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

doi:10.1172/JCI64413

Back

Journal article

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

Di Zenzo, Giovanni Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
Di Lullo, Giulia Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Corti, Davide Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Humabs BioMed SA, Bellinzona, Switzerland
Calabresi, Valentina Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
Sinistro, Anna Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
Vanzetta, Fabrizia Humabs BioMed SA, Bellinzona, Switzerland
Didona, Biagio Dermatology Division, Rome, Italy
Cianchini, Giuseppe Dermatology Division, IDI-IRCCS, Rome, Italy
Hertl, Michael Department of Dermatology and Allergology, Philipps University, Marburg, Germany
Eming, Rudiger Department of Dermatology and Allergology, Philipps University, Marburg, Germany
Amagai, Masayuki Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
Ohyama, Bungo Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan
Hashimoto, Takashi Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan
Sloostra, Jerry Pepscan Presto, Lelystad, The Netherlands
Sallusto, Federica Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Zambruno, Giovanna Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland

04.09.2012

Published in:

The journal of clinical investigation. - 2012, vol. 122, no. 10, p. 3781-3790

English 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.

Language