Identification of novel therapeutic targets for blocking acantholysis in pemphigus

Imke A.K. Burmester, Sarah Flaswinkel, Clara Sophie Thies, Anika Kasprick, Mayumi Kamaguchi, Valéria Bumiller-Bini, Shirin Emtenani, Nick Feldmann, Khalaf Kridin, Enno Schmidt, Nina van Beek, Detlef Zillikens, Christoph M. Hammers, Jennifer E. Hundt, Ralf J. Ludwig

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background and Purpose: Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3, and/or non-Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half-life. However, topical modulation of PV autoantibody-induced blistering is an attractive target because it could promptly relieve symptoms. Experimental Approach: To address this issue, we performed an unbiased screening in a complex biological system using 141 low MW inhibitors from a chemical library. Specifically, we evaluated PV IgG-induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model. key Results: Overall, this approach led to the identification of four molecules involved in PV IgG-induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2. Conclusion and Implications: This unbiased screening revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life-threatening skin disease.

Original languageEnglish
Pages (from-to)5114-5130
Number of pages17
JournalBritish Journal of Pharmacology
Volume177
Issue number22
DOIs
StatePublished - 1 Nov 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

Keywords

  • autoimmunity
  • cell signaling
  • model system
  • pemphigus
  • skin

Fingerprint

Dive into the research topics of 'Identification of novel therapeutic targets for blocking acantholysis in pemphigus'. Together they form a unique fingerprint.

Cite this