Abstract
In pemphigus vulgaris (PV), autoantibodies directed against the desmosomal cadherin desmoglein (Dsg) 3 cause loss of intercellular adhesion. It is known that Dsg3 interactions are directly inhibited by autoantibody binding and that Dsg2 is upregulated in epidermis of PV patients. Here, we investigated whether heterophilic Dsg2-Dsg3 interactions occur and would modulate PV pathogenesis. Dsg2 was upregulated in PV patients’ biopsies and in a human ex vivo pemphigus skin model. Immunoprecipitation and cell-free atomic force microscopy (AFM) experiments demonstrated heterophilic Dsg2-Dsg3 interactions. Similarly, in Dsg3-deficient keratinocytes with severely disturbed intercellular adhesion Dsg2 was upregulated in the desmosome containing fraction. AFM revealed that Dsg2-Dsg3 heterophilic interactions showed binding frequency, strength, Ca2+-dependency and catch-bond behavior comparable to homophilic Dsg3-Dsg3 or homophilic Dsg2-Dsg2 interactions. However, heterophilic Dsg2-Dsg3 interactions had a longer lifetime compared to homophilic Dsg2-Dsg2 interactions and PV autoantibody-induced direct inhibition was significantly less pronounced for heterophilic Dsg2-Dsg3 interactions compared to homophilic Dsg3 interactions. In contrast, a monoclonal anti-Dsg2 inhibitory antibody reduced heterophilic Dsg2-Dsg3 and homophilic Dsg2-Dsg2 binding to the same degree and further impaired intercellular adhesion in Dsg3-deficient keratinocytes. Taken together, the data demonstrate that Dsg2 undergoes heterophilic interactions with Dsg3, which may attenuate autoantibody-induced loss of keratinocyte adhesion in pemphigus.
Highlights
Desmosomes are highly regulated protein complexes mediating strong intercellular adhesion in tissues constantly exposed to high mechanical stress such as skin and heart [1, 2]
Primary keratinocytes derived from these mice show a highly disturbed intercellular adhesion
Dsg2 staining in PV1-IgG injected samples was increased, which was pronounced in keratinocytes surrounding the blisters where autoantibodies were bound predominantly (Figures 1B, arrows, C)
Summary
Desmosomes are highly regulated protein complexes mediating strong intercellular adhesion in tissues constantly exposed to high mechanical stress such as skin and heart [1, 2]. They are composed of the desmosomal cadherins desmoglein (Dsg) 1-4 and desmocollin (Dsc) 1-3, which mediate intercellular adhesion in a Ca2+-dependent manner [3]. Desmosomal cadherins are known to interact with their counterparts in a homo- and heterophilic manner [5,6,7,8] For those interactions, an interaction mechanism comparable to the. Dsg and Dsg show a reversed distribution gradient with predominant expression of Dsg in the basal layers
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