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 2012-09-04 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. application/pdf https://susi.usi.ch/global/documents/319142 https://localhost:5000/ark:/12658/srd1319142 https://susi.usi.ch/documents/319142/files/DiZenzo_JCI_2012.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI64413 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319142 info:eu-repo/semantics/openAccess CC BY The journal of clinical investigation. - 2012, vol. 122, no. 10, p. 3781-3790 info:eu-repo/classification/udc/61 Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface http://purl.org/coar/resource_type/c_6501