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Clin Immunol. 2015 Oct;160(2):226-36. doi: 10.1016/j.clim.2015.06.002. Epub 2015 Jun 9.

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

Author information

1
Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK.
2
Center for Regenerative Therapies, Fetscherstrasse 105, 01317 Dresden, Germany.
3
Division of Epidemiology, School of Medicine, Worsley Building, University of Leeds, LS2 9JT, UK.
4
FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK.
5
Division of Diabetes & Nutritional Sciences, Hodgkin Building, King's College London Guy's Campus, London SE1 1UL, UK. Electronic address: mchristie@lincoln.ac.uk.

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.

KEYWORDS:

Autoantibody; Determinant spreading; Epitope; Monoclonal antibody; Type 1 diabetes

PMID:
26071317
DOI:
10.1016/j.clim.2015.06.002
[Indexed for MEDLINE]
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