Granzyme B inhibition reduces disease severity in autoimmune blistering diseases

Sho Hiroyasu, Matthew R. Zeglinski, Hongyan Zhao, Megan A. Pawluk, Christopher T. Turner, Anika Kasprick, Chiharu Tateishi, Wataru Nishie, Angela Burleigh, Peter A. Lennox, Nancy Van Laeken, Nick J. Carr, Frank Petersen, Richard I. Crawford, Hiroshi Shimizu, Daisuke Tsuruta, Ralf J. Ludwig, David J. Granville*

*Korrespondierende/r Autor/-in für diese Arbeit
1 Zitat (Scopus)

Abstract

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

OriginalspracheEnglisch
Aufsatznummer302
ZeitschriftNature Communications
Jahrgang12
Ausgabenummer1
Seiten (von - bis)302
ISSN1751-8628
DOIs
PublikationsstatusVeröffentlicht - 01.12.2021

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)
  • Zentren: Center for Research on Inflammation of the Skin (CRIS)

DFG-Fachsystematik

  • 2.21-05 Immunologie
  • 2.22-19 Dermatologie

Fingerprint

Untersuchen Sie die Forschungsthemen von „Granzyme B inhibition reduces disease severity in autoimmune blistering diseases“. Zusammen bilden sie einen einzigartigen Fingerprint.

Zitieren