title: Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients.
abstract: Pemphigus vulgaris (PV) is a potentially fatal blistering disease caused by autoantibodies (autoAbs) against desmoglein 3 (Dsg3). Here, we clone anti-Dsg3 antibodies (Abs) from four PV patients and identify pathogenic VH1-46 autoAbs from all four patients. Unexpectedly, VH1-46 autoAbs had relatively few replacement mutations. We reverted antibody somatic mutations to their germline sequences to determine the requirement of mutations for autoreactivity. Three of five VH1-46 germline-reverted Abs maintain Dsg3 binding, compared with zero of five non-VH1-46 germline-reverted Abs. Site-directed mutagenesis of VH1-46 Abs demonstrates that acidic amino-acid residues introduced by somatic mutation or heavy chain VDJ recombination are necessary and sufficient for Dsg3 binding. Our data suggest that VH1-46 autoantibody gene usage is commonly found in PV because VH1-46 Abs require few to no mutations to acquire Dsg3 autoreactivity, which may favour their early selection. Common VH gene usage indicates common humoral immune responses, even among unrelated patients.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael Jeffrey
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Agnes S Y
authors.initials: AS
authors.lastname: Lo
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xuming
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Nagler
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Ellebrecht
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Mukherjee
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Hammers
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Preety M
authors.initials: PM
authors.lastname: Sharma
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Uduman
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ann H
authors.initials: AH
authors.lastname: Rux
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Farber
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Courtney B
authors.initials: CB
authors.lastname: Rubin
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Sachais
authors.affiliation: The Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York 10029, USA.
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Posner
authors.affiliation: The Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York 10029, USA.
authors.forename: Lisa A
authors.identifier: 0000000193897918
authors.initials: LA
authors.lastname: Cavacini
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
mesh_terms: D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics* / Q000276:immunology; D051184:Desmoglein 3 / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D010392:Pemphigus / Q000235:genetics* / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D022801:Complementarity Determining Regions; C071894:DSG3 protein, human; D051184:Desmoglein 3