Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is associated with inflammation and disease severity in...

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease characterized by immune inflammatory response imbalance. The role of the proinflammatory cytokine tumour necrosis factor-like weak inducer of apoptosis (TWEAK) in the pathogenesis of PV is unclear.

To evaluate the inflammatory status in PV and investigate the role of TWEAK in initiating and exacerbating inflammation, as well as its effects on desmoglein (Dsg) internalization at keratinocyte membranes induced by PV cell models and individual PV IgG components.

We collected serum samples from 60 patients with new-onset PV and 55 healthy controls, to evaluate correlations between serum anti-Dsg antibody levels and disease severity, inflammatory cytokines [TWEAK, interleukin (IL)-1β, IL-2R, IL-6, IL-10, tumour necrosis factor (TNF)-α] and chemokines (CCL2, CCL5, CXCL8). Subsequently, lesional skin samples from nine patients were collected to analyse local TWEAK, PV IgG expression and immune cell infiltration. Finally, an in vitro PV cell model was established to investigate the inflammatory potential and cell adhesion injury of PV IgG, individual PV IgG components and TWEAK induction.

Serum anti-Dsg1 antibody levels in patients with new-onset PV were positively correlated with the Pemphigus Disease Area Index score and levels of inflammatory cytokines (TWEAK, IL-6, TNF-α) and chemokines (CCL5, CXCL8). Furthermore, infiltration of immune cells (neutrophils, macrophages and T cells) was seen in the perilesional areas of skin lesions. In vitro experiments showed that TWEAK exacerbates desmosomal internalization in keratinocytes triggered by PV IgG components. Moreover, PV IgG components induce overexpression of TWEAK and CXCL8 in keratinocytes, whereas IL-6, TNF-α and CCL5 were upregulated via TWEAK-dependent pathways, amplifying inflammatory cascades.

This study found elevated levels of inflammatory cytokines (TWEAK, IL-6, TNF-α) and chemokines (CCL5, CXCL8) in the circulation of patients with PV, which correlated with disease severity. Additionally, localized immune dysregulation involving neutrophils, macrophages and T cells was seen in PV skin lesions. We highlight the involvement of TWEAK in enhancing chemokine expression and cell adhesion injury in PV, which suggests a promising therapeutic avenue targeting TWEAK and inflammatory cytokines in the management of PV.