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Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface
Giovanni Di Zenzo, … , Giovanna Zambruno, Antonio Lanzavecchia
Giovanni Di Zenzo, … , Giovanna Zambruno, Antonio Lanzavecchia
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3781-3790. https://doi.org/10.1172/JCI64413.
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Research Article Autoimmunity

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

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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.

Authors

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

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Figure 1

Human antibodies bind conformational epitopes in the DSG3 ectodomain.

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Human antibodies bind conformational epitopes in the DSG3 ectodomain.
(A...
(A) Cryosections of human skin were stained with biotinylated human mAbs isolated from PV patients. Shown are 4 representative antibodies out of the 15 analyzed. The cutaneous basement membrane zone is marked by a dotted line. Scale bars: 100 μm. (B) Staining of human epidermis performed as in A with antibody PVB28 in the presence (with) or absence (w/o) of Ca+. Scale bars: 100 μm. (C) Binding of the indicated antibodies to DSG3-coated plates in the presence or absence of EDTA as assessed by ELISA. Data are representative of 2 separate experiments (mean ± SEM).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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