Tracking the Antibody Immunome in Type 1 Diabetes Using Protein Arrays.
We performed an unbiased proteome-scale profiling of humoral autoimmunity in recent-onset type 1 diabetes (T1D) patients and nondiabetic controls against ∼10 000 human proteins using a Nucleic Acid Programmable Protein Array (NAPPA) platform, complemented by a knowledge-based selection of proteins from genes enriched in human pancreas. Although the global response was similar between cases and controls, we identified and then validated six specific novel T1D-associated autoantibodies (AAbs) with sensitivities that ranged from 16 to 27% at 95% specificity. These included AAbs against PTPRN2, MLH1, MTIF3, PPIL2, NUP50 (from NAPPA screening), and QRFPR (by targeted ELISA). Immunohistochemistry demonstrated that NUP50 protein behaved differently in islet cells, where it stained both nucleus and cytoplasm, compared with only nuclear staining in exocrine pancreas. Conversely, PPIL2 staining was absent in islet cells, despite its presence in exocrine cells. The combination of anti-PTPRN2, -MLH1, -PPIL2, and -QRFPR had an AUC of 0.74 and 37.5% sensitivity at 95% specificity. These data indicate that these markers behave independently and support the use of unbiased screening to find biomarkers because the majority was not predicted based on predicted abundance. Our study enriches the knowledge of the "autoantibody-ome" in unprecedented breadth and width.
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Xiaofang
X
Bian
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida 32603, United States.
Clive
C
Wasserfall
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Garrick
G
Wallstrom
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Jie
J
Wang
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Haoyu
H
Wang
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Kristi
K
Barker
Department of Pediatrics, College of Medicine, University of Florida , Gainesville, Florida 30607, United States.
Desmond
D
Schatz
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida 32603, United States.
Mark
M
Atkinson
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Ji
J
Qiu
The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University , Tempe, Arizona 85287, United States.
Joshua
J
LaBaer
D000293:Adolescent; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002648:Child; D021983:Cyclophilins / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D008297:Male; D000070957:MutL Protein Homolog 1 / Q000235:genetics / Q000276:immunology*; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D040081:Protein Array Analysis; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D012680:Sensitivity and Specificity; D055815:Young Adult
D001323:Autoantibodies; D015415:Biomarkers; C501486:MLH1 protein, human; C476582:QRFPR protein, human; D043562:Receptors, G-Protein-Coupled; C102889:PTPRN2 protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D000070957:MutL Protein Homolog 1; D021983:Cyclophilins; C099773:PPIL2 protein, human
autoantibody (AAb); biomarkers; nucleic acid programmable protein array (NAPPA); protein array; type 1 diabetes (T1D)