Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Chromogranin A and IAPP - Autoantigens for CD4 T Cells (#43)

Kathryn Haskins 1
  1. U. Colorado School of Medicine, Denver, CO, United States

We have taken a proteomics approach to the identification of autoantigens in NOD beta cell extracts, using a panel of pathogenic CD4 T cell clones for detection of antigenic proteins.   This work has led to the recent discovery of two new autoantigens - chromogranin A (ChgA) and islet amyloid polypeptide (IAPP) -  for CD4 T cells in the NOD mouse.  Using tetramers consisting of I-Ag7 complexed with either a BDC-2.5 peptide mimotope or a highly antigenic peptide from IAPP, we have been investigating the role of T cells reactive to ChgA and IAPP in the NOD mouse.   T cells reactive to these antigens are readily detected in the pancreas of pre-diabetic and diabetic NOD mice and can be expanded from spleen upon stimulation of antigen, suggesting that autoreactive CD4 T cells specific for these antigens may be useful indicators of the disease process.  We have now confirmed that a peptide from ChgA is antigenic for T cells from human T1D patients and future work will be directed toward determining whether T cells in humans directed to ChgA and IAPP can serve as biomarkers of human disease.  Another important rationale for investigating autoantigens in T1D lies in their potential for therapy and antigen-specific approaches are being pursued as a means of inducing tolerance in a number of autoimmune diseases.  We have data to indicate that a peptide from ChgA not only prevents transfer of disease by diabetogenic ChgA-reactive T cell clones, but can also reverse disease in new onset diabetic mice and prevent graft rejection.  Future directions of our work include further analysis of ChgA and IAPP-reactive T cells in NOD mice and human patients to establish their role as biomarkers and targets of antigen-specific tolerance induction.  In addition, we are endeavoring to find answers to the critically important issue of autoantigen generation in the islet beta cell and how peptides from these antigens become ligands for T cells.  We have found that cross-linking of peptide monomers or aggregation of peptide with other proteins can lead to increased antigenicity and we hypothesize that aberrant aggregation of proteins in beta cells could provide a source of neo-antigen peptides.