title: Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus.
abstract: Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first- and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.
authors.affiliation: Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203;
authors.forename: Thomas
authors.initials: T
authors.lastname: Sajda
authors.affiliation: Division of Dermatology and Cutaneous Sciences, Michigan State University, East Lansing, MI 48824;
authors.forename: Julian
authors.initials: J
authors.lastname: Hazelton
authors.affiliation: Division of Dermatology and Cutaneous Sciences, Michigan State University, East Lansing, MI 48824;
authors.forename: Milan
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203;
authors.forename: Kristina
authors.initials: K
authors.lastname: Seiffert-Sinha
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94304; steinman@stanford.edu aasinha@buffalo.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Division of Rheumatology and Immunology, Stanford University School of Medicine, Palo Alto, CA 94304;
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haab
authors.affiliation: Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203; steinman@stanford.edu aasinha@buffalo.edu.
authors.forename: Animesh A
authors.initials: AA
authors.lastname: Sinha
mesh_terms: D000918:Antibody Specificity; D001324:Autoantigens / Q000276:immunology*; D016022:Case-Control Studies; D051182:Desmogleins / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D010392:Pemphigus / Q000276:immunology*; D040081:Protein Array Analysis
chemical_list: D001324:Autoantigens; D051182:Desmogleins; D006680:HLA Antigens
keywords: autoantibody; pemphigus; protein microarray
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