Pemphigus vulgaris and foliaceus IgG autoantibodies directly block heterophilic trans-interaction between desmoglein and desmocollin

Abstract Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus (PF) and vulgaris (PV) cause blisters through loss of desmosomal adhesion. It is controversial whether blister formation is due to direct inhibition of Dsg or intracellular signaling events causing desmosome destabilization or both. Recent studies show that heterophilic binding between Dsg and desmocollin (Dsc) is the fundamental adhesive unit of desmosomes. To eliminate cellular contributions to potential pathogenicity of pemphigus Abs, bead assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed. A mixture of Dsg beads and Dsc beads formed large aggregates, confirming that the heterophilic binding is dominant. The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas non-pathogenic mAbs did not. All sera tested from 8 PF and 8 mucosal PV patients with active disease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively. When paired sera obtained from 7 PF and 6 PV patients in active disease and remission were compared, the former inhibited aggregation better than the latter. These findings strongly suggest that steric hindrance of heterophilic transinteraction between Dsg and Dsc is important for disease pathology in both PF and PV.