In this new century of
pemphigus research, the search for novel treatments is switching from a monospecific approach, focused on immunosuppression, to a polyspecific approach that includes drugs acting on novel pathophysiologic pathways. Current research argues that
acantholysis in
pemphigus occurs as an active process resulting from intracellular signaling triggered as a result of
IgG binding to the keratinocyte membrane
antigens in a receptor-
ligand fashion. Recent progress regarding the pathophysiology of
pemphigus acantholysis led to, or was accompanied by, breakthrough discoveries of safer treatments. Both the identification of
cell-surface receptors to
acetylcholine among the nondesmoglein (Dsg) targets for
pemphigus antibodies, and the elucidation of the
cholinergic control of keratinocyte cell adhesion provide an explanation for the therapeutic efficacy of
cholinomimetics in patients with
pemphigus. In patients' skin, Fas-L,
TNFalpha, and, probably, IL-1alpha act as autocrine/paracrine co-factors for anti-keratinocyte
IgG. Thus, it appears that an array of interconnected signaling cascades is responsible for
acantholysis and cell death in
pemphigus. Future studies should define the signaling pathways mediating
acantholysis that occur in individual
pemphigus patients and identify the
membrane proteins (receptors) triggering signaling along a specific pathway upon their
ligation by
autoantibodies. It will be important to determine which pathway 1) leads directly to a loss of cell-cell adhesion (primary pathway), 2) which is being activated due to cell shrinkage/detachment (secondary pathway), 3) which contributes to utilization of altered
proteins and organelles (scavenging pathway), and 4) which represents the cell defense (protective pathway). To dissect out the signaling pathways originating from binding of
pemphigus IgG to non-Dsg targets on the keratinocyte plasma membrane experiments should be performed in cultures of murine keratinocytes grown from the Dsg3-/- mice or human keratinocytes with the knocked-down expression of the Dsg1 and/or Dsg3 gene by the RNA interference.