A NEW study used high-throughput proteomics to uncover molecular clusters and biomarkers linked to disease severity in bullous pemphigoid (BP), offering insights that could guide personalised treatment strategies.
Bullous pemphigoid is a chronic autoimmune blistering disorder driven by autoantibodies targeting BP180 and BP230 proteins in the skin. While type 2 inflammation has been implicated in BP pathogenesis, the broader landscape of immune dysregulation and its relationship with clinical severity remains incompletely understood.
Researchers analysed 29 skin biopsies and 27 matched serum samples from patients with BP, alongside samples from 14 healthy controls, using the Olink Target 96 Inflammation panel. They applied unsupervised clustering, principal component analysis, differential expression, gene set enrichment, and k-means clustering to identify molecular subgroups and define inflammatory signatures. Proteomic results were cross-validated with publicly available single-cell RNA sequencing data from BP skin lesions.
Distinct Inflammatory Signatures in Bullous Pemphigoid Skin and Serum
The analysis revealed distinct inflammatory profiles in BP compared with controls, identifying 22 and 16 differentially expressed proteins in skin and serum, respectively. Key proteins elevated in both compartments included CCL13, IL-6, OSM, TNFSF14, and CCL19. Notably, cutaneous CCL13, primarily expressed by keratinocytes, showed a strong correlation with the bullous pemphigoid disease activity index and autoantibody titres, highlighting its potential as a biomarker of disease severity.
Two molecular skin clusters were identified. One cluster exhibited broader type 2 inflammatory activation and higher BP180-IgG antibody titres, with CCL13 emerging as a primary driver of cluster separation. Additionally, higher baseline serum IL22RA1 levels were observed in patients who did not respond to therapy after one year, suggesting a potential predictive biomarker for treatment outcomes. Proteomic findings were largely concordant with transcriptomic data from single-cell analyses, reinforcing the robustness of the results.
Implications For Personalised Therapy in Bullous Pemphigoid
The study concludes that BP exhibits significant biological heterogeneity, with distinct inflammatory endotypes that could inform endotype-driven, personalised therapeutic strategies. CCL13, in particular, may serve as a key biomarker for disease activity and cluster assignment, offering a potential target for future interventions. These findings advance understanding of BP pathophysiology and highlight the value of integrated proteomic and transcriptomic analyses in guiding precision dermatology.
Reference
Calabrese L et al. High-throughput proteomics uncovers molecular clusters and biomarkers of severity in bullous pemphigoid. J Eur Acad Dermatol Venereol.2025;doi: 10.1111/jdv.70252
