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Proinsulin C-peptide is an autoantigen in people with type 1 diabetes.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Oct 16; Vol. 115 (42), pp. 10732-10737. Date of Electronic Publication: 2018 Oct 01. - Publication Year :
- 2018
-
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 <superscript>+</superscript> T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI <subscript>33-63</subscript> ), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4 <superscript>+</superscript> T cells in people with T1D. CD4 <superscript>+</superscript> 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 <superscript>+</superscript> 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-DQ8 trans , or HLA-DQ2 trans , 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 <superscript>+</superscript> 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 <superscript>+</superscript> T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.<br />Competing Interests: Conflict of interest statement: A provisional patent has been filed by St. Vincent’s Institute to protect the use of full-length C-peptide in T cell assays and antigen-specific therapies (2017904853).
- Subjects :
- Adolescent
Adult
Cells, Cultured
Child
Child, Preschool
Diabetes Mellitus, Type 1 immunology
Diabetes Mellitus, Type 1 metabolism
Humans
Middle Aged
Young Adult
Autoantigens immunology
C-Peptide immunology
C-Peptide metabolism
CD4-Positive T-Lymphocytes immunology
Diabetes Mellitus, Type 1 diagnosis
HLA Antigens immunology
Islets of Langerhans immunology
Proinsulin immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 42
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 30275329
- Full Text :
- https://doi.org/10.1073/pnas.1809208115