title: Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6.
abstract: Shared VH1-46 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 PV and 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 cross-reactive 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.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Michael Jeffrey
authors.identifier: 0000-0002-4628-303X
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Ellebrecht
authors.affiliation: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors.forename: Christoph M
authors.identifier: 0000-0001-5631-2415
authors.initials: CM
authors.lastname: Hammers
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Eric M
authors.initials: EM
authors.lastname: Mukherjee
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.
authors.forename: Gopal
authors.identifier: 0000-0001-9670-1757
authors.initials: G
authors.lastname: Sapparapu
authors.affiliation: Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA 24016.
authors.forename: Crystal E
authors.initials: CE
authors.lastname: Boudreaux
authors.affiliation: Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA 24016.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: McDonald
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.
authors.forename: James E
authors.identifier: 0000-0002-0049-1079
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104; aimee.payne@uphs.upenn.edu.
authors.forename: Aimee S
authors.identifier: 0000-0001-9389-7918
authors.initials: AS
authors.lastname: Payne
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D003429:Cross Reactions; D051184:Desmoglein 3 / Q000276:immunology*; D054637:Dual-Specificity Phosphatases / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D057166:High-Throughput Screening Assays; D006801:Humans; D008856:Microscopy, Fluorescence; D010392:Pemphigus / Q000276:immunology; D016133:Polymerase Chain Reaction; D012400:Rotavirus Infections / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D001324:Autoantigens; D036022:Capsid Proteins; C071894:DSG3 protein, human; D051184:Desmoglein 3; C061332:VP6 protein, Rotavirus; C489855:dual specificity phosphatase 12; D054637:Dual-Specificity Phosphatases