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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.

Original publication

DOI

10.1016/j.clim.2015.06.002

Type

Journal article

Journal

Clin Immunol

Publication Date

10/2015

Volume

160

Pages

226 - 236

Keywords

Autoantibody, Determinant spreading, Epitope, Monoclonal antibody, Type 1 diabetes, Adolescent, Adult, Amino Acid Sequence, Autoantibodies, Autoantigens, Autoimmunity, B-Lymphocytes, Child, Diabetes Mellitus, Type 1, Epitopes, Humans, Receptor-Like Protein Tyrosine Phosphatases, Class 8, T-Lymphocytes, Young Adult