescentic GN, albuminuria, renal impairment, and accumulation of CD4 T cells and macrophages in glomeruli. Because Fcgamma receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcgammaRIIb-deficient background. Immunization with either alpha3 or alpha3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcgammaRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcgammaRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01-restricted T cell epitope alpha3 can induce T cell responses and injury in anti-GBM GN.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23411782

U2 - 10.1681/ASN.2012070705

DO - 10.1681/ASN.2012070705

M3 - Article

VL - 24

SP - 419

EP - 431

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 3

ER -