Proinsulin C-peptide is an autoantigen in people with type 1 diabetes.
Proc Natl Acad Sci U S A
; 115(42): 10732-10737, 2018 10 16.
Article
em En
| MEDLINE
| ID: mdl-30275329
ABSTRACT
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI33-63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide-specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide-specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proinsulina
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Autoantígenos
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Peptídeo C
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Linfócitos T CD4-Positivos
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Ilhotas Pancreáticas
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Diabetes Mellitus Tipo 1
/
Antígenos HLA
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Child
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Child, preschool
/
Humans
/
Middle aged
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Austrália