Low pathogenicity of anti‐desmoglein 3 immunoglobulin G autoantibodies contributes to the atypical clinical phenotypes in pemphigus

Abstract

The clinical phenotypes of pemphigus can be explained by the desmoglein (Dsg) compensation theory. However, some atypical cases such as cutaneous pemphigus vulgaris (cPV), in which patients have anti-Dsg3 antibodies without oral erosions, do not conform to this theory. To explain the discrepancy between clinical phenotypes and anti-Dsg antibody profiles, the pathogenic strength of immunoglobulin (Ig)G autoantibodies against Dsg3 must be taken into consideration. We analyzed the epitopes and blister-inducing pathogenic strength of the sera from three patients having IgG against Dsg3 without oral erosions with domain-swapped recombinant proteins and dissociation assay using cultured normal human epidermal keratinocytes. The results showed that all sera contained IgG directed against the amino terminal EC1 domain of Dsg3, as is found in most PV sera. However, dissociation assays revealed that the pathogenic strength of the anti-Dsg3 antibodies in all three cases was extremely lower than that of typical PV cases with mucosal involvement. In conclusion, when anti-Dsg3 IgG antibodies are not sufficient to inhibit the expression of Dsg3 in the oral mucosa, but can inhibit the expression in the skin, skin blisters can result. Therefore, the pathogenicity of anti-Dsg3 antibodies should be regarded as a key factor contributing to the clinical phenotype in pemphigus patients with conflicting antibody profiles.

Case of paraneoplastic pemphigus with immunoglobulin (Ig)G and IgA antibodies to various antigens

“…Although both anti-Dsg1 and Dsg3 antibodies were positive by ELISA and IgG deposit was observed around the keratinocyte by DIF, we could not histopathologically find acantholysis. In agreement with a recent study, 4 it appeared that the pathogenic strength of several antibodies in our case may be lower than typical pemphigus vulgaris cases with acantholysis. The patient was not affected by bronchiolitis obliterans, which develops as a serious complication of paraneoplastic pemphigus.…”

Keratins Regulate p38MAPK-Dependent Desmoglein Binding Properties in Pemphigus

“…Beginning of depletion of Dsg3 molecules was not detectable before 1 h after incubation with PV-IgG in wt keratinocytes which is contradictory to other studies where depletion was already detectable after 30 min of autoantibody incubation ( 57 , 58 ). However, these differences in our opinion can be explained by different model systems, methodical approach and several PV-IgG fractions used in the respective studies ( 51 , 59 – 61 ). Changes in molecule mobility may depend on PKC signaling ( 22 , 23 , 25 ) and be accompanied with changes in clustering of the desmosomal molecules.…”

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

“…2C). 2) Cutaneous blisters in PV were associated with the anti-Dsg3 antibody that did not induce keratinocyte separation in vitro (49), suggesting that non-Dsg antibodies, such as AMA, were required to overcome the epidermal integrity. 3) Anti-Dsg antibodies produced by PV patients during remission, people with some other diseases, and some healthy individuals (6, 50) do not produce PV-like lesions, perhaps because they lack partnering autoantibodies.…”