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

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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

Original languageEnglish
Pages (from-to)226-236
Number of pages11
JournalCLINICAL IMMUNOLOGY
Volume160
Issue number2
DOIs
Published1 Oct 2015

King's Authors

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.

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