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Immune response in pemphigus and beyond: progresses and emerging concepts

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Abstract

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients’ results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.

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Article 11 May 2017

Michael Kasperkiewicz, Christoph T. Ellebrecht, … Masayuki Amagai

Abbreviations

AutoAb:

Autoantibody

Dsg:

Desmoglein

PV:

Pemphigus vulgaris

PF:

Pemphigus foliaceus

FS:

Fogo selvagem

mAb:

Monoclonal antibody

preDsg:

Precursor Dsg

matDsg:

Mature Dsg

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Acknowledgments

The present work has been supported by the following bodies: the Italian Ministry of Health (Ricerca Finalizzata grant n. RF2309790 and Ricerca Corrente 2015, to G.D.), the Framework Programme FP7 (Coordination theme I, Health-F2, 2008–2013, to E.M and L.B), the Swiss National Foundation for Scientific Research (31003A-135689 to E.M.; 3100A0-121966 to L.B.) and the Martha Foundation Zürich to E.M.. We are greatly indebted to many investigators and friends who supported our studies over the years by sharing ideas and providing support and working tools.

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    Authors and Affiliations

    1. Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy

      Giovanni Di Zenzo

    2. Department of Dermatology, University of California Irvine Health, Irvine, CA, USA

      Kyle T. Amber

    3. Vetsuisse Faculty, Molecular Dermatology and Stem Cell Research, Institute of Animal Pathology, Bern, Switzerland

      Beyza S. Sayar & Eliane J. Müller

    4. Vetsuisse Faculty, DermFocus, Bern, Switzerland

      Beyza S. Sayar, Eliane J. Müller & Luca Borradori

    5. Department of Dermatology, University Hospital of Bern, Bern, Switzerland

      Beyza S. Sayar, Eliane J. Müller & Luca Borradori

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    1. Giovanni Di Zenzo
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    3. Beyza S. Sayar
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    4. Eliane J. Müller
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    Correspondence to Eliane J. Müller or Luca Borradori.

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    This article is a contribution to the Special Issue on Immunodermatology - Guest Editors: Lars French and Alexander Navarini

    Giovanni Di Zenzo, Kyle T. Amber, Eliane J. Müller and Luca Borradori contributed equally to this work.

    Giovanni Di Zenzo and Kyle T. Amber are both first authors.

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    Di Zenzo, G., Amber, K.T., Sayar, B.S. et al. Immune response in pemphigus and beyond: progresses and emerging concepts. Semin Immunopathol 38, 57–74 (2016). https://doi.org/10.1007/s00281-015-0541-1

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