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

- Epitopes for MoAbs to IA-2 JM domain contain regions 611-616 and 635-636.
- Epitope for MoAbs to IA-2 PTP domain contains a core region 831-859.
- MoAbs to IA-2 JM domain blocks binding of PTP domain MoAbs.
- JM MoAbs stabilise PTP domain peptides during Ab-antigen processing.
- Structural relationships between JM and PTP domains may explain epitope spreading.

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.