The HLA-DRB1*15:01-restricted Goodpasture's T cell epitope induces GN.
J Am Soc Nephrol
; 24(3): 419-31, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-23411782
ABSTRACT
Human anti-glomerular basement membrane (GBM) disease strongly associates with HLA-DRB1*1501. 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*1501 transgenic mice with whole recombinant α3(IV)NC1 and with overlapping α3(IV)NC1 peptides, we defined a HLA-DRB1*1501-restricted α3(IV)NC1 T cell epitope (α3136-146) with four critical residues. This peptide was not immunogenic in HLA-DRB1*0101 transgenic or C57BL/6 mice. The T cell epitope is naturally processed from α3(IV)NC1. CD4(+) T cell clones, generated from HLA-DRB1*1501 transgenic mice and specific for α3136-146, transferred disease into naive HLA-DRB1*1501 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*1501 transgenic FcγRIIb-deficient mice, but HLA-DRB1*0101 transgenic FcγRIIb-deficient mice were unaffected. Taken together, these results demonstrate that the HLA-DRB1*1501-restricted T cell epitope α3136-146 can induce T cell responses and injury in anti-GBM GN.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autoantígenos
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Doença Antimembrana Basal Glomerular
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Colágeno Tipo IV
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Cadeias HLA-DRB1
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Am Soc Nephrol
Assunto da revista:
NEFROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Austrália