Prevalence and pathogenic activity of anti-Desmocollin-3 antibodies in patients with pemphigus vulgaris and pemphigus foliaceus

Abstract Background Desmocollin-3 (DSC3) is a calcium-dependent desmosomal cadherin that plays an essential role in cell–cell adhesion. IgG antibodies (Abs) directed against the extracellular (EC) domain of DSC3 have occasionally been detected in rare types of pemphigus. Investigations into the prevalence of anti-EC-DSC3 IgG Abs and those targeting the intracellular (IC) domain of DSC3 in pemphigus vulgaris and pemphigus foliaceus sera, and their potential pathogenic activity, have yielded conflicting results. Objectives To assess the prevalence and pathogenicity of Abs directed against the EC and IC domains of DSC3 in patients with pemphigus. Methods Anti-DSC3 IgG and IgA directed against the EC and IC domains of DSC3 were assayed in 146 patients with pemphigus using a newly developed addressable laser bead immunoassay. The pathogenicity of these autoAbs was first tested in vitro using a keratinocyte dissociation assay with patients’ sera or from C57BL/6 mice immunized with recombinant IC-DSC3. In vivo pathogenicity was tested by passive transfer of an anti-IC-DSC3 monoclonal Ab (mAb) derived from a hybridoma (A9) into neonatal mice. Results Anti-EC-DSC3 or anti-IC-DSC3 IgG and/or IgA Abs were detected in 21.2% of sera from patients with pemphigus vs. 4.0% (P < 0.001) and 5.0% (P < 0.001) of sera from healthy donors, respectively. Most anti-DSC3 Abs corresponded to IgA. Anti-IC-DSC3 Abs were detected in 44% of patients with pemphigus whose serum anti-desmoglein (DSG) 1–3 Ab profile was inconsistent with their clinical and histological features, according to compensation theory. Anti-IC-DSC3 IgG and IgA Abs induced a dissociation of the keratinocyte monolayer in vitro, which was abolished by preadsorption of these IgG or IgA fractions with recombinant IC-DSC3. In addition, IgG from mice immunized with recombinant IC-DSC3 induced acantholysis in vitro. Finally, in neonatal mice, the passive transfer of an anti-IC-DSC3 mAb in combination with anti-DSG1–3 Abs exacerbated blister formation. Conclusions Our findings suggest that anti-IC-DSC3 Abs are pathogenic and explain the discordance seen in some patients with regard to their clinical phenotype and their anti-DSG1–3 Ab profile.