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Subjects:
Dermatology
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Immunology
Pemphigus vulgaris is a potentially fatal disease characterised by blister formation affecting the skin and mouth.
- pemphigus vulgaris
- acantholysis
- apoptosis
- caspase
- caspase inhibitor
1. Introduction
Pemphigus Vulgaris (PV) is a life-threatening IgG-mediated autoimmune disease characterised by mucocutaneous blistering resulting from detachment of keratinocytes, known as acantholysis. This affects 0.1–0.5 per 100,000 people globally and mortality rate in these patients can reach 60–90% without effective disease management [1]. The use of corticosteroids significantly reduces the mortality rate to 10% [1]. However, the long-term use of corticosteroids leads to severe adverse effects, including peptic ulcer disease, adrenal insufficiency, osteoporosis, and can increase treatment-related morbidity [1,2]. Even with these adverse effects, corticosteroids, with or without immune suppressants, remain the first-line therapy due to their rapid effect in treating PV [3]. Therefore, the search for novel, more specific therapeutic targets that improve PV treatment efficacy and minimise adverse effects is necessary; this cannot be achieved without gaining a deeper understanding of how acantholysis and blister formation occurs in PV.
The pathophysiological mechanisms of PV are still incompletely understood, though the etiopathogenesis is thought to be multifactorial. This involves a complex series of events elicited by binding of PV-IgG to their target antigens, as well as by non-IgG serum factors. One of the proposed pathomechanisms, apoptolysis [4], reconciles the findings that link apoptotic and acantholytic pathways that determine blister formation. Specifically, auto-antibody binding to a myriads of pemphigus autoantigens leads to initiation of apoptotic enzyme cascades in keratinocytes, resulting in basal cell shrinkage and supra-basal acantholysis [4]. Studies show that there is a notable increase in the expression of both caspases and apoptotic cells in PV patients [5,6,7,8,9], and that apoptosis in PV takes place via both intrinsic and extrinsic pathways. The extrinsic apoptotic pathway in PV includes the Fas receptor (FasR) which is located at the cell surface of keratinocytes [10]. Apoptosis is also induced through the intrinsic pathway via mitochondrial dysfunction and release of cytochrome c to activate caspase-9 and caspase-3, which in turn trigger apoptosis of the cell.
Although there is uncertainty on the relationship between apoptosis and acantholysis, it has been shown that the inhibition of caspases can prevent both processes in PV [11,12]. Given that both pathways lead to caspase activation and are known to be activated in PV [11,12], it would be reasonable to focus on caspase activation rather than apoptosis with an aim of developing mechanism-based pharmacological treatments. Furthermore, while caspases target a large spectrum of molecules, they also cleave desmosomal proteins including desmogleins [13]. Proteolytic processing of desmosomal cadherins leads to cell–cell detachment and cell shrinkage [13]. It is plausible, therefore, that PV-IgG or PV sera induce the pathological activation of caspases in keratinocytes which may lead to acantholysis [11,12]. To this regard, a recent scoping review discussing the possible pathogenic mechanisms of PV noted the caspase pathway as a possible key driver of blister formation [14].
The vital function of caspases in the intracellular cascade of acantholysis in PV makes this class of molecules a potential pharmacological target for novel mechanism-based treatments of the disease.
2. Caspase Inhibition in Pemphigus Vulgaris Treatment
2.1. Effect of Caspase Inhibition
Prevention of cell–cell detachment and/or blister formation was achieved for pan-caspase inhibitors in the form of: (1) absence or reduction of PV blistering [6,11,19]. (2) absence or reduction of acantholysis or cell–cell adhesion strength [17,18,19]. Additionally, Schmidt et al. [21] reported that pan-caspase inhibition had no effect on cell dissociation. Caspase-3 inhibition only reduces blisters, and failed to fully prevent PV phenotype [17,20]. Interestingly, Wang et al. [12] reported that caspase-1 inhibition can prevent cell death and lesion formation; however, other caspases may be responsible for this effect as the inhibitor used in the study (YVAD-CHO) is accepted to be non-specific. Additionally, this study did not report p-values and results on blockage of lesions in cell cultures, which undermines the reliability of their results [12]. Whilst it is interesting that desmosomal proteins can be cleaved by caspases during apoptosis [11,22], the type of proteolytic processing depends on the apoptotic stimulus [23]. Therefore, it is possible that PV IgG or sera, particularly when used at different concentrations, induce distinct caspase activation cascades that result in varying degrees of cell–cell dyscohesion.
Some studies were unable to demonstrate complete inhibition of PV with caspase inhibition [17,18,20,21]. These findings may indicate that other signalling molecules may be driving the disease process even in the presence of caspase inhibition. Therefore, the effect of caspase inhibition in clinically preventing disease adequately is questionable. This suggests that there is currently insufficient evidence to focus preclinical and clinical research interest into a specific caspase inhibitor as various molecular pathways are capable of inducing blistering and/or acantholysis.
Current literature on caspase inhibition in PV indicates that apoptotic pathways are involved. The Fas/Fas ligand system may be involved in keratinocyte apoptosis in PV through downstream activation of caspase-8 [24]. Additionally, executioner caspase inhibition can lead to significant reductions in PVIgG-dependent elevation of cytochrome c [25], and hence cell death. These studies, in part, support the concept of apoptolysis; however, more research is required to ascertain the occurrence of acantholysis.
2.2. Contradicting Findings in Current Literature
Contradicting TUNEL results were reported by Wang et al. [12] and Schmidt et al. [21], which may be explained by the differences in the methods and materials used. The use of TUNEL assay as an indicator for acantholysis relies on an assumption that there is a direct relationship between apoptosis, DNA fragmentation and acantholysis. Although both Wang et al. and Schmidt et al. followed the same Promega protocol for TUNEL assay, different results were reported. Wang et al. [12] observed DNA fragmentation in PV-IgG-induced acantholysis; whereas, Schmidt et al. [21] showed that no TUNEL reactivity was observed. Both studies used the PV patient skin lesion biopsies, but Wang et al. [12] did not include relevant information about tissue processing after the biopsy, while Schmidt et al. [21] recorded the process in detail. Tissue processing may explain the discrepancies with the results.
Use of other techniques may be more accurate for determining acantholysis without reliance on biomarkers of apoptosis. The use of cytokeratin retraction in the Schmidt et al. [21] article may be a better direct indicator of acantholysis. However, caspase inhibitor z-VAD-fmk could not prevent the PV-IgG mediated acantholysis; this contradicts the findings described in other studies. Additionally, a control group is necessary to confirm the efficacy of the z-VAD-fmk agent.
3. Conclusions
Given that the role of caspases in PV demonstrates that caspase inhibition may reduce acantholysis in PV, further well-designed studies are required to confirm this relationship. Additionally, there are no caspase inhibitor medications clinically approved for use [35]. Thus, if caspase inhibitors are to be considered in future therapeutic treatment of PV, safety concerns and side effects in humans would need to be thoroughly evaluated.
This entry is adapted from the peer-reviewed paper 10.3390/biology11020314
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