Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction.
The autoimmune blistering skin disease pemphigus is caused by autoantibodies against keratinocyte surface Ags. In pemphigus vulgaris (PV), autoantibodies are primarily directed against desmosomal cadherins desmoglein (Dsg) 3 and Dsg 1, whereas pemphigus foliaceus (PF) patients only have Abs against Dsg 1. At present, it is unclear whether Dsg autoantibodies contribute to pemphigus pathogenesis by direct inhibition of Dsg transinteraction. Using atomic force microscopy, we provide evidence that PV-IgG directly interfere with homophilic Dsg 3 but, similar to PF-IgG, not with homophilic Dsg 1 transinteraction, indicating that the molecular mechanisms in PV and PF pathogenesis substantially differ. PV-IgG (containing Dsg 3 or Dsg 1 and Dsg 3 autoantibodies) as well as PV-IgG Fab reduced binding activity of Dsg 3 by approximately 60%, comparable to Ca(2+) depletion. Similarly, the mouse monoclonal PV Ab AK 23 targeting the N-terminal Dsg 3 domain and AK 23 Fab reduced Dsg 3 transinteraction. In contrast, neither PV-IgG nor PF-IgG blocked Dsg 1 transinteraction. In HaCaT monolayers, however, both PV- and PF-IgG caused keratinocyte dissociation as well as loss of Dsg 1 and Dsg 3 transinteraction as revealed by laser tweezer assay. These data demonstrate that PV-IgG and PF-IgG reduce Dsg transinteraction by cell-dependent mechanisms and suggest that in addition, Abs to Dsg 3 contribute to PV by direct inhibition of Dsg transinteraction.
Heupel
Wolfgang-Moritz
WM
Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
Zillikens
Detlef
D
Drenckhahn
Detlev
D
Waschke
Jens
J
D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002474:Cell-Free System; D051183:Desmoglein 1 / Q000276:immunology / Q000378:metabolism; D051184:Desmoglein 3 / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D018625:Microscopy, Atomic Force; D010392:Pemphigus / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding
D051183:Desmoglein 1; D051184:Desmoglein 3; D007074:Immunoglobulin G