The next article in the series is a Review by Michael Hertl
and colleagues (19
), who offer a new perspective on the pathogenesis
of a family of rare, autoimmune blistering skin diseases known
as pemphigus and pemphigoid. The name pemphigus is derived from
the Greek word pemphix
, meaning "bubble" or "blister," originally
coined by McBride in 1777 and Wichmann in 1791. The more severe
forms of pemphigus are potentially life threatening and involve
the skin as well as the oral mucosa (20
The autoantigens in pemphigus are epidermal desmosomal cadherinsthat mediate the intercellular adhesion of keratinocytes, specificallydesmoglein 1 in pemphigus foliaceous and desmoglein 3 in pemphigusvulgaris (PV). Likewise, the autoantibodies in bullous pemphigoids(BPs) are 2 hemidesmosomal proteins that are involved in cellbasement membrane attachment of basal keratinocytes, specificallythe 180-kDa BP antigen (BP180, also known as type XVII collagen)and the 230-kDa BP antigen (BP230).
The pathognomonic blisters of pemphigus arise from the bindingof circulating autoantigenic IgG molecules to these keratinocyteproteins and the subsequent disruption of intercellular adhesioneither through a direct effect on desmosomal or hemidesmosomalarchitecture, by triggering cell signaling processes that resultin loss of cell adhesion (acantholysis), or both. Thus the criticalrole of the B cell in generating the secreted autoantibodiesfound in pemphigus patients has long been known. Hertl and colleaguesfocus instead on the emerging importance of the T cell in pemphigus(19). These authors describe a "multiple hit" model of lossof immune tolerance in pemphigus. The authors review severallines of evidence that collectively show that neither circulatingIgG nor autoreactive T cells alone are sufficient to elicitPV and suggest that a third population of cells, Tregs, maybe critical in its pathogenesis.
The role of Tregs in suppressing immune responses, controllingautoimmunity, and maintaining tolerance has not been widelystudied in the setting of pemphigus; however, some recent worksuggests a potential imbalance of these cells in PV patients.One study found that Tregs were found in the autoreactive Tcells of a large number of healthy individuals but in only 20%of PV patients, raising the possibility that the Tregs wererequired to keep the autoreactive T cells from evoking disease.A multiple hit model in pemphigus would therefore require anautoreactive B cell, an autoreactive T cell, and finally a lossof Treg suppressor activity in order to set the stage for PV.The requirement of this rare constellation of events might explainthe relatively low population incidence of PV, at only 1–2cases per 100,000 individuals. Hertl and colleagues suggestthat focusing on Tregs may represent a new therapeutic opportunityin the restoration of immune tolerance in the pemphigus familyof autoimmune bullous diseases.