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

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

Research output: Contribution to journalArticle

44 Scopus citations

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 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 transgenicmice 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 a3(IV)NC1. CD4+ T cell clones, generated from HLADRB1* 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 FcγRIIbdeficient 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 (US)
Pages (from-to)419-431
Number of pages13
JournalJournal of the American Society of Nephrology
Volume24
Issue number3
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'The HLA-DRB1*15:01-restricted goodpasture's T cell epitope induces GN'. Together they form a unique fingerprint.

  • Cite this

    Ooi, J. D., Chang, J., O'Sullivan, K. M., Pedchenko, V., Hudson, B. G., Vandenbark, A. A., Fugger, L., Holdsworth, S. R., & Kitching, A. R. (2013). The HLA-DRB1*15:01-restricted goodpasture's T cell epitope induces GN. Journal of the American Society of Nephrology, 24(3), 419-431. https://doi.org/10.1681/ASN.2012070705