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 language | English |
|---|---|
| Pages (from-to) | 3781-3790 |
| Number of pages | 10 |
| Journal | Journal of Clinical Investigation |
| Volume | 122 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2012 Oct 1 |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
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TY - JOUR
T1 - Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface
AU - Di Zenzo, Giovanni
AU - Di Lullo, Giulia
AU - Corti, Davide
AU - Calabresi, Valentina
AU - Sinistro, Anna
AU - Vanzetta, Fabrizia
AU - Didona, Biagio
AU - Cianchini, Giuseppe
AU - Hertl, Michael
AU - Eming, Rudiger
AU - Amagai, Masayuki
AU - Ohyama, Bungo
AU - Hashimoto, Takashi
AU - Sloostra, Jerry
AU - Sallusto, Federica
AU - Zambruno, Giovanna
AU - Lanzavecchia, Antonio
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867156668&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867156668&partnerID=8YFLogxK
U2 - 10.1172/JCI64413
DO - 10.1172/JCI64413
M3 - Article
C2 - 22996451
AN - SCOPUS:84867156668
VL - 122
SP - 3781
EP - 3790
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -