Granzyme B inhibition reduces disease severity in autoimmune blistering diseases.

Animals Autoantigens / metabolism Autoimmune Diseases / enzymology Blister Chemokine CXCL2 / metabolism Chemotactic Factors / pharmacology Disease Models, Animal Epidermolysis Bullosa / enzymology Granzymes / antagonists & inhibitors Humans Inflammation / pathology Integrin alpha6 / metabolism Interleukin-8 / metabolism Neutrophil Infiltration / drug effects Non-Fibrillar Collagens / metabolism Pemphigoid, Bullous / enzymology Severity of Illness Index Collagen Type XVII

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
12 01 2021
Historique:
received: 29 11 2019
accepted: 07 12 2020
entrez: 13 1 2021
pubmed: 14 1 2021
medline: 22 1 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-20604-3 PMID: 33436591 PMC: PMC7804321
pubmed: 33436591
doi: 10.1038/s41467-020-20604-3
pii: 10.1038/s41467-020-20604-3
pmc: PMC7804321
doi:

Substances chimiques

Autoantigens 0
Chemokine CXCL2 0
Chemotactic Factors 0
Cxcl2 protein, mouse 0
Integrin alpha6 0
Interleukin-8 0
Non-Fibrillar Collagens 0
GZMB protein, human EC 3.4.21.-
Granzymes EC 3.4.21.-
Gzmb protein, mouse EC 3.4.21.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

302

Subventions

Organisme : CIHR
Pays : Canada

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Auteurs

Sho Hiroyasu (S)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada.
ORCID: 0000-0002-8290-2272

Matthew R Zeglinski (MR)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada.

Hongyan Zhao (H)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada.

Megan A Pawluk (MA)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada.
ORCID: 0000-0002-8709-5115

Christopher T Turner (CT)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada.
ORCID: 0000-0001-7409-4386

Anika Kasprick (A)

Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.

Chiharu Tateishi (C)

Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Wataru Nishie (W)

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Angela Burleigh (A)

Department of Dermatology and Skin Science, UBC, Vancouver, BC, Canada.

Peter A Lennox (PA)

Department of Surgery, UBC, Vancouver, BC, Canada.

Nancy Van Laeken (N)

Department of Surgery, UBC, Vancouver, BC, Canada.

Nick J Carr (NJ)

Department of Surgery, UBC, Vancouver, BC, Canada.

Frank Petersen (F)

Priority Area Asthma and Allergy, Members of the German Center for Lung Research, Research Center Borstel, Borstel, Germany.

Richard I Crawford (RI)

Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada.
Department of Dermatology and Skin Science, UBC, Vancouver, BC, Canada.

Hiroshi Shimizu (H)

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Daisuke Tsuruta (D)

Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Ralf J Ludwig (RJ)

Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
ORCID: 0000-0002-1394-1737

David J Granville (DJ)

International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute (VCHRI), Vancouver, BC, Canada. David.Granville@hli.ubc.ca.
Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC, Canada. David.Granville@hli.ubc.ca.
BC Professional Firefighters' Burn and Wound Healing Research Laboratory, VCHRI, Vancouver, BC, Canada. David.Granville@hli.ubc.ca.
ORCID: 0000-0001-6985-2816

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Autoantigènes › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › États, signes et symptômes pathologiques › États anatomopathologiques › Cloque › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Chimiokines › Protéines inflammatoires des macrophages › Chimiokine CXCL2 › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Facteurs biologiques › Facteurs chimiotactiques › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Dermatoses vésiculobulleuses › Épidermolyse bulleuse › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Protéases à sérine › Serine endopeptidases › Granzymes › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Intégrines › Intégrines alpha › Intégrine alpha6 › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-8 › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Phénomènes du système immunitaire › Infiltration par les neutrophiles › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Scléroprotéines › Protéines de la matrice extracellulaire › Collagène › Collagènes non fibrillaires › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Pemphigoïde bulleuse › Granzyme B inhibition reduces disease severity...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Enquêtes et questionnaires › Enquêtes de santé › Indicateurs d'état de santé › Acuité des besoins du patient › Indice de gravité de la maladie › Granzyme B inhibition reduces disease severity...