Chromogranin A is a T cell antigen in human type 1 diabetes.
Chromogranin A (ChgA) is a beta cell secretory granule protein and a peptide of ChgA, WE14, was recently identified as a ligand for diabetogenic CD4 T cell clones derived from the NOD mouse. In this study we compared responses of human CD4 T cells from recent onset type 1 diabetic (T1D) and control subjects to WE14 and to an enzymatically modified version of this peptide. T cell responders to antigens were detected in PBMCs from study subjects by an indirect CD4 ELISPOT assay for IFN-γ. T1D patients (n = 27) were recent onset patients within one year of diagnosis, typed for HLA-DQ8. Controls (n = 31) were either 1st degree relatives with no antibodies or from the HLA-matched general population cohort of DAISY/TEDDY. A second cohort of patients (n = 11) and control subjects (n = 11) was tested at lower peptide concentrations. We found that WE14 is recognized by T cells from diabetic subjects vs. controls in a dose dependent manner. Treatment of WE14 with transglutaminase increased reactivity to the peptide in some patients. This work suggests that ChgA is an important target antigen in human T1D subjects and that post-translational modification may play a role in its reactivity and relationship to disease.
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Peter.Gottlieb@UCDenver.edu.
Peter A
PA
Gottlieb
Integrated Department of Immunology, University of Colorado at Denver School of Medicine and National Jewish Health, 1400 Jackson Street, Denver, CO 80205, USA. Electronic address: Thomas.Delong@UCDenver.edu.
Thomas
T
Delong
Integrated Department of Immunology, University of Colorado at Denver School of Medicine and National Jewish Health, 1400 Jackson Street, Denver, CO 80205, USA. Electronic address: Rocky.Baker@UCDenver.edu.
Rocky L
RL
Baker
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Lisa.Fitzgerald-Miller@UCDenver.edu.
Lisa
L
Fitzgerald-Miller
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Rebecca.Wagner@UCDenver.edu.
Rebecca
R
Wagner
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Gabrielle.Cook@UCDenver.edu.
Gabrielle
G
Cook
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Marian.Rewers@UCDenver.edu.
Marian R
MR
Rewers
Barbara Davis Center for Diabetes, 1775 Aurora Ct, Aurora, CO 80045, USA. Electronic address: Aaron.Michels@UCDenver.edu.
Aaron
A
Michels
Integrated Department of Immunology, University of Colorado at Denver School of Medicine and National Jewish Health, 1400 Jackson Street, Denver, CO 80205, USA. Electronic address: Katie.Haskins@UCDenver.edu.
Kathryn
K
Haskins
D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002648:Child; D053379:Chromogranin A / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D061251:Primary Cell Culture; D011503:Transglutaminases / Q000378:metabolism / Q000494:pharmacology
D001324:Autoantigens; D015704:CD4 Antigens; C506150:CHGA protein, human; D053379:Chromogranin A; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D010455:Peptides; D011503:Transglutaminases
Autoantigen; Autoreactive CD4 T cells; Chromogranin A; Human; Post-translational modification; Type 1 diabetes