Autoantibodies against
desmoglein (Dsg) 1 and Dsg3 primarily cause
blister formation in the
autoimmune disease pemphigus vulgaris (PV). Src was proposed to contribute to loss of keratinocyte cohesion. However, the role and underlying mechanisms are unclear and were studied here. In keratinocytes, cell cohesion in response to
autoantibodies was reduced in Src-dependent manner by two patient-derived PV-
IgG fractions as well as by AK23 but not by a third PV-
IgG fraction, although Src was activated by all
autoantibodies. Loss of cell cohesion was progredient in a timeframe of 24 h and AK23, similar to PV-
IgG, interfered with reconstitution of cell cohesion after Ca2+-switch, indicating that the
autoantibodies also interfered with desmosome assembly. Dsg3 co-localized along cell contacts and interacted with the Src substrate
cortactin. In keratinocytes isolated from
cortactin-deficient mice, cell adhesion was impaired and Src-mediated inhibition of AK23-induced loss of cell cohesion for 24 h was significantly reduced compared to wild-type (wt) cells. Similarly, AK23 impaired reconstitution of cell adhesion was Src-dependent only in the presence of
cortactin. Likewise, Src inhibition significantly reduced AK23-induced skin blistering in wt but not
cortactin-deficient mice. These data suggest that the Src-mediated long-term effects of AK23 on loss of cell cohesion and skin blistering are dependent on
cortactin-mediated desmosome assembly. However, in human epidermis PV-
IgG-induced skin blistering and ultrastructural alterations of desmosomes were not affected by Src inhibition, indicating that Src may not be critical for skin blistering in intact human skin, at least when high levels of
autoantibodies targeting Dsg1 are present.