RESUMEN
CD8+ T cells destroy insulin-producing pancreatic ß cells in type 1 diabetes through HLA class I-restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.
Asunto(s)
Diabetes Mellitus Tipo 1 , Antígeno HLA-A24 , Insulina , Precursores de Proteínas , Receptores de Antígenos de Linfocitos T , Humanos , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/genética , Precursores de Proteínas/inmunología , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Insulina/inmunología , Insulina/metabolismo , Antígeno HLA-A24/inmunología , Antígeno HLA-A24/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Linfocitos T CD8-positivos/inmunología , Femenino , MasculinoRESUMEN
OBJECTIVES: To evaluate the usefulness and effectiveness of a new structured education module for children with type 1 diabetes: Structured Education Reassuring Empowering Nurturing (SEREN) 'Diabetes at Diagnosis'. DESIGN: Retrospective questionnaire-based service evaluation. SETTING: 12/14 paediatric diabetes centres across Wales took part. PARTICIPANTS: Children diagnosed with type 1 diabetes 1 year before (pre-SEREN group) and 1 year after the introduction of SEREN (post-SEREN group) were selected using a national diabetes register. RESOURCE: 'Diabetes at Diagnosis' delivers structured education to empower children and families with self-management of type 1 diabetes. EVALUATION: Primary outcomes were patient-reported effectiveness and user-friendliness of the educational resources and quality of life (PedsQL). Age-appropriate child and parent questionnaires were provided. Clinical outcomes included glycated haemoglobin (HbA1c) at 6 and 12 months, service engagement and diabetes-related hospital admissions in the first year. RESULTS: 89/106 responded pre-SEREN and 108/115 post-SEREN, with no demographic differences at diagnosis. Parent scores for educational package evaluation significantly improved post-SEREN, with a non-significant trend towards improved results in children. PedsQL scores were similar. There was no change in HbA1c overall. Subgroup analyses at 12 months showed a trend towards a lower HbA1c in key stage 1-2 (62 vs 58 mmol/mol, p=0.06) and increased HbA1c in key stage 3-4 (56 vs 66 mmol/mol, p=0.009). There were no differences in hospital admissions or missed clinic appointments. CONCLUSIONS: This is an evaluation of the only standardised type 1 diabetes structured education programme in use for children throughout Wales. This module improved parent-reported outcomes and showed a non-significant trend towards improved usefulness in children, without a difference in a PedsQL scores overall. Ongoing evaluation of the cohort who received subsequent SEREN modules may show the long-term benefit of the programme.