Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface

Giovanni Di Zenzo, Giulia Di Lullo, Davide Corti, Valentina Calabresi, Anna Sinistro, Fabrizia Vanzetta, Biagio Didona, Giuseppe Cianchini, Michael Hertl, Rudiger Eming, Masayuki Amagai, Bungo Ohyama, Takashi Hashimoto, Jerry Sloostra, Federica Sallusto, Giovanna Zambruno, Antonio Lanzavecchia

Research output: Contribution to journalArticle

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Abstract

Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.

Original languageEnglish
Pages (from-to)3781-3790
Number of pages10
JournalJournal of Clinical Investigation
Volume122
Issue number10
DOIs
Publication statusPublished - 2012 Oct 1

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Desmoglein 3
Pemphigus
Autoantibodies
Mutation
Antibodies
Adhesives
Keratinocytes
Desmogleins
Immunodominant Epitopes
Cell Adhesion
Autoimmune Diseases
Epitopes
Mucous Membrane
Immunoglobulin G
Light
Antigens
Skin
Serum
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Di Zenzo, G., Di Lullo, G., Corti, D., Calabresi, V., Sinistro, A., Vanzetta, F., ... Lanzavecchia, A. (2012). Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. Journal of Clinical Investigation, 122(10), 3781-3790. https://doi.org/10.1172/JCI64413

Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. / Di Zenzo, Giovanni; Di Lullo, Giulia; Corti, Davide; Calabresi, Valentina; Sinistro, Anna; Vanzetta, Fabrizia; Didona, Biagio; Cianchini, Giuseppe; Hertl, Michael; Eming, Rudiger; Amagai, Masayuki; Ohyama, Bungo; Hashimoto, Takashi; Sloostra, Jerry; Sallusto, Federica; Zambruno, Giovanna; Lanzavecchia, Antonio.

In: Journal of Clinical Investigation, Vol. 122, No. 10, 01.10.2012, p. 3781-3790.

Research output: Contribution to journalArticle

Di Zenzo, G, Di Lullo, G, Corti, D, Calabresi, V, Sinistro, A, Vanzetta, F, Didona, B, Cianchini, G, Hertl, M, Eming, R, Amagai, M, Ohyama, B, Hashimoto, T, Sloostra, J, Sallusto, F, Zambruno, G & Lanzavecchia, A 2012, 'Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface', Journal of Clinical Investigation, vol. 122, no. 10, pp. 3781-3790. https://doi.org/10.1172/JCI64413
Di Zenzo G, Di Lullo G, Corti D, Calabresi V, Sinistro A, Vanzetta F et al. Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. Journal of Clinical Investigation. 2012 Oct 1;122(10):3781-3790. https://doi.org/10.1172/JCI64413
Di Zenzo, Giovanni ; Di Lullo, Giulia ; Corti, Davide ; Calabresi, Valentina ; Sinistro, Anna ; Vanzetta, Fabrizia ; Didona, Biagio ; Cianchini, Giuseppe ; Hertl, Michael ; Eming, Rudiger ; Amagai, Masayuki ; Ohyama, Bungo ; Hashimoto, Takashi ; Sloostra, Jerry ; Sallusto, Federica ; Zambruno, Giovanna ; Lanzavecchia, Antonio. / Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 10. pp. 3781-3790.
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