title: Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading.
abstract: Diversification of autoimmunity to islet autoantigens is critical for progression to Type 1 diabetes. B-cells participate in diversification by modifying antigen processing, thereby influencing which peptides are presented to T-cells. In Type 1 diabetes, JM antibodies are associated with T-cell responses to PTP domain peptides. We investigated whether this is the consequence of close structural alignment of JM and PTP domain determinants on IA-2. Fab fragments of IA-2 antibodies with epitopes mapped to the JM domain blocked IA-2 binding of antibodies that recognise epitopes in the IA-2 PTP domain. Peptides from both the JM and PTP domains were protected from degradation during proteolysis of JM antibody:IA-2 complexes and included those representing major T-cell determinants in Type 1 diabetes. The results demonstrate close structural relationships between JM and PTP domain epitopes on IA-2. Stabilisation of PTP domain peptides during proteolysis in JM-specific B-cells may explain determinant spreading in IA-2 autoimmunity.
authors.affiliation: Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: McLaughlin
authors.affiliation: Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Richardson
authors.affiliation: Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Williams
authors.affiliation: Center for Regenerative Therapies, Fetscherstrasse 105, 01317 Dresden, Germany.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.affiliation: Division of Epidemiology, School of Medicine, Worsley Building, University of Leeds, LS2 9JT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Division of Epidemiology, School of Medicine, Worsley Building, University of Leeds, LS2 9JT, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Feltbower
authors.affiliation: FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Powell
authors.affiliation: FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Rees Smith
authors.affiliation: FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Furmaniak
authors.affiliation: Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK. Electronic address: mchristie@lincoln.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Christie
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; C096322:ICA512 autoantibody; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
keywords: Autoantibody; Determinant spreading; Epitope; Monoclonal antibody; Type 1 diabetes