Table II.

Hypotheses and realities in the knowledge of pemphigus.

Hypotheses	Realities
The epidermal integrity is mediated exclusively by the Dsg 1 and 3 adhesion molecules	Neither Dsg 1 nor Dsg 3 can solely sustain keratinocyte adhesion in epidermis. Patients with striate palmoplantar keratoderma featuring N-terminal deletion in Dsg 1 do not develop skin blisters [350], In turn, the conditional Dsc3nu” mutant mouse develops PV phenotype despite the presence of intact Dsg 3 [43]. If the integrity of epidermis would rely exclusively on Dsg 1 and 3, the epidermis should disintegrate to a single cell suspension in the PV patients who develop both anti-Dsg 1 and 3 antibodies (Figure 2)
Acantholysis is PV is caused by steric hindrance of Dsg 3 by autoantibodies	Electron microscopic studies of limited acantholysis produced by anti-Dsg 3 antibody in murine epidermis revealed that steric hindrance of Dsg 3 leads to a desmosomal split without keratin retraction [84,85], The ultrastructural changes in the skin of PV patients are quite different. Desmosomes remain intact till the late stages of acantholysis when they are cleaved behind the desmosomal plaque, due to shearing forces produced by collapsing cells, and float free in the intercellular space [55,86-90], Acantholysis is PV results from PV antibody-dependent signaling events collectively described by the term apoptolysis [1]
Clinical and histological features of PF and PV can be reproduced solely by Dsg 1 and 3 antibodies, respectively	The experiments using the Dsgl-Ig and Dsg3-Ig chimeras that absorbed out all disease causing pemphigus antibodies, thus giving a rise to a notion that anti-Dsg 1/3 antibodies are the sole cause of pemphigus, were flawed by the presence of non-Dsg antibodies (Figure 3)
An interplay between Dsg 1 and 3 antibodies determines the mucocutaneous phenotype in patients with autoimmune pemphigus	PF patients can develop antibodies against both Dsg 1 and Dsg 3 [108,116,117], and the Dsg 1/3 antibody pattern does not match the predicted morphologic phenotype ofPV [96,118,119]
The titers of anti-Dsg 1 or 3 antibodies correlate closely with the severely of the disease	The Dsg 1/3 antibody titers do not correlate with disease activity [91-93], While Dsg 3 antibody can be absent in PV patients in active stage of disease, it can be present in PV patients during remission [94-96] as well as in healthy subjects and patients with irrelevant medical conditions [97-109]
The sera of patients with autoimmune pemphigus contain autoantibodies only to the Dsg 1/3 targets	More than 50 organ-specific and non-organ-specific proteins have been reported to date as specific targets for autoantibodies produced by PV and/or PF patients (Table I)
Systemic corticosteroids treat pemphigus patients exclusively by inhibiting autoantibody production	The therapeutic effect of “pulse” therapy with methylprednisolone commences within a few days, whereas autoantibody titers decline within 3-4 weeks [294-296], The rapid therapeutic effect is apparently mediated by direct anti-acantholytic action of glucocorticosteroids that protects keratinocytes from an autoantibody-induced damage [214]
Paraneoplastic pemphigus (PNP) is a variant of classical pemphigus	PNP is not related to PV and PF, but represents a clinical variant of the paraneoplastic autoimmune multiorgan syndrome (PAMS) in which patients, in addition to small airway occlusion, may display a spectrum of at least five clinical variants, i.e. pemphigus like (a.k.a. PNP), pemphigoid like, erythema multiforme like, graft vs. host disease like, and lichen planus like [10,12,13]