Pemphigus--paradigm of autoantibody-mediated autoimmunity

Pemphigus encompasses a group of life-threatening autoimmune blistering diseases due to a loss of adhesion between keratinocytes, called acantholysis, which is caused by autoantibodies (AAb) against intercellular adhesion structures of epidermal keratinocytes. In pemphigus vulgaris (PV), the blisters are located in the suprabasal layer whereas in pemphigus foliaceus (PF), a clinically less severe disease, the blisters occur within the upper layers of the epidermis. In PV and PF, the AAb target the extracellular portions of desmoglein 3 (Dsg3) and Dsg1, respectively. AAb production in PV and PF is polyclonal and most AAb are of the IgG4 subclass in acute onset or active disease while patients in remission have mainly AAb of the IgG1 subtype. Evidence for the pathogenicity of these circulating AAb is provided by the observations that (1) the activity of pemphigus correlates with AAb titers, (2) newborns of mothers with active pemphigus temporarily exhibit blisters due to the transplacentar transfer of maternal AAb and (3) pemphigus-like lesions are induced in neonatal mice by transfer of IgG from PV patients. Clinically, pemphigus is characterized by extensive cutaneous blisters and erosions of the mucous membranes (PV). Patients with untreated pemphigus are prone to infections, loss of body fluids and proteins and to weight loss due to painful oral and esophageal erosions. The major therapeutic strategy in pemphigus is chronic immunosuppressive therapy with glucocorticosteroids in combination with immunosuppressive adjuvants.