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Different Signaling Patterns Contribute to Loss of Keratinocyte Cohesion Dependent on Autoantibody Profile in Pemphigus
Author(s) -
Walter Elias,
Egu Desalegn,
Vielmuth Franziska,
Rotkopf Lukas,
Spindler Volker,
Waschke Jens
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.465.1
Subject(s) - pemphigus foliaceus , desmosome , pemphigus vulgaris , pemphigus , mucocutaneous zone , desmoglein , desmoglein 3 , autoantibody , antibody , immunology , keratinocyte , desmoglein 1 , medicine , biology , cell , pathology , cell culture , disease , genetics
Pemphigus is an autoimmune blistering skin disease. 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 caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in desmoglein (Dsg) 3 distribution were caused by mucosal (anti‐Dsg3 antibodies), mucocutaneous (anti‐Dsg1 and anti‐Dsg3 antibodies) as well as atypical cutaneous (anti‐Dsg3 antibodies only) PV‐IgG. All PV‐IgG fractions and AK23 compromised Dsg3 but not Dsg1 interactions and enhanced Src activity. In contrast, rapid Ca 2+ influx and Erk activation were induced by mucocutaneous PV‐IgG and pemphigus foliaceus (PF) IgG (both containing anti‐Dsg1) 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. 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 including p38MAPK, PKC and Src may explain why in several experimental models of pemphigus selective inhibition of one of these pathways was protective. Accordingly, in an ex vivo human skin model where mucocutaneous PV‐IgG but not AK23 induced blistering, inhibition of p38MAPK was protective and abolished ultrastructural alterations and reduction of desmosomes.