Hemidesmosome Mutations Contribute to the Onset and Severity of Acquired Autoimmune Bullous Diseases

Hemidesmosomes are structures that anchor junctions between basal epithelial cells and the basement membrane, essential for skin integrity. Genetic mutation of hemidesmosomes was well documented for the inherited bullous disorder, but is rarely investigated for acquired bullous disorders. We designed a 16-gene targeted capture panel and sequenced 202 patients with hemidesmosomes-related acquired disorders and 123 healthy controls, identifying 114 pathogenic variants in 15 genes, including 20.2% novel variants. Clinical relevance (disease severity and outcome) and immunohistochemistry results demonstrated that ITGA6, LAMC2, and EPPK1 mutations significantly affected the expression of hemidesmosome-related proteins, compared with controls with non-carriers. Functional studies in Caenorhabditis elegans models with transmission electron microscopy and confocal microscopy demonstrated that ITGA6 (ina-1) mutation can disrupt the hemidesmosomes assembly network, such as cytolinker (vab-10a) and apical (mup-4) and basal (let-805), thereby disrupting the hemidesmosome structure. This represents a quantitative to qualitative change in pemphigoid disease. Transcriptomic and serum proteomic analyses further revealed that ITGA6 mutations perturb epithelial development and hemidesmosome integrity, with both missense/loss-of-function variants leading to activation of  NOD-like receptor-NF-κB-TNF-pyroptosis signaling pathways. These findings highlight the critical role of hemidesmosome genetic variants in the development of not only inherited but also acquired autoimmune bullous disorders.