Pemphigus: a Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches

Robert Pollmann, Thomas Schmidt, Rüdiger Eming, Michael Hertl

Pemphigus is a group of rare, potentially devastating autoimmune diseases of the skin and mucous membranes with high morbidity and potentially lethal outcome. The major clinical variant, pemphigus vulgaris (PV) is caused by a loss of intercellular adhesion of epidermal keratinocytes which is induced by IgG autoantibodies against components of desmosomes. Specifically, IgG against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), preferentially target their ectodomains which are presumably critical for the transinteraction and signalling function of these adhesion molecules. There is a close immunogenetic association of PV with the human leukocyte antigen (HLA) class II alleles, HLA-DRB1*04:02 and HLA-DQB1*05:03. These have been shown to be critical for the presentation of immunodominant peptides to autoreactive CD4+ T helper cells. The importance of autoaggressive T-B cell interaction in the induction of pathogenic IgG autoantibodies which directly cause epidermal loss of adhesion has been demonstrated both clinically (by the use of the anti-CD20 monoclonal antibody rituximab) and experimentally (in PV mouse models). The strong association of clinically active pemphigus with autoantibodies of the IgG4 and IgE subclasses strongly suggests that T helper 2 cells are critical regulators of the immune pathogenesis of pemphigus. Novel therapeutic approaches target autoreactive T and B cells to specifically interfere with the T cell-dependent activation of B cells leading to the generation of autoantibody-producing plasma cells. Our improved understanding of the autoantibody-driven effector phase of pemphigus has led to the introduction of novel therapies that target pathogenic autoantibodies such as immunoadsorption and drugs that block pathogenic autoantibody-induced cell signalling events.