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

Ooi JD, Chang J, O'Sullivan KM, Pedchenko V, Hudson BG, Vandenbark AA, Fugger L, Holdsworth SR, Kitching AR
J Am Soc Nephrol. 2013 24 (3): 419-31

PMID: 23411782 · PMCID: PMC3582203 · DOI:10.1681/ASN.2012070705

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.

MeSH Terms (18)

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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