Abstract
Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disorder characterized and caused by autoantibodies against type VII collagen (COL7). Although it has been noticed that EBA in both patients and mice is associated with an increased scratching, it is not clear whether and how the scratching contributes to disease manifestation. Hence, we here aimed to validate this clinical observation and also to investigate the potential contribution of increased scratching in EBA pathogenesis in mice. Longitudinal assessment of scratching behavior revealed an increased frequency of scratching as early as 12 hours after injection of anti-COL7 IgG into the skin of mice. Subsequently, scratching events became even more frequent in mice. In contrast, mice injected with a control antibody showed an unaltered scratching behavior throughout the observation period. Based on these observations, we hypothesized that mechanical irritation may promote the induction of inflammation in experimental EBA. To challenge this assumption, the local anesthetic dyclonine hydrochloride was topically applied before injection of anti-COL7 IgG. Dyclonine hydrochloride reduced the scratching events and impaired clinical disease manifestation. In therapeutic experimental settings, i.e. administration of the local anesthetic 24 hours after injection of anti-COL7 IgG, dyclonine hydrochloride only inhibited the scratching behavior, but had no significant effect on clinical disease development. In addition, eosinophils were detected in the skin before the injection of anti-COL7 IgG and significantly increased 48 hours after the antibody injection. Collectively, our results suggest that scratching behavior contributes to the initiation phase of disease manifestation in experimental EBA.
Highlights
Autoimmune bullous dermatoses (AIBD) represent a group of acquired organ-specific autoimmune diseases mediated by autoantibodies targeting proteins which are essential for integrity of skin and mucous membranes [1, 2]
We first investigated whether injection of pathogenic antibodies against murine COL7 (mCOL7) could affect the scratching behavior of mice
IgG, mice injected with rabbit anti-mCOL7 IgG showed significantly higher scratching frequencies at all three time points after antibody injection, and the difference increased over time (Figure 1C), suggesting that injection of pathogenic antibodies against mCOL7 promoted scratching behavior in anti-mCOL7 IgG-injected mice
Summary
Autoimmune bullous dermatoses (AIBD) represent a group of acquired organ-specific autoimmune diseases mediated by autoantibodies targeting proteins which are essential for integrity of skin and mucous membranes [1, 2] Within this group, epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disorder characterized and caused by autoantibodies against type VII collagen (COL7) [3, 4]. To better understand the pathogenesis of EBA, several mouse models have been established either by immunizing mice with recombinant murine COL7 (mCOL7) [5] or by transfer of antibodies against COL7 into mice [6,7,8] With these valuable experimental models, considerable progress has been achieved in our understanding of how autoantibodies against COL7 cause inflammation and tissue damage [9]. After binding to its target antigen, autoantibody-induced inflammation and blistering is modulated by several cell types, such as neutrophils [14, 15] and T cells [16], as well as several molecular pathways, including complement activation [6, 17], reactive oxygen species [18], specific proteases [19], lipid mediators [20], signaling molecules [21], and several cytokines [22, 23]
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