# Tyrosine kinase signaling pathways as therapeutic targets in autoimmune subepidermal blistering skin diseases (pemphigoid diseases)

## TL;DR

This paper reviews how tyrosine kinase signaling pathways contribute to autoimmune skin blistering diseases and explores their potential as therapeutic targets.

## Contribution

The paper provides a comprehensive review of tyrosine kinase signaling pathways as emerging therapeutic targets in pemphigoid diseases.

## Key findings

- Non-receptor tyrosine kinases like Src-family and Syk are crucial in Fcγ-receptor signaling in pemphigoid diseases.
- JAK-family kinases play a key role in cytokine signaling, including IL-4 and IL-13 pathways.
- Inhibition of these tyrosine kinases with small molecule inhibitors shows promise in treating pemphigoid diseases.

## Abstract

Pemphigoid diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita, are severe organ-specific autoimmune diseases characterized by subepidermal skin blistering with increasing incidence in recent years. Although there have been substantial advances in understanding the pathomechanism of these diseases in the last decades, and the first specific therapy targeting the IL-4 and IL-13 pathway (dupilumab) has been approved by the FDA for bullous pemphigoid, further research is needed to eventually improve patient care. The characteristics of pemphigoid diseases include the formation of immune complexes and their recognition by Fcγ-receptors, as well as the development of a characteristic inflammatory cytokine microenvironment in the skin of the affected patients. Several non-receptor tyrosine kinases are involved in these events, playing a very important role in various signaling processes of immune cells. While certain Src-family kinases and the Syk tyrosine kinase play a very important role in signaling by Fcγ-receptors, JAK-family kinases are crucial players in the signaling of various cytokine receptors including, among others, the receptors of IL-4 and IL-13. The inhibition of these tyrosine kinases with small molecule inhibitors is an emerging therapeutic option in the treatment of an increasing number of immune-mediated diseases. Moreover, numerous studies have been conducted to examine proteins (including PLCγ2 and CARD9) in signal transduction following Fcγ-receptor activation in in vitro and in vivo experimental pemphigoid models, and an increasing number of case studies involving JAK inhibitors report the successful application of these drugs in various pemphigoid diseases. This review summarizes our current understanding of the therapeutically most promising tyrosine kinase signaling pathways in the pathogenesis of pemphigoid diseases.