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

Alice Cho, Amber L. Caldara, Nina A. Ran, Zach Menne, Robert C. Kauffman, Maurizio Affer, Alexandra Llovet, Carson Norwood, Aaron Scanlan, Grace Mantus, Bridget Bradley, Stephanie Zimmer, Thomas Schmidt, Michael Hertl, Aimee S. Payne, Ron Feldman, Andrew P. Kowalczyk, Jens Wrammert

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)909-922.e6
JournalCell Reports
Volume28
Issue number4
DOIs
StatePublished - Jul 23 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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