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

Cirillo, Nicola; Prime, Stephen S.

doi:10.3390/biom11101506

Cited by 18 publications

(15 citation statements)

References 54 publications

(48 reference statements)

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“…These cells contain and release upon activation dozens of cytokines, chemokines, hydrolytic degrading enzymes, including matrix metalloprotease 9 (MMP9) and neutrophil elastase, as well reactive oxygen species. This inflammatory cascade ultimately leads to tissue damage and subepidermal blister formation (17)(18)(19)(20)(21).…”

Section: Pathogenesis Of Bullous Pemphigoidmentioning

confidence: 99%

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

et al. 2022

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Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement -mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

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Section: Pathogenesis Of Bullous Pemphigoidmentioning

confidence: 99%

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

et al. 2022

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“…Since molecules related to metalloproteinases such as ADAM5, ADAM10, ADAM15 and ADAM17, can affect cell adhesion ( 8 ) and ADAM10 and ADAM17 are involved in the turnover of Dsg2 ( 17 , 24 , 31 ), we investigated the effects of ADAM10 and ADAM17 on intercellular adhesion of keratinocytes using specific inhibitors. First, we performed dispase-based dissociation assays to analyze the intercellular adhesion of immortalized murine (MEK) and human (HaCaT) as well as primary human (NHEK) epidermal keratinocytes ( Figures 1A, B ).…”

Section: Resultsmentioning

confidence: 99%

“…Beside direct inhibition of the interaction of demosomal cadherins, the antibody binding has been shown to trigger intercellular signaling pathways, which indirectly result in loss of desmoglein-mediated interaction and thus intraepidermal blistering. Kinases such as p38MAPK, PLC, ERK, and Src are activated by autoantibody binding and contribute to alterations of the keratin cytoskeleton and desmoglein internalization (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Nevertheless, the exact mechanisms causing blisters are not fully understood, yet.…”

Section: Introductionmentioning

confidence: 99%

Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris

et al. 2022

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The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile.

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“…The administration of anti-FasL antibodies after PVIgG injection blocks blister formation in wild-type mice, and mice lacking secreted soluble FasL develop a milder disease upon PVIgG injection [ 32 ]. Similarly, we have shown that MMP-9 is overexpressed in both in vivo and in vitro models of PV [ 33 ] and that MMP inhibition is a promising route to non-immunosuppressive PV treatment [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Caspase Inhibition as a Possible Therapeutic Strategy for Pemphigus Vulgaris: A Systematic Review of Current Evidence

HudaSanna

Chau

Chen

et al. 2022

Biology

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Background: Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell–cell detachment (acantholysis) resulting in mucocutaneous blistering. The exact pathogenesis of blister formation is unknown and this has hampered the development of non-steroidal, mechanism-based treatments for this autoimmune disease. This systematic review aims to investigate the role of caspases in the pathogenesis of PV to inform the choice of more targeted therapeutic agents. Methods: A systematic search of MEDLINE/PubMed and Scopus databases was conducted to identify eligible studies. Multiple phases of inclusion and exclusion of the primary articles were conducted in pairs, and studies were recorded and analysed according to the latest version of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Risk of bias assessment was conducted for extracted in vivo animal intervention studies using SYRCLE’s risk of bias tool. Results: Eight articles from a total of 2338 in vitro, in vivo, and human studies met the inclusion criteria, with a high degree of inter-rater reliability. By and large, the results show that caspase activation was pathogenic in experimental PV because pan-caspase inhibitors could block or reduce PV acantholysis and blistering in vitro and in vivo, respectively. The pathogenic pathways identified involved caspase-1 and caspase-3. One study failed to show any improvement in the PV model with a caspase inhibitor. The majority of animal studies had high or unclear risk of bias. Conclusion: There are consistent data pointing towards a pathogenic role of caspase activation in PV acantholysis. However, high-quality evidence to confirm that caspase inhibition can prevent PV-induced blistering in vivo is limited. Therefore, further research is required to test the preclinical efficacy of caspase inhibitors in PV.

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

Cited by 18 publications

References 54 publications

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris

Caspase Inhibition as a Possible Therapeutic Strategy for Pemphigus Vulgaris: A Systematic Review of Current Evidence

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