# Bullous Pemphigoid Develops Independently of DAP12

## TL;DR

This study shows that bullous pemphigoid, an autoimmune skin disease, does not depend on DAP12 signaling for its development in a mouse model.

## Contribution

The study reveals that DAP12 signaling is not essential for bullous pemphigoid disease progression in mice.

## Key findings

- Disease activity in bullous pemphigoid is similar in DAP12-deficient and wildtype mice.
- TREM1 is upregulated in wildtype BP lesions, while TREM2+ cells are reduced.
- PI3Kδ inhibition does not affect disease progression in the mouse model.

## Abstract

The adaptor molecule DNAX-activating protein of 12 kDa (DAP12) is broadly expressed in innate immune cells, but its role in autoimmunity remains unclear due to its dual regulatory functions. We investigated the contribution of the DAP12 pathway to bullous pemphigoid (BP), the most common autoimmune blistering disease, using a mouse model induced by transfer of anti-type XVII collagen (Col17) IgG. Repeated anti-Col17 IgG injections over 12 days produced comparable disease activity in DAP12-deficient and wildtype mice (n = 17/group), indicating that disease induction occurs independently of DAP12 signaling. Flow cytometry and immunofluorescence analysis of lesional skin further revealed a strong upregulation of the DAP12-associated triggering receptors expressed on myeloid cells (TREM) 1 in wildtype BP lesions, whereas TREM2+ cell frequencies in anti-Col17 IgG-treated wildtype and DAP12 knock-out animals were significantly lower than in healthy controls. Additional flow cytometry analysis demonstrated altered inflammatory infiltrates with notably reduced frequencies of Siglec-f+ eosinophils in DAP12-deficient vs. wildtype lesional skin. In addition, pharmacological inhibition of PI3Kδ, a downstream kinase of the DAP12/TREM pathway, did not affect disease progression in anti-Col17 IgG-induced BP. Collectively, these findings indicate that while DAP12 signaling modulates local immune cell composition, the DAP12/TREM1/2-axis does not influence overall disease activity in experimental BP.