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

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Abstract

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.

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Acknowledgements

We are grateful to Günther Henkel and Irina Nuhn for the clinical photographs. This review was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation-FOR 2497) to TS, RE and MH.

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  1. Robert Pollmann, Thomas Schmidt, Rüdiger Eming and Michael Hertl contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology and Allergology, Philipps-University, Baldingerstraße, D-35043, Marburg, Germany

    Robert Pollmann, Thomas Schmidt, Rüdiger Eming & Michael Hertl

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  1. Robert Pollmann
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  2. Thomas Schmidt
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  3. Rüdiger Eming
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  4. Michael Hertl
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Correspondence to Michael Hertl.

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Pollmann, R., Schmidt, T., Eming, R. et al. Pemphigus: a Comprehensive Review on Pathogenesis, Clinical Presentation and Novel Therapeutic Approaches. Clinic Rev Allerg Immunol 54, 1–25 (2018). https://doi.org/10.1007/s12016-017-8662-z

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