Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients

Michael Jeffrey Cho, Agnes S.Y. Lo, Xuming Mao, Arielle R. Nagler, Christoph T. Ellebrecht, Eric M. Mukherjee, Christoph M. Hammers, Eun-Jung Choi, Preety M. Sharma, Mohamed Uduman, Hong Li, Ann H. Rux, Sara A. Farber, Courtney B. Rubin, Steven H. Kleinstein, Bruce S. Sachais, Marshall R. Posner, Lisa A. Cavacini and Aimee S. Payne ()
Additional contact information
Michael Jeffrey Cho: University of Pennsylvania
Agnes S.Y. Lo: Beth Israel Deaconess Medical Center
Xuming Mao: University of Pennsylvania
Arielle R. Nagler: University of Pennsylvania
Christoph T. Ellebrecht: University of Pennsylvania
Eric M. Mukherjee: University of Pennsylvania
Christoph M. Hammers: University of Pennsylvania
Eun-Jung Choi: University of Pennsylvania
Preety M. Sharma: University of Pennsylvania
Mohamed Uduman: Yale University, Yale University School of Medicine
Hong Li: University of Pennsylvania
Ann H. Rux: University of Pennsylvania
Sara A. Farber: University of Pennsylvania
Courtney B. Rubin: University of Pennsylvania
Steven H. Kleinstein: Yale University, Yale University School of Medicine
Bruce S. Sachais: University of Pennsylvania
Marshall R. Posner: The Tisch Cancer Institute, Mount Sinai Medical Center
Lisa A. Cavacini: The Tisch Cancer Institute, Mount Sinai Medical Center
Aimee S. Payne: University of Pennsylvania

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5167

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