title: Immune response in pemphigus and beyond: progresses and emerging concepts.
abstract: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Zenzo
authors.affiliation: Department of Dermatology, University of California Irvine Health, Irvine, CA, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Amber
authors.affiliation: Vetsuisse Faculty, Molecular Dermatology and Stem Cell Research, Institute of Animal Pathology, Bern, Switzerland.|Vetsuisse Faculty, DermFocus, Bern, Switzerland.|Department of Dermatology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Beyza S
authors.initials: BS
authors.lastname: Sayar
authors.affiliation: Vetsuisse Faculty, Molecular Dermatology and Stem Cell Research, Institute of Animal Pathology, Bern, Switzerland. Eliane.Mueller@vetsuisse.unibe.ch.|Vetsuisse Faculty, DermFocus, Bern, Switzerland. Eliane.Mueller@vetsuisse.unibe.ch.|Department of Dermatology, University Hospital of Bern, Bern, Switzerland. Eliane.Mueller@vetsuisse.unibe.ch.
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.affiliation: Vetsuisse Faculty, DermFocus, Bern, Switzerland. Luca.Borradori@insel.ch.|Department of Dermatology, University Hospital of Bern, Bern, Switzerland. Luca.Borradori@insel.ch.
authors.forename: Luca
authors.initials: L
authors.lastname: Borradori
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D051182:Desmogleins / Q000276:immunology; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009928:Organ Specificity / Q000276:immunology; D010392:Pemphigus / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology* / Q000628:therapy; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D051182:Desmogleins; D000939:Epitopes; D007106:Immune Sera; D007130:Immunoglobulin Idiotypes
keywords: Acantholysis; Autoantibody; Cadherins; Cell-cell adhesion; Desmoglein; Desmosome; Fogo selvagem; Mature desmoglein; Monoclonal antibody; Pathogenesis; Pemphigus foliaceus; Pemphigus vulgaris; Precursor Dsg; Signaling pathways