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

Autor:	Cho MJ; Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;, Ellebrecht CT; Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;, Hammers CM; Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;, Mukherjee EM; Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104;, Sapparapu G; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and., Boudreaux CE; Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA 24016., McDonald SM; Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA 24016., Crowe JE Jr; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and., Payne AS; Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104; aimee.payne@uphs.upenn.edu.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2016 Aug 15; Vol. 197 (4), pp. 1065-73. Date of Electronic Publication: 2016 Jul 11.
DOI:	10.4049/jimmunol.1600567
Abstrakt:	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.)
Databáze:	MEDLINE
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