IgA pemphigus is a vesiculopustular variant of the pemphigus group, characterized by detection of IgA, but not IgG against epidermal cell adhesion proteins. A patient with clinical, histopathological, and immunological characteristics of the IgA-Pemphigus vulgaris (IgA-PV) type was studied: Serum autoantibodies (autoAbs) exhibited Desmoglein (Dsg) 3, but no Dsg1 reactivity in both Dsg-IgA1 ELISA and indirect immunofluorescence (IF) of transfected cells; direct IFs showed ntercellular cell-surface IgA. No IgG reactivity was detected. EDTA-pretreated Dsg3-ELISAs and blotting studies confirmed binding of autoAbs to both Ca2+-sensitive conformational and linear epitopes. Applying phage display, we obtained 3 anti-Dsg3 monoclonal Abs (mAbs) from this patient, shown to be derived from 2 B-cell clones genetically and using the VH gene 3-23. Binding to Dsg3 was confirmed by ELISA and IF, and direct pathogenicity was observed in skin organ culture injection studies and keratinocyte dissociation assays (under elimination of Dsg1-compensation), recapitulating the effects of this patient’s serum abs in those same assays. Further validating our mAbs, we showed, by inhibition ELISA, binding to Dsg3-epitopes also bound by serum abs; final validation will be pursued by LC-MS
2  of affinity-purified anti-Dsg3 serum IgA. Since no Dsg1-IgA reactivity was
detected in our patient, despite clinical affection of both skin and mucous membranes, additional pathophysiologic mechanisms must be involved; histologically, neutrophils figure prominently in IgA pemphigus and in this patient. We now dissect the potential contribution of neutrophil activation by Dsg3:anti-Dsg3-IgA immune complexes to disease. Shown cross-reactivity of our Dsg3-mAbs to murine keratinocytes may facilitate development of a mouse model.

Anti-desmoglein 3 autoantibodies cloned from the IgA1 repertoire of an IgA pemphigus patient are directly pathogenic,  but not sufficient for disease induction