Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody
Epidermolysis bullosa is a group of severe skin blistering disorders, which currently have no cure. The pathology of epidermolysis bullosa is recognized as having an inflammatory component, but the role of inflammation in different epidermolysis bullosa disorders is unclear. Epidermolysis bullosa si...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | JID Innovations |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667026722000029 |
| _version_ | 1818394170725761024 |
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| author | Cedric Badowski Tong San Tan Teimur Aliev David Trudil Maria Larina Viсtoria Argentova Muhammad Jasrie Firdaus Paula Benny Vivien S.T. Woo E. Birgitte Lane |
| author_facet | Cedric Badowski Tong San Tan Teimur Aliev David Trudil Maria Larina Viсtoria Argentova Muhammad Jasrie Firdaus Paula Benny Vivien S.T. Woo E. Birgitte Lane |
| author_sort | Cedric Badowski |
| collection | DOAJ |
| description | Epidermolysis bullosa is a group of severe skin blistering disorders, which currently have no cure. The pathology of epidermolysis bullosa is recognized as having an inflammatory component, but the role of inflammation in different epidermolysis bullosa disorders is unclear. Epidermolysis bullosa simplex (EBS) is primarily caused by sequence variants in keratin genes; its most severe form, EBS generalized severe, is characterized by aggregates of keratin proteins, and cell models of EBS generalized severe show constitutively elevated stress. IFN-γ is a major mediator of inflammation, and we show that the addition of IFN-γ alone to disease model keratinocytes promotes keratin aggregation, decreases cell–cell junctions, delays wound closure, and reduces cell proliferation. IFN-γ exposure weakens the intercellular cohesion of monolayers on mechanical stress, with IFN-γ–treated EBS monolayers more fragmented than IFN-γ–treated wild-type monolayers. A humanized monoclonal antibody to IFN-γ neutralized the detrimental effects on keratinocytes, restoring cell proliferation, increasing cell–cell adhesion, accelerating wound closure in the presence of IFN-γ, and reducing IFN-γ–mediated keratin aggregation in EBS cells. These suggest that treatment with IFN-γ blocking antibodies may constitute a promising new therapeutic strategy for patients with EBS and may also have ameliorating effects on other inflammatory skin diseases. |
| first_indexed | 2024-12-14T05:56:57Z |
| format | Article |
| id | doaj.art-1f3f8a32ff68444688d6a6207c54b3c5 |
| institution | Directory Open Access Journal |
| issn | 2667-0267 |
| language | English |
| last_indexed | 2024-12-14T05:56:57Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JID Innovations |
| spelling | doaj.art-1f3f8a32ff68444688d6a6207c54b3c52022-12-21T23:14:32ZengElsevierJID Innovations2667-02672022-03-0122100096Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal AntibodyCedric Badowski0Tong San Tan1Teimur Aliev2David Trudil3Maria Larina4Viсtoria Argentova5Muhammad Jasrie Firdaus6Paula Benny7Vivien S.T. Woo8E. Birgitte Lane9Institute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeFaculty of Chemistry, Lomonosov Moscow State University, Moscow, RussiaNHDetect Corporation, Reisterstown, Maryland, USAShemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, Moscow, RussiaInstitute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, SingaporeInstitute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeInstitute of Medical Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Correspondence: E. Birgitte Lane, Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A∗STAR), Immunos Building, 8A Biomedical Grove, Singapore 138648, Singapore.Epidermolysis bullosa is a group of severe skin blistering disorders, which currently have no cure. The pathology of epidermolysis bullosa is recognized as having an inflammatory component, but the role of inflammation in different epidermolysis bullosa disorders is unclear. Epidermolysis bullosa simplex (EBS) is primarily caused by sequence variants in keratin genes; its most severe form, EBS generalized severe, is characterized by aggregates of keratin proteins, and cell models of EBS generalized severe show constitutively elevated stress. IFN-γ is a major mediator of inflammation, and we show that the addition of IFN-γ alone to disease model keratinocytes promotes keratin aggregation, decreases cell–cell junctions, delays wound closure, and reduces cell proliferation. IFN-γ exposure weakens the intercellular cohesion of monolayers on mechanical stress, with IFN-γ–treated EBS monolayers more fragmented than IFN-γ–treated wild-type monolayers. A humanized monoclonal antibody to IFN-γ neutralized the detrimental effects on keratinocytes, restoring cell proliferation, increasing cell–cell adhesion, accelerating wound closure in the presence of IFN-γ, and reducing IFN-γ–mediated keratin aggregation in EBS cells. These suggest that treatment with IFN-γ blocking antibodies may constitute a promising new therapeutic strategy for patients with EBS and may also have ameliorating effects on other inflammatory skin diseases.http://www.sciencedirect.com/science/article/pii/S2667026722000029 |
| spellingShingle | Cedric Badowski Tong San Tan Teimur Aliev David Trudil Maria Larina Viсtoria Argentova Muhammad Jasrie Firdaus Paula Benny Vivien S.T. Woo E. Birgitte Lane Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody JID Innovations |
| title | Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody |
| title_full | Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody |
| title_fullStr | Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody |
| title_full_unstemmed | Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody |
| title_short | Detrimental Effects of IFN-γ on an Epidermolysis Bullosa Simplex Cell Model and Protection by a Humanized Anti–IFN-γ Monoclonal Antibody |
| title_sort | detrimental effects of ifn γ on an epidermolysis bullosa simplex cell model and protection by a humanized anti ifn γ monoclonal antibody |
| url | http://www.sciencedirect.com/science/article/pii/S2667026722000029 |
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