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 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.
authors: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia.
authors: Joshua D
authors: JD
authors: Ooi
authors: Janet
authors: J
authors: Chang
authors: Kim M
authors: KM
authors: O'Sullivan
authors: Vadim
authors: V
authors: Pedchenko
authors: Billy G
authors: BG
authors: Hudson
authors: Arthur A
authors: AA
authors: Vandenbark
authors: Lars
authors: L
authors: Fugger
authors: Stephen R
authors: SR
authors: Holdsworth
authors: A Richard
authors: AR
authors: Kitching
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D018984:Epitopes, T-Lymphocyte; C080571:Fc gamma receptor IIB; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C057112:type IV collagen alpha3 chain