Abstract
Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1 + aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.
Highlights
Pemphigus is an autoimmune dermatosis characterized by blistering of the epidermis and/or mucous membranes[1]
Activation of p38MAPK was found under all pathological conditions which is in line with all publications where a role of this pathway in pemphigus pathogenesis has been reported downstream of pemphigus vulgaris (PV)-IgG, pemphigus foliaceus (PF)-IgG and AK2316, 19, 23, 25, 33–41
It is possible that p38MAPK and sarcoma-associated kinase (Src) are relevant for Dsg[3] clustering as proposed before[25, 33, 43] the role of this process leading to loss of cell cohesion is not clear since it was detected in unaffected skin of mucosal PV (m-PV) and mucocutaneous PV (mc-PV) patients as well[26]
Summary
Pemphigus is an autoimmune dermatosis characterized by blistering of the epidermis and/or mucous membranes[1]. It was shown that modulation of signaling events prevents pemphigus skin blistering in a set of different models[16] These pathways include, but are not limited to, Ca2+ influx[17], protein kinase C (PKC)[18], sarcoma-associated kinase (Src)[19, 20] and p38 protein-activated kinase (p38MAPK) signaling[21]. We found signaling patterns correlating with clinical phenotype and autoantibody profile and observed key mechanisms for desmosome regulation including p38MAPK-, PKC- and Src activation which may resolve the question why in several models of pemphigus inhibition of one single signaling pathway is protective
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