@article{5c137879a28b456c951b8a4249db6376,
title = "Single-Cell Analysis Suggests that Ongoing Affinity Maturation Drives the Emergence of Pemphigus Vulgaris Autoimmune Disease",
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.",
author = "Alice Cho and Caldara, {Amber L.} and Ran, {Nina A.} and Zach Menne and Kauffman, {Robert C.} and Maurizio Affer and Alexandra Llovet and Carson Norwood and Aaron Scanlan and Grace Mantus and Bridget Bradley and Stephanie Zimmer and Thomas Schmidt and Michael Hertl and Payne, {Aimee S.} and Ron Feldman and Kowalczyk, {Andrew P.} and Jens Wrammert",
note = "Funding Information: We thank R. Karaffa at the Emory School of Medicine flow cytometry core and A. Rae at Emory Pediatric flow cytometry core for their technical assistance with cell-sorting experiments. We thank Drs. R. Ahmed and M. Slifka for providing samples used in this paper. 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.) Funding Information: We thank R. Karaffa at the Emory School of Medicine flow cytometry core and A. Rae at Emory Pediatric flow cytometry core for their technical assistance with cell-sorting experiments. We thank Drs. R. Ahmed and M. Slifka for providing samples used in this paper. 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.), A.C. carried out experiments, analyzed the data, and wrote the manuscript. A.L.C. contributed to pathogenicity and IF assays. N.A.R. carried out domain-mapping experiments. Z.M. and M.A. contributed to the competition assays. C.N. and A.L. contributed to ELISA assays. R.C.K. A.S. and G.M. contributed to the analysis of isotype usage. B.B. contributed to analysis of data. S.Z. contributed to pathogenicity assays. T.S. and M.H. provided essential reagents and feedback on the manuscript. A.S.P. R.F. and A.P.K. contributed to analysis, critical discussion, and editing of the manuscript. J.W. conceived the research, oversaw the experiments and data analysis, and wrote the manuscript. A.S.P. has served as a consultant for Syntimmune, holds equity in Cabaletta Bio, and is an inventor on patents licensed by Novartis and Cabaletta Bio focused on targeted cellular therapy of autoimmunity. M.H. has received unrestricted grants from Topas Therapeuticals, Fresenius and Biotest, and has served as a consultant for Argenx and Allmirall. R.F. has served as a consultant for Cabeletta, Bioverative, and Celtaxys. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jul,
day = "23",
doi = "10.1016/j.celrep.2019.06.066",
language = "English (US)",
volume = "28",
pages = "909--922.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}