title: Discovery of Phosphorylated Peripherin as a Major Humoral Autoantigen in Type 1 Diabetes Mellitus.
abstract: A major goal in understanding autoimmune diseases is to define the antigens that elicit a self-destructive immune response, but this is a difficult endeavor. In an effort to discover autoantigens associated with type 1 diabetes (T1D), we used epitope surrogate technology that screens combinatorial libraries of synthetic molecules for compounds that could recognize disease-linked autoantibodies and enrich them from serum. Autoantibodies from one patient revealed a highly phosphorylated form of peripherin, a neuroendocrine filament protein, as a candidate T1D antigen. Peripherin antibodies were detected in 72% of donor patient sera. Further analysis revealed that the T1D-associated antibodies only recognized a dimeric conformation of peripherin. These data explain why peripherin was dismissed as an important T1D antigen previously. The discovery of this novel autoantigen would not have been possible using standard methods, such as hybridizing serum antibodies to recombinant protein arrays, highlighting the power of epitope surrogate technology for probing the mechanism of autoimmune diseases.
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Doran
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Morimoto
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Simanski
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Koesema
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Lorraine F
authors.initials: LF
authors.lastname: Clark
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pels
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Stoops
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33101, USA; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Skyler
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: kodadek@scripps.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D064531:Peripherins / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D001324:Autoantigens; C578994:PRPH protein, human; D064531:Peripherins