TY - JOUR
T1 - Identification of novel therapeutic targets for blocking acantholysis in pemphigus
AU - Burmester, Imke A.K.
AU - Flaswinkel, Sarah
AU - Thies, Clara Sophie
AU - Kasprick, Anika
AU - Kamaguchi, Mayumi
AU - Bumiller-Bini, Valéria
AU - Emtenani, Shirin
AU - Feldmann, Nick
AU - Kridin, Khalaf
AU - Schmidt, Enno
AU - van Beek, Nina
AU - Zillikens, Detlef
AU - Hammers, Christoph M.
AU - Hundt, Jennifer E.
AU - Ludwig, Ralf J.
N1 - Publisher Copyright:
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
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UR - https://www.mendeley.com/catalogue/24a213e9-539e-3b67-b7c5-60abbf4fed85/
U2 - 10.1111/bph.15233
DO - 10.1111/bph.15233
M3 - Journal articles
C2 - 32815159
AN - SCOPUS:85091243339
SN - 0007-1188
VL - 177
SP - 5114
EP - 5130
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 22
ER -