title: Nanorobotic investigation identifies novel visual, structural and functional correlates of autoimmune pathology in a blistering skin disease model.
abstract: There remain major gaps in our knowledge regarding the detailed mechanisms by which autoantibodies mediate damage at the tissue level. We have undertaken novel strategies at the interface of engineering and clinical medicine to integrate nanoscale visual and structural data using nanorobotic atomic force microscopy with cell functional analyses to reveal previously unattainable details of autoimmune processes in real-time. Pemphigus vulgaris is a life-threatening autoimmune blistering skin condition in which there is disruption of desmosomal cell-cell adhesion structures that are associated with the presence of antibodies directed against specific epithelial proteins including Desmoglein (Dsg) 3. We demonstrate that pathogenic (blister-forming) anti-Dsg3 antibodies, distinct from non-pathogenic (non-blister forming) anti-Dsg3 antibodies, alter the structural and functional properties of keratinocytes in two sequential steps--an initial loss of cell adhesion and a later induction of apoptosis-related signaling pathways, but not full apoptotic cell death. We propose a "2-Hit" model for autoimmune disruption associated with skin-specific pathogenic autoantibodies. These data provide unprecedented details of autoimmune processes at the tissue level and offer a novel conceptual framework for understanding the action of self-reactive antibodies.
authors.affiliation: Department of Dermatology, University at Buffalo, Clinical and Translational Research Center, Buffalo, New York, United States of America.
authors.forename: Kristina
authors.initials: K
authors.lastname: Seiffert-Sinha
authors.affiliation: Department of Electrical and Computer Engineering, Michigan State University, The Robotics and Automation Laboratory, East Lansing, Michigan, United States of America.
authors.forename: Ruiguo
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Electrical and Computer Engineering, Michigan State University, The Robotics and Automation Laboratory, East Lansing, Michigan, United States of America.
authors.forename: Carmen K
authors.initials: CK
authors.lastname: Fung
authors.affiliation: Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: King W
authors.initials: KW
authors.lastname: Lai
authors.affiliation: College of Human Medicine, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Patterson
authors.affiliation: Department of Dermatology, University of Pennsylvania, 217A Clinical Research Building, Philadelphia, Pennsylvania, United States of America.
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
authors.affiliation: Department of Electrical and Computer Engineering, Michigan State University, The Robotics and Automation Laboratory, East Lansing, Michigan, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Xi
authors.affiliation: Department of Dermatology, University at Buffalo, Clinical and Translational Research Center, Buffalo, New York, United States of America.
authors.forename: Animesh A
authors.initials: AA
authors.lastname: Sinha
mesh_terms: D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D036103:Nanotechnology; D012371:Robotics; D012871:Skin Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology