Analysis of the inflammatory microenviroment, serum biomarkers and T-cell repertoire to early identify patients with mucous membrane pemphigoid at risk of scarring

Introduction Mucous membrane pemphigoid (MMP) is a rare autoimmune subepithelial blistering disorder that predominantly affects mucosal surfaces, most commonly the oral and conjunctival mucosa. The disease follows a chronic-relapsing course. While oral lesions typically heal without permanent sequelae, ocular involvement progresses to irreversible scarring and visual impairment. The mechanisms underlying these divergent clinical outcomes remain poorly understood, and reliable serum biomarkers predicting ocular involvement are currently lacking. Objectives This study aimed (i) to evaluate the prevalence of autoantibodies against integrin β4 in patients with MMP and to assess their association with ocular involvement, and (ii) to characterize the local and systemic immune profiles of MMP, with particular emphasis on differences between ocular and oral lesions. Materials and Methods Serum samples from 85 patients with MMP, 30 patients with bullous pemphigoid (BP), and 14 healthy controls were collected across multiple European centers. Autoantibodies against integrin β4 were detected by immunoblotting, with specificity confirmed using A431 cells before and after targeted silencing of the integrin β4 gene. In parallel, proteomic analyses were performed on lesional tissue and serum samples from 22 patients with MMP, including 10 with exclusively oral involvement and 12 with ocular involvement. Results Autoantibodies against integrin β4 were detected in 13 of 85 patients with MMP but were absent in BP patients and healthy controls. No significant association was observed between the presence of these antibodies and ocular disease. Proteomic profiling revealed marked differences in lesional immune responses. Ocular MMP lesions showed increased expression of Th17/Th1-associated mediators, including IL-17C, CXCL9, and CXCL10, as well as fibrosis-related markers such as CCL19. In contrast, oral lesions were enriched in alarmins, particularly IL-18, and factors involved in tissue repair and angiogenesis, including VEGF-A and CXCL12. Systemic inflammatory profiles were comparable between oral and ocular MMP and were characterized by elevated Th2/fibrotic mediators and chemokines involved in neutrophil recruitment and activation of dendritic, T, and B cells. Conclusions Autoantibodies against integrin β4 appear to be specific for MMP but do not serve as biomarkers of ocular involvement. A polarized Th17/Th1 inflammatory milieu and CCL19 expression may contribute to fibrotic processes underlying ocular cicatricial pemphigoid.