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

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  • 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)

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.

Suggested Citation

  • 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 , 2014. "Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5167
    DOI: 10.1038/ncomms5167
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