A Scoping Review of the Role of Metalloproteinases in the Pathogenesis of Autoimmune Pemphigus and Pemphigoid.

Nicola Cirillo,Stephen S Prime

doi:10.3390/biom11101506

Nicola Cirillo, Stephen S Prime

Open Access

https://doi.org/10.3390/biom11101506

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Abstract

Pemphigus and pemphigoid diseases are potentially life-threatening autoimmune blistering disorders that are characterized by intraepithelial and subepithelial blister formation, respectively. In both disease groups, skin and/or mucosal blistering develop as a result of a disruption of intercellular adhesion (pemphigus) and cell-extracellular matrix (ECM) adhesion (pemphigoid). Given that metalloproteinases can target cell adhesion molecules, the purpose of the present study was to investigate the role of these enzymes in the pathogenesis of these bullous dermatoses. Studies examining MMPs (matrix metalloproteinases) and the ADAM (a disintegrin and metalloproteinase) family of proteases in pemphigus and pemphigoid were selected from articles published in the repository of the National Library of Medicine (MEDLINE/PubMed) and bioRxiv. Multiple phases of screening were conducted, and relevant data were extracted and tabulated, with 29 articles included in the final qualitative analysis. The majority of the literature investigated the role of specific components of the MMP family primarily in bullous pemphigoid (BP) whereas studies that focused on pemphigus were rarer. The most commonly studied metalloproteinase was MMP-9 followed by MMP-2; other MMPs included MMP-1, MMP-3, MMP-8, MMP-12 and MMP-13. Molecules related to MMPs were also included, namely, ADAM5, 8, 10, 15, 17, together with TIMP-1 and TIMP-3. The results demonstrated that ADAM10 and MMP-9 activity is necessary for blister formation in experimental models of pemphigus vulgaris (PV) and BP, respectively. The data linking MMPs to the pathogenesis of experimental BP were relatively strong but the evidence for involvement of metalloproteinases in PV was more tentative. These molecules represent potential candidates for the development of mechanism-based treatments of these blistering diseases.

Highlights

Pemphigus and pemphigoid are members of a heterogeneous group of chronic, potentially fatal autoimmune diseases associated with blistering of the skin and mucosae.Once considered part of the same disease spectrum, these bullous dermatoses were first classified as distinct entities by Lever in 1953 [1]
The results demonstrated that ADAM10 and MMP-9 activity is necessary for blister formation in experimental models of pemphigus vulgaris (PV) and bullous pemphigoid (BP), respectively
MMP-2 was thought to be produced predominantly by fibroblasts whereas MMP-9 was localized to the epidermis and endothelial cells [45]; later, MMP-9 was found to be secreted by eosinophils at the site of blister formation [40]

Summary

Introduction

Pemphigus and pemphigoid are members of a heterogeneous group of chronic, potentially fatal autoimmune diseases associated with blistering of the skin and mucosae. Once considered part of the same disease spectrum, these bullous dermatoses were first classified as distinct entities by Lever in 1953 [1]. Pemphigus presents as an intraepithelial split (acantholysis) whereas in pemphigoid, the blisters develop at the dermo-epidermal junction resulting in a subepithelial split. Pemphigus diseases are characterized by flaccid blisters and erosions and are treated with high dose corticosteroids and immunosuppressants. Pemphigoid presents with tense blisters and erosions, a negative Nikolsky sign and, commonly, is controlled using topical steroids in more severe cases, systemic steroids are an option [2]

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