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 language | English |
|---|---|
| Pages (from-to) | 5114-5130 |
| Number of pages | 17 |
| Journal | British Journal of Pharmacology |
| Volume | 177 |
| Issue number | 22 |
| DOIs | |
| State | Published - 1 Nov 2020 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society
Funding
R.J.L. has received research funding from Miltenyi Biotec, Biogen, Biotest, Almirall, True North Therapeutics, UCB Pharma, ArgenX, TxCell, Topadur, Incyte, and Admirx and fees for consulting or speaking from ArgenX, Immunogenetics, Novartis, and Lilly. D.Z. has received support through research and development grants as well as for consulting or lecturing from Biotest, Fresenius, Miltenyi Biotec, Roche Pharma, Biogen, AbbVie, UCB, Janssen, Euroimmun, Dompe, Novartis, and ArgenX. C.M.H. is advisor to ArgenX and viDa Therapeutics. All other authors declare no conflicts of interest. We are thankful for the excellent technical support of Nadine Merg, Christianna Czyz, Uta Radine, Paul Kunth, and Vanessa Krull. This work has been financially supported by the Research Training Group “Modulation of Autoimmunity” (GRK 1727) and the Excellence Clusters “Inflammation at Interfaces” (EXC 306) and “Precision Medicine in Chronic Inflammation” (EXC 2167), all from the Deutsche Forschungsgemeinschaft, as well as a scholarship provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) to V.B.B. We thank Dr John R. Stanley for providing us with the anti‐Dsg3/1 scFv used herein. Open access funding enabled and organized by Projekt DEAL. We are thankful for the excellent technical support of Nadine Merg, Christianna Czyz, Uta Radine, Paul Kunth, and Vanessa Krull. This work has been financially supported by the Research Training Group ?Modulation of Autoimmunity? (GRK 1727) and the Excellence Clusters ?Inflammation at Interfaces? (EXC 306) and ?Precision Medicine in Chronic Inflammation? (EXC 2167), all from the Deutsche Forschungsgemeinschaft, as well as a scholarship provided by the Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) to V.B.B. We thank Dr John R. Stanley for providing us with the anti-Dsg3/1 scFv used herein. Open access funding enabled and organized by Projekt DEAL.
| Funders | Funder number |
|---|---|
| Aperfei?oamento de Pessoal de N?vel Superior | |
| Biogen | |
| Deutsche Forschungsgemeinschaft | |
| Coordenação de Aperfeiçoamento de Pessoal de Nível Superior | |
| Miltenyi Biotec |
Keywords
- autoimmunity
- cell signaling
- model system
- pemphigus
- skin
