Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 419 - 431 |
| Number of pages | 13 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2013 |
Cite this
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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 journal › Article › Research › peer-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 -