Autoantibody-Specific Signalling in Pemphigus

Abstract

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.

Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?

“…Therefore, monoclonal antibodies may not be capable of inducing all of the signaling responses that are observed upon PV IgG treatment. Furthermore, loss of Dsg3 after anti-Dsg3 treatment may even not be the key event per se that leads to the cellular responses that include diverse signaling cascades and even activation of apoptotic pathways (reviewed in [8]).…”

“…Various hypotheses have been put forward to explain the mechanisms of loss of desmosomal adhesion upon autoantibody binding. While steric hindrance due to antibody binding to Dsg and Dsc plays an important role, there is ample evidence for the involvement of antibody-induced, Dsg-mediated signaling through cascades such as the mitogen-activated protein kinase (MAPK) p38 and extracellularly regulated kinase (ERK), as well as other signaling pathways (reviewed in [2,[6][7][8]). For reviews on the detailed mechanisms of loss of keratinocyte adhesion and signaling in PV, please also refer to [8,9].…”

Autoimmune Pemphigus: Latest Advances and Emerging Therapies

“…In PNP, autoantibody binding also seems to inhibit A2ML1 (α-2 microglobulin-like 1) impacting the activation of a protease inhibitor (Inaoki et al, 2001;Schepens et al, 2010;Numata et al, 2013) (Figure 2C). For a recent indepth review of this topic see (Schmitt and Waschke, 2021).…”

Apremilast prevents blistering in human epidermis by stabilization of keratinocyte adhesion in pemphigus

“…Therefore, a precise understanding of the mechanisms leading to loss of intercellular adhesion in keratinocytes is of high clinical impact. Reported mechanisms comprise direct inhibition of Dsg3 interaction and dysregulation of various intracellular signaling pathways upon autoantibody binding, which finally cause alterations of the keratin cytoskeleton as well as depletion of Dsg molecules from cell membranes of keratinocytes [14][15][16][17] . However, the plethora of signaling mechanisms involved is not yet fully elucidated.…”