Autoantibody-Specific Signalling in Pemphigus

Pemphigus is a severe autoimmune disease impairing barrier functions of epidermis and mucosa. Autoantibodies primarily target the desmosomal adhesion molecules desmoglein (Dsg) 1 and Dsg 3 and induce loss of desmosomal adhesion. Strikingly, autoantibody profiles in pemphigus correlate with clinical phenotypes. Mucosal-dominant pemphigus vulgaris (PV) is characterised by autoantibodies (PV-IgG) against Dsg3 whereas epidermal blistering in PV and pemphigus foliaceus (PF) is associated with autoantibodies against Dsg1. Therapy in pemphigus is evolving towards specific suppression of autoantibody formation and autoantibody depletion. Nevertheless, during the acute phase and relapses of the disease additional treatment options to stabilise desmosomes and thereby rescue keratinocyte adhesion would be beneficial. Therefore, the mechanisms by which autoantibodies interfere with adhesion of desmosomes need to be characterised in detail. Besides direct inhibition of Dsg adhesion, autoantibodies engage signalling pathways interfering with different steps of desmosome turn-over. With this respect, recent data indicate that autoantibodies induce separate signalling responses in keratinocytes via specific signalling complexes organised by Dsg1 and Dsg3 which transfer the signal of autoantibody binding into the cell. This hypothesis may also explain the different clinical pemphigus phenotypes.

Automated summary

Pemphigus is a severe autoimmune disease that impairs barrier functions of the epidermis and mucosa by targeting desmosomal adhesion molecules Dsg1 and Dsg3. Therapy for pemphigus is focusing on specific suppression of autoantibody formation, but additional treatment options to stabilize desmosomes during acute phase and relapses may be beneficial. Autoantibodies interfere with desmosome adhesion through inhibiting Dsg adhesion and engaging signaling pathways, leading to different clinical pemphigus phenotypes.