title: Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes.
abstract: Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking. Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8+T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.|Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maria J L
authors.initials: MJ
authors.lastname: Kracht
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Antoinette M
authors.initials: AM
authors.lastname: Joosten
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.affiliation: Center for Proteomics &Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.affiliation: Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Zaldumbide
authors.affiliation: Departments of Immunohematology &Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.|Department of Diabetes Immunology, Diabetes &Metabolism Research Institute at the Beckman Diabetes Research Institute, City of Hope, Duarte, California, USA.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000276:immunology; D008297:Male; D016366:Open Reading Frames; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; D006683:HLA-DQ Antigens; D007328:Insulin; D010455:Peptides; D012333:RNA, Messenger