Journal Article

Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction

Russo, Valerio, Granville, David J., Shen, Yue, Carr, Nick J., Overall, Christopher M., Franzke, Claus-Werner, Lim, Darielle J., Machado, Yoan, Zeglinski, Matthew R., Nabai, Layla, Oram, Cameron P., Crawford, Richard I., Zhao, Hongyan, Van Laeken, Nancy, Solis, Nestor, Hiroyasu, Sho, Lennox, Peter A., Klein, Theo

2018

Overview

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 631/1647/2067 / 631/80/474 / 692/1807/1812 / 692/699/249/1313 / 692/699/4033 / 82/29 / 82/58 / 82/81 / Autoantigens - metabolism / Bullous pemphigoid / Collagen / Collagen Type XVII / Dermatitis / Dermatitis herpetiformis / Dermatitis Herpetiformis - metabolism / Dermis / Dermis - metabolism / Epidermis / Epidermis - metabolism / Epidermolysis bullosa / Epidermolysis bullosa acquisita / Granzyme B / Granzymes - metabolism / Humanities and Social Sciences / Humans / Immunohistochemistry / In Vitro Techniques / Inflammation / Mass spectrometry / Mass spectroscopy / multidisciplinary / Non-Fibrillar Collagens - metabolism / Pemphigoid, Bullous - metabolism / Proteolysis / Science / Science (multidisciplinary) / Serine / Serine proteinase / Skin / Skin - metabolism / Skin diseases / Tandem Mass Spectrometry