Pemphigus vulgaris (PV) is a rare, but severe immune-mediated blistering skin disease mediated by autoantibodies which bind to the cell surface of keratinocytes. The first recorded instance of Pemphigus disease was by Hippocrates (460–370 BC) who described pemphigoid fever as "pemphigodes pyertoi." Galen (131–201 AD) named a pustular disease of the mouth as "febris pemphigodes." In 1791, Wichmann used the term "pemphigus" to indicate a pathology characterized by flaccid bullae and painful oral ulcerations. In 1964 Beutner and Jordon reported autoantibodies in the sera of pemphigus patients, reactive with an "intercellular substance" of skin and mucosa, by using indirect immunofluorescence [1, 2]. Eventually, in 1990 Amagai, Klaus-Kovtun and Stanley identified the "intercellular substance" as desmoglein-3, a 130-kDa desmosomal adhesion molecule . Today the pathogenicity of anti-Dsg3 autoantibodies is a datum of fact since transfer of patient derived anti-Dsg3 serum IgG antibodies into mice induces a bullous skin disease resembling PV .
Histopathologically, PV is characterized by suprabasal intraepidermal bullae with acantholysis and inflammatory infiltrate of eosinophils. Immunopathologically, IgG and C3 deposits are found in intercellular/cell surface areas in skin lesions. Typically, Nikolsky's sign is present in this disease: sheetlike removal of skin by gentle pushing with a finger [5, 6]. Although histologically well characterized, the course of the pemphigus pathological events and the specific pathway of the blistering process is not fully understood. In parallel, the molecular basis and the biochemical events of the pemphigus pathology remain to be clearly defined.
Therapeutically, PV treatments include corticosteroids, immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine, and methotrexate), anti-inflammatory agents (gold, dapsone, tetracycline and nicotinamide) [5–12], plasmapheresis  and, more recently, intravenous immunoglobulins [14–17] and cholinergic agonists . The final goal of these treatments is to reduce inflammation and/or production of the pathogenic autoreactive antibodies. There are several limitations that make current treatment protocols less than ideal: 1) no single therapy, other than high-dose steroid administration, has been reported resolutive so far; 2) prolonged immunosuppression may be associated with severe side effects, including an enhanced susceptibility to opportunistic infections; 3) the efficacy of high-dose steroid administration is transient, and relapses are the rule as soon as the steroid treatment is discontinued. Moreover, the side-effects of corticosteroid treatment are numerous and heavy, one example for all being represented by steroid-induced diabetes [19–21].
In such a context, the need for the development of alternative, effective and safe treatments for PV is unquestionable and mandatory. In our labs, we are testing the possibility of applying peptide-immunotherapy targeted to specific low-similarity protein segments, thereby treating the disease without the risk of collateral cross reactions [22–31]. Accordingly, in the present approach to PV peptide immunotherapy we have used a linear low-similarity segment of the protein autoantigen associated to PV, desmoglein-3 (Dsg3) amino acid 59–60 corresponding to the sequence REWVKFAKPCRE [32, 33]. The low-similarity peptide was defined using a proteome-base computer-assisted algorithm network in order to identify Dsg3 peptide fragments potentially able to interfere with and/or stop the PV pathological event chain and, at the same time, eliminate possible collateral effects due to cross reactions. Following a series of in vitro and animal experiments [32–34], our studies have progressively focused on the Dsg349–60REWVKFAKPCRE peptide sequence that 1) is uniquely expressed in Dsg3 and, consequently, cannot induce/provoke collateral secondary autoimmune cross-reactions [22–34]; 2) is hosted in a Dsg3 domain involved in the intramolecular epitope spreading characterizing the progression of PV from mucous to muco-cutaneous stage ; 3) does not produce pathogenic antibodies .
Here we describe a case report illustrating the potential therapeutic use of the computer-designed Dsg349–60REWVKFAKPCRE peptide in PV.