Determinants of VH1-46 cross-reactivity to pemphigus vulgaris autoantigen desmoglein 3 and rotavirus antigen VP6

Michael Jeffrey Cho, Christoph T. Ellebrecht, Christoph M. Hammers, Eric M. Mukherjee, Gopal Sapparapu, Crystal E. Boudreaux, Sarah M. McDonald, James E. Crowe, Aimee S. Payne*

*Corresponding author for this work
12 Citations (Scopus)


SharedVH1-46 gene usage has been described in B cells reacting to desmoglein 3 (Dsg3) in the autoimmune disease pemphigus vulgaris (PV), as well as B cells responding to rotavirus capsid protein VP6. In both diseases,VH1-46 B cells bearing few to no somatic mutations can recognize the disease Ag. This intriguing connection between an autoimmune response to self-antigen and an immune response to foreign Ag prompted us to investigate whether VH1-46 B cells may be predisposed to Dsg3-VP6 cross-reactivity. Focused testing of VH1-46 mAbs previously isolated from PVand rotavirus-exposed individuals indicates that cross-reactivity is rare, found in only one of seven VH1-46 IgG clonotypes. High-throughput screening of IgG B cell repertoires from two PV patients identified no additional cross-reactive clonotypes. Screening of IgM B cell repertoires from one non-PV and three PV patients identified specific crossreactive Abs in one PV patient, but notably all six cross-reactive clonotypes used VH1-46. Site-directed mutagenesis studies indicate that amino acid residues predisposing VH1-46 Abs to Dsg3 reactivity reside in CDR2. However, somatic mutations only rarely promote Dsg3-VP6 cross-reactivity; most mutations abolish VP6 and/or Dsg3 reactivity. Nevertheless, functional testing identified two cross-reactive VH1-46 Abs that both disrupt keratinocyte adhesion and inhibit rotavirus replication, indicating the potential for VH1-46 Abs to have both pathologic autoimmune and protective immune functions. Taken together, these studies suggest that certain VH1-46 B cell populations may be predisposed to Dsg3-VP6 cross-reactivity, but multiple mechanisms prevent the onset of autoimmunity after rotavirus exposure.

Original languageEnglish
JournalJournal of Immunology
Issue number4
Pages (from-to)1065-1073
Number of pages9
Publication statusPublished - 15.08.2016

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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