title: p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris.
abstract: Pemphigus vulgaris (PV) is a potentially fatal blistering disease characterized by autoantibodies against the desmosomal adhesion protein desmoglein (Dsg) 3. Whether autoantibody steric hindrance or signaling through pathways such as p38 MAPK is primary in disease pathogenesis is controversial. PV mAbs that cause endocytosis of Dsg3 but do not dissociate keratinocytes because of compensatory adhesion by Dsg1 do not activate p38. The same mAbs plus exfoliative toxin to inactivate Dsg1 but not exfoliative toxin alone activate p38, suggesting that p38 activation is secondary to loss of adhesion. Mice with epidermal p38α deficiency blister after passive transfer of PV mAbs; however, acantholytic cells retain cell surface Dsg3 compared with wild-type mice. In cultured keratinocytes, p38 knockdown prevents loss of desmosomal Dsg3 by PV mAbs, and exogenous p38 activation causes internalization of Dsg3, desmocollin 3, and desmoplakin. p38α MAPK is therefore not required for the loss of intercellular adhesion in PV, but may function downstream to augment blistering via Dsg3 endocytosis. Treatments aimed at increasing keratinocyte adhesion could be used in conjunction with immunosuppressive agents, potentially leading to safer and more effective combination therapy regimens.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Xuming
authors.initials: X
authors.lastname: Mao
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
authors.forename: Aimee S
authors.initials: AS
authors.lastname: Payne
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D051184:Desmoglein 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D004817:Epidermis / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010392:Pemphigus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C071894:DSG3 protein, human; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases