James Crowe
Faculty Member
Last active: 3/31/2020

Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6.

Cho MJ, Ellebrecht CT, Hammers CM, Mukherjee EM, Sapparapu G, Boudreaux CE, McDonald SM, Crowe JE, Payne AS
J Immunol. 2016 197 (4): 1065-73

PMID: 27402694 · PMCID: PMC4976025 · DOI:10.4049/jimmunol.1600567

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.

Copyright © 2016 by The American Association of Immunologists, Inc.

MeSH Terms (13)

Antigens, Viral Autoantigens Capsid Proteins Cross Reactions Desmoglein 3 Dual-Specificity Phosphatases Enzyme-Linked Immunosorbent Assay High-Throughput Screening Assays Humans Microscopy, Fluorescence Pemphigus Polymerase Chain Reaction Rotavirus Infections

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