ST18 Enhances PV-IgG-Induced Loss of Keratinocyte Cohesion in Parallel to Increased ERK Activation

Discussions Autoantibodies targeting Dsg1 and Dsg3 are pathogenic and cause blister formation by inducing structural desmosomal changes in the skin of PV patients (42). However, the mechanisms underlying disease development and the factors enhancing its manifestation have not yet been fully elucidated. Secondary factors promoting severity of the disease include non-Dsg antibodies (43) as well as genetic alterations such as recently reported ST18 SNPs (29–31) and may also entail keratinocyte-derived cytokine release. Here, we investigate the effect of ST18 overexpression and cytokine secretion on PV-IgG mediated loss of adhesion. We observed that in both HaCaT and NHEK the release of key pro-inflammatory molecules such as IL-1α, IL-6, TNF-α, and IFN-γ is not strictly required for PV-IgG-induced loss of cell cohesion. However, ST18 overexpression did not only modulate cytokine release in some of the experiments but also altered ERK activity. Pemphigus, as an autoimmune disease, depends highly on the activity of T-cells, the differentiation of which is regulated by autocrine cytokine signaling and is modulated by paracrine cytokine secretion from other cell type such as keratinocytes (44, 45). In skin, the production and secretion of cytokines has been recognized long ago and therefore intensely studied (46). These pro-inflammatory cytokines can also modulate keratinocyte behavior and could therefore be relevant for blister formation in pemphig...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research