Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6
| Autor: | Christoph M. Hammers, Sarah M. McDonald, Michael Jeffrey Cho, Gopal Sapparapu, Christoph T. Ellebrecht, James E. Crowe, Aimee S. Payne, Eric M. Mukherjee, Crystal E. Boudreaux |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Autoimmune disease education.field_of_study Immunology Pemphigus vulgaris Biology medicine.disease medicine.disease_cause Virology Autoimmunity 03 medical and health sciences Pemphigus 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Antigen Rotavirus Desmoglein 3 medicine Immunology and Allergy education B cell 030215 immunology |
| Zdroj: | The Journal of Immunology. 197:1065-1073 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1600567 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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