Abstract
Pemphigus is an autoimmune dermatosis in which mucocutaneous blisters are induced primarily by autoantibodies against Desmoglein (Dsg) 1 and 3. Pemphigus vulgaris (PV) usually is associated with autoantibodies against Dsg3 whereas pemphigus foliaceus (PF) patients present autoantibodies against Dsg1. Several signaling pathways were proposed to cause loss of keratinocyte adhesion. However, relevance of different signaling pathways and role of Dsg1 and 3 to trigger signaling are not fully understood. Here, we show that Ca2+ chelation reduced PV-IgG- and PF-IgG-mediated loss of HaCaT keratinocyte cohesion whereas EGFR inhibition did not inhibit effects of PF-IgG. PV-IgG activated EGFR in a Src-dependent manner whereas both PV-IgG and PF-IgG caused Ca2+ influx independent of EGFR. ERK activation was Src-dependent in response to PV-IgG but not PF-IgG. To delineate the roles of Dsg isoforms to trigger signaling pathways, Dsg3- and Dsg2-deficient HaCaT keratinocyte cell lines were generated using CRISPR/Cas9. Dsg3- but not Dsg2-deficient cells were protected against PV-IgG-induced loss of cell adhesion. Ca2+ influx and ERK activation in response to PF-IgG were preserved in both cell lines.
Highlights
Pemphigus is an autoimmune blistering disease affecting mucous membranes and the epidermis [1]
We investigated the relevance of Ca2+ influx and epidermal growth factor receptor (EGFR) signaling for loss of keratinocyte adhesion in response to IgG fractions containing different profiles of aDsg1 and aDsg3 antibodies from patients suffering from mPV, mc-Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) in dispase-based dissociation assays
This study demonstrates that IgG-induced signaling mechanisms in keratinocytes correlate with different autoantibody profiles in PV and PF
Summary
Pemphigus is an autoimmune blistering disease affecting mucous membranes and the epidermis [1]. The pathogenesis of pemphigus is complex and includes genetic factors facilitating production of autoantibodies and enhancing susceptibility of keratinocytes for loss of cell adhesion [2, 3]. Factors contributing to blister formation include antibodies against the desmosomal cadherins desmoglein (Dsg) 1 and 3 [1] as well as non-antibody factors such as soluble Fas ligand [4]. Autoantibodies against other keratinocyte antigens are found in patients’ sera and blister fluid and may augment pathogenic effects, their role for blister formation is undefined at present [5, 6]. Desmosomes are highly specialized adhesive contacts most abundant in tissues subjected to high mechanical stress such as the epidermis and heart muscle [8].
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