Higher Levels of Granzyme B Play Key Role in EBA, Other Skin Blistering Diseases, Study Suggests

Higher Levels of Granzyme B Play Key Role in EBA, Other Skin Blistering Diseases, Study Suggests

An enzyme called granzyme B (GzmB) may be a key mediator of blistering in patients with epidermolysis bullosa acquisita (EBA) and other autoimmune skin disorders, according to a Canadian study.

These findings suggest that a single treatment strategy could be developed for different conditions.

The research, “Granzyme B is elevated in autoimmune blistering diseases and cleaves key anchoring proteins of the dermal-epidermal junction,” was published in the journal Scientific Reports.

Skin blistering is a hallmark of several dermatological conditions, including EBA and other autoimmune diseases that target the dermal-epidermal junction (DEJ) — the area between the dermis and epidermis, two skin layers — causing its detachment.

GzmB plays a role in immune cell-mediated apoptosis, which refers to “programmed” cell death, as opposed to cell death caused by an injury. The accumulation of GzmB in the space outside cells (extracellular) has been linked with inflammatory conditions, and studies have shown that GzmB targets multiple proteins as well as messenger molecules known as cytokines, affecting tissue structure and function.

GzmB buildup at the DEJ is a known event in autoimmune skin blistering disorders, but little is known about its mechanism of action besides participating in the apoptosis of keratinocytes, the predominant cell type in the epidermis — the skin’s outer layer.

Given the accumulation of GzmB in DEJ and its potential to target proteins in the extracellular matrix (ECM), which provides structural and biochemical support to cells, scientists hypothesized that GzmB disrupts DEJ through cleavage of alpha6/beta4 integrin, collagen VII, and collagen XVII, which are essential proteins for cell adhesion in DEJ. All three of these proteins have been implicated in different types of EB.

Using in vitro experiments and analytical assays, researchers found that GzmB delivered at a physiologically relevant concentration causes separation of the DEJ in healthy human skin. This detachment was prevented with a GzmB-specific inhibitor.

Researchers then observed that alpha6/beta4 integrin, collagen VII, and collagen XVII were all targeted by GzmB outside the cells, and identified several specific degradation sites in each protein.

Subsequent analyses revealed that the level of GzmB was elevated in samples from patients with EBA and two other autoimmune skin conditions called bullous pemphigoid and dermatitis herpetiformis, in comparison with samples from healthy individuals. In contrast, alpha6/beta4 integrin, collagen VII, and collagen XVII were all reduced or absent in the area of blistering.

“This work demonstrates for the first time a role for extracellular GzmB in the blistering process,” the researchers wrote. The similar findings in different types of skin conditions indicate that “GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach,” they concluded.

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