Single-Cell Analysis Suggests that Ongoing Affinity Maturation Drives the Emergence of Pemphigus Vulgaris Autoimmune Disease

• Type of Material: Article
• Authors: Alice Cho, Emory University; Amber L. Caldara, Emory University; Nina A. Ran, University of Pennsylvania; Zach Menne, Emory University; Robert C. Kauffman, Emory University; Maurizio Affer, Emory University; Alexandra Llovet, Emory University; Carson Norwood, Emory University; Aaron Scanlan, Emory University; Grace Mantus, Emory University; Bridget Bradley, Emory University; Stephanie Zimmer, Emory University; Thomas Schmidt, Philipps University; Michael Hertl, Philipps University; Aimee S. Payne, University of Pennsylvania; Ron Feldman, Emory University; Andrew Kowalczyk, Emory University; Jens Wrammert, Emory University
• Language: English
• Date: 2019-07-23
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2019.06.066
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 28
• Issue: 4
• Start Page: 909
• End Page: +
• Grant/Funding Information: This study was supported by grants from the NIH (Human Immunology Pilot award under U19 AI057266 (J.W.); the International Pemphigus and Pemphigoid Foundation (J.W.); the Charles and Daneen Stiefel Scholar Award from the Dermatology Foundation (A.P.); the Deutsche Forschungsgemeinschaft (FOR 2497 PEGASUS, M.H. and T.S.); and the National Center for Advancing Translational Sciences of the NIH under award TL1TR001880 (N.R.)
• Keywords: Cell Biology; DESMOGLEIN 3; DENGUE VIRUS-INFECTION; REPERTOIRE; Science & Technology; HUMAN MONOCLONAL-ANTIBODIES; ANTIGEN; RITUXIMAB; Life Sciences & Biomedicine; IGG ANTIBODIES; B-CELLS; AUTOANTIBODIES; SOMATIC MUTATIONS
• Research Categories: Health Sciences, Immunology; Biology, Cell

Abstract

Pemphigus vulgaris (PV) is an autoimmune disease characterized by blistering sores on skin and mucosal membranes, caused by autoantibodies primarily targeting the cellular adhesion protein, desmoglein-3 (Dsg3). To better understand how Dsg3-specific autoantibodies develop and cause disease in humans, we performed a cross-sectional study of PV patients before and after treatment to track relevant cellular responses underlying disease pathogenesis, and we provide an in-depth analysis of two patients by generating a panel of mAbs from single Dsg3-specific memory B cells (MBCs). Additionally, we analyzed a paired sample from one patient collected 15-months prior to disease diagnosis. We find that Dsg3-specific MBCs have an activated phenotype and show signs of ongoing affinity maturation and clonal selection. Monoclonal antibodies (mAbs) with pathogenic activity primarily target epitopes in the extracellular domains EC1 and EC2 of Dsg3, though they can also bind to the EC4 domain. Combining antibodies targeting different epitopes synergistically enhances in vitro pathogenicity.