IgA pemphigus is an autoimmune blistering skin disease characterized by tissue-bound and circulating IgA, but not IgG, autoantibodies (autoAbs) against epidermal cadherins. Patients present with vesiculopustular skin eruptions, intraepidermal acantholysis and neutrophilic infiltrates. We cloned anti- Desmoglein (Dsg) 3 monoclonal antibodies (mAbs) from an active IgA pemphigus vulgaris (IgA PV) patient, as confirmed by direct immunofluorescence (IF) microscopy and serum anti-Dsg3 IgA reactivity. Isolated Dsg3- specific IgA mAbs (in form of single-chain variable fragments, scFvs) bound to Dsg3 by ELISA and IF, and sera from the same patient and from unrelated active IgA/IgG PV patients led to decreased binding of our scFvs, indicating binding to similar epitopes as polyclonal IgA/IgG serum autoAbs. In human skin organ culture, our mAbs showed dose-dependent pathogenicity, indicating that in IgA PV anti-Dsg3 IgA mAbs are necessary but insufficient for disease induction alone, because concurrent inactivation of Dsg1 was required in our models, but absent in the patient. Additional Fc-dependent mechanisms potentially involved were then studied in an in vitro model, using recombinant human full anti-Dsg3 mAbs in the IgG1/IgA1 format: Incubation of skin cryosections with a full anti-Dsg3-IgA1 mAb and peripheral polymorphonuclear cells led to intraepidermal acantholysis, whereas the same mAb in the IgG1 format was ineffective. We here present conclusive evidence demonstrating that interaction of the anti-Dsg3 IgA1-Fc-part with its receptor is required and sufficient for pathogenicity in IgA pemphigus, without necessitating inactivation of compensatory Dsg1. Blocking this interaction may be a well suited therapeutic avenue for this difficult-to-treat skin disorder.

Pathogenicity of anti-desmoglein 3 IgA1 autoantibodies is Fc-dependent in IgA pemphigus