{"doi":"10.2337/db23-0622","title":"An Insulin-Chromogranin A Hybrid Peptide Activates DR11-Restricted T Cells in Human Type 1 Diabetes","abstract":"Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule peptides are detectable within murine and human islets. The 2.5HIP (C-peptide-chromogranin A [CgA] HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in the nonobese diabetic mouse. However, the relevance of this epitope in human disease is currently unclear. A recent study probed T-cell reactivity toward HIPs in patients with type 1 diabetes, documenting responses in one-third of the patients and isolating several HIP-reactive T-cell clones. In this study, we isolated a novel T-cell clone and showed that it responds vigorously to the human equivalent of the 2.5HIP (designated HIP9). Although the responding patient carried the risk-associated DRB1*04:01/DQ8 haplotype, the response was restricted by DRB1*11:03 (DR11). HLA class II tetramer staining revealed higher frequencies of HIP9-reactive T cells in individuals with diabetes than in control participants. Furthermore, in DR11+ participants carrying the DRB4 allele, HIP9-reactive T-cell frequencies were higher than observed frequencies for the immunodominant proinsulin 9-28 epitope. Finally, there was a negative correlation between HIP9-reactive T-cell frequency and age at diagnosis. These results provide direct evidence that this C-peptide-CgA HIP is relevant in human type 1 diabetes and suggest a mechanism by which nonrisk HLA haplotypes may contribute to the development of β-cell autoimmunity.","journal":"Diabetes","year":2024,"id":452860,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":357605,"name":"Perrin Guyer","orcid":null,"position":1,"is_corresponding":false},{"id":356452,"name":"Rocky L. Baker","orcid":"0000-0001-8361-8655","position":2,"is_corresponding":false},{"id":1275453,"name":"Joylynn Gallegos","orcid":null,"position":3,"is_corresponding":false},{"id":699768,"name":"Anita C. Hohenstein","orcid":"0000-0002-3655-6276","position":4,"is_corresponding":false},{"id":336608,"name":"Peter A. Gottlieb","orcid":"0000-0002-7601-8536","position":5,"is_corresponding":false},{"id":418338,"name":"Chantal Mathieu","orcid":"0000-0002-6099-2406","position":6,"is_corresponding":false},{"id":457127,"name":"Lut Overbergh","orcid":"0000-0001-7126-356X","position":7,"is_corresponding":false},{"id":356453,"name":"Kathryn Haskins","orcid":"0000-0002-5430-6254","position":8,"is_corresponding":false},{"id":108429,"name":"Eddie A. James","orcid":"0000-0002-7217-5729","position":9,"is_corresponding":false},{"id":458089,"name":"Aïsha Callebaut","orcid":null,"position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T02:02:54.415477Z","pmid":"38295386","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}