Lars Henrik Fugger

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Joshua D Ooi
  • ,
  • Janet Chang
  • ,
  • Kim M O'Sullivan
  • ,
  • Vadim Pedchenko
  • ,
  • Billy G Hudson
  • ,
  • Arthur A Vandenbark
  • ,
  • Lars Fugger
  • Stephen R Holdsworth
  • ,
  • A Richard Kitching
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 α3 chain of type IV collagen, α3(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 α3(IV)NC1 and with overlapping α3(IV)NC1 peptides, we defined a HLA-DRB1*15:01-restricted α3(IV)NC1 T cell epitope (α3136-146) 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 α3(IV)NC1. CD4(+) T cell clones, generated from HLA-DRB1*15:01 transgenic mice and specific for α3136-146, 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 Fcγ receptors are implicated in disease susceptibility, we crossed HLA transgenic mice onto an FcγRIIb-deficient background. Immunization with either α3136-146 or α3(IV)NC1 induced GN in HLA-DRB1*15:01 transgenic FcγRIIb-deficient mice, but HLA-DRB1*01:01 transgenic FcγRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*15:01-restricted T cell epitope α3136-146 can induce T cell responses and injury in anti-GBM GN.
Original languageEnglish
JournalJournal of the American Society of Nephrology
Volume24
Issue3
Pages (from-to)419-31
Number of pages13
ISSN1046-6673
DOIs
Publication statusPublished - Feb 2013

    Research areas

  • Amino Acid Sequence, Animals, Anti-Glomerular Basement Membrane Disease, Autoantigens, Autoimmunity, Collagen Type IV, Disease Models, Animal, Epitopes, T-Lymphocyte, HLA-DRB1 Chains, Humans, Immunization, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Sequence Data, Receptors, IgG, Recombinant Fusion Proteins

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