Background: Pemphigus vulgaris (PV) is an autoimmune disease characterized by blister formation in the epidermis and oral mucosa due to loss of keratinocyte cohesion. Autoantibodies present in patients with PV (PV-IgG) are known to primarily target desmoglein (Dsg)1 and Dsg3 in desmosomes. The mucosal-dominant subtype of PV (mdPV) is caused by PV-IgG autoantibodies against the cadherin-type adhesion molecule Dsg3. p38 mitogen-activated protein kinase (p38MAPK) signalling has been characterized as an important pathway downstream of PV-IgG binding and its inhibition is protective in ex vivo human skin. However, the role of p38MAPK signalling in mdPV is unknown as no experimental model has been available. Objectives: To establish a human ex vivo oral mucosa culture, and evaluate the p38MAPK dependency of blister formation and of ultrastructural alterations of desmosomes induced by mdPV-IgG. Methods: Human labial mucosa was injected with mdPV-IgG as well as AK23, a pathogenic mouse monoclonal Dsg3 antibody, in the presence or absence of p38MAPK inhibitors. Viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay. Blister score was determined following haematoxylin and eosin staining and Dsg3 distribution by immunostaining. Samples were processed for transmission electron microscopy to analyse desmosome ultrastructure. Results: Both AK23 and mdPV-IgG induced blisters and caused reduction in desmosome size and number in labial mucosa. Inhibition of p38MAPK was not effective in preventing these alterations. Conclusions: In contrast with human epidermis, PV-IgG and AK23 induce blisters and desmosome ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK. What's already known about this topic?. Pemphigus vulgaris IgG (PV-IgG) induces blistering as well as a reduction in desmosome number and size mediated by p38 mitogen-activated protein kinase (p38MAPK) signalling in ex vivo human skin. What does this study add?. This study establishes a new human ex vivo mucosa model to test pathomechanisms mediated by PV-IgG. The study demonstrates that both AK23 and mucosal-dominant PV induce blisters and associated ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK signalling. What is the translational message?. This study highlights the respective tissue-specific responses of oral mucosa and skin related to PV pathogenesis, similar to the patient situation.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)