Fine mapping of diabetes-associated IA-2 specific autoantibodies

Massimo Bearzatto, Vito Lampasona, Cristina Belloni, Ezio Bonifacio

Research output: Contribution to journalArticle

Abstract

The related tyrosine phosphatase-like proteins (PTP) IA-2 and IA-2β are autoantigens of type 1 diabetes. Autoantibodies are predominantly against IA-2. We utilized the close homology between IA-2 and IA-2β PTP domains to design chimeras and mutants in order to identify humoral IA-2-specific epitopes. Fifteen sera with antibodies to IA-2 specific PTP domain epitopes were tested against IA-2β741-848/IA-2795-889/IA-2β 943-1033, IA-2β741-848/IA-2795-845/IA- 2β900-1033, and IA-2β741-898/IA-2 845-875/IA-2β930-1033chimeras. Two sera bound IA-2β741-848/IA-2795-889/IA-2β 943-1033and IA-2β741-848/IA-2795-845/IA- 2β900-1033only indicating that the IA-2 specific residues 859, 862, and/or 867 were critical for antibody binding. Mutation of glutamine 862 abolished binding in one of these sera. Seven sera bound only the IA-2β741-848/IA-2795-889/IA-2β 943-1033chimera, indicating that binding required IA-2 specific amino acids within both 795-845 and 846-875, or that IA-2 residues 876-888 were important for binding. Mutation of glutamine 862 abolished binding in two of these sera, and mutation of residues 876, 877, 878, and 880 markedly reduced binding in two others. Six sera bound all three chimeras indicating that they contained multiple IA-2 specific PTP domain antibodies. In three of these sera, mutation of residues at positions 876, 877, 878, 880, and/or residues 862 and 822 reduced antibody binding by more than 50%. These findings indicate that glutamine at position 862, and residues 876-880 of the WPD loop of IA-2 are important for several of the IA-2 specific PTP domain epitopes.

Original languageEnglish
Pages (from-to)377-382
Number of pages6
JournalJournal of Autoimmunity
Volume21
Issue number4
DOIs
Publication statusPublished - Dec 2003

Keywords

  • Antigens/peptides/epitopes
  • Autoantibodies
  • Autoimmunity
  • Diabetes
  • Protein phosphatases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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