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.