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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Autoantibodies / immunology*
  • Autoantigens / immunology
  • Autoimmunity / immunology
  • B-Lymphocytes / immunology*
  • Child
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes / immunology
  • Humans
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology*
  • T-Lymphocytes / immunology*
  • Young Adult

Substances

  • Autoantibodies
  • Autoantigens
  • Epitopes
  • ICA512 autoantibody
  • PTPRN protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8