The specific proteolysis hypothesis of pemphigus: Does the song remain the same?

SummaryWithin the last decade, a number of theories on the pathogenesis of pemphigus vulgaris (PV) have followed one another. Of these, plesminogen activation and desmoglein compensation hypotheses have been substantiated by a conspicuous body of evidence. A significant change of this scenario occurred with the discovery that autoimmunity in PV can target acetylcholine receptors and that PV serum elicits a pletora of intracellular signals. Since then, a myriad of explanations accounting for PV acantholysis have appeared in the literature. However, as revolutionary as they can be, the majority of organic theories seemed to be highly speculative. We have recently obtained evidence for a proteolytic cleavage of desmoglein 3 in an in vitro model of PV; furthermore, our previous findings suggested the possible involvement of proteases such as matrix metalloproteinase (MMP) 9 in PV acantholysis both in vitro and in vivo. Hence, in formulating the “specific proteolysis theory” we have kept the rationale and the well-established evidence of both plasminogen activation and desmoglein compensation hypotheses. However, the specific proteolysis theory proposed by us is not just a return to the past. On the basis of the current knowledge on MMP substrate specificity we propose that Dsg1 and Dsg3, along with other important cadherins which are likely to be proteolytically targeted in PV, could be cleaved by either ADAM or typical MMPs, respectively. Whether this view was confirmed by further investigations, these enzymes could be specifically targeted by selective drugs which would permit more rational approaches to the treatment of pemphigus.