title: High-dose pemphigus antibodies against linear epitopes of desmoglein 3 (Dsg3) can induce acantholysis and depletion of Dsg3 from keratinocytes.
abstract: We have previously demonstrated that serum autoantibodies of patients with pemphigus vulgaris (PV) may affect desmoglein 3 (Dsg3)-mediated adhesion by decreasing its half-life and inducing Dsg3 cleavage. Here we sought to gain more insights into the role of Dsg3-targetting IgG in acantholysis. To do so, alterations of keratinocyte morphology and cell-cell adhesion strength were investigated in the presence of PV serum, PV IgG, and IgG purified from PV patients' sera against linear epitopes of Dsg3 (anti-Dsg3-L IgG). Changes in Dsg3 protein levels were assessed by Western blotting. Results showed that both PV serum and PV IgG were able to induce acantholysis and decrease the total amount of Dsg3 in cell lysates. Polyclonal anti-Dsg3-L IgG displayed Dsg3-depleting activity solely when used at 1 microg/ml, i.e. under non-physiologic conditions. Furthermore, cell-cell detachment induced by PV IgG and anti-Dsg3-L IgG seemed to precede the loss of Dsg3 from keratinocytes, suggesting that depletion/degradation of Dsg3 represents a late event in acantholysis. Collectively, the data presented here demonstrate that PV IgG recognizing non-conformational epitopes of Dsg3 are pathogenic when administered on doses largely exceeding those found in PV sera.
authors.affiliation: Regional Center on Craniofacial Malformations-MRI, Italy. cirillo.sun@libero.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Cirillo
authors.forename: Felice
authors.initials: F
authors.lastname: Femiano
authors.forename: Fernando
authors.initials: F
authors.lastname: Gombos
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lanza
mesh_terms: D000051:Acantholysis; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity; D002448:Cell Adhesion; D002460:Cell Line; D051184:Desmoglein 3 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010392:Pemphigus / Q000276:immunology* / Q000503:physiopathology; D011487:Protein Conformation
chemical_list: D001323:Autoantibodies; C071894:DSG3 protein, human; D051184:Desmoglein 3; D018985:Epitopes, B-Lymphocyte