Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading.

Kerry A McLaughlin, Carolyn C Richardson, Stefan Williams, Ezio Bonifacio, Diana Morgan, Richard G Feltbower, Michael Powell, Bernard Rees Smith, Jadwiga Furmaniak, Michael R Christie

Clinical immunology (Orlando, Fla.) 2015 Oct

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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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Kerry A McLaughlin, Carolyn C Richardson, Stefan Williams, Ezio Bonifacio, Diana Morgan, Richard G Feltbower, Michael Powell, Bernard Rees Smith, Jadwiga Furmaniak, Michael R Christie. Relationships between major epitopes of the IA-2 autoantigen in Type 1 diabetes: Implications for determinant spreading. Clinical immunology (Orlando, Fla.). 2015 Oct;160(2):226-36