Abstract
Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures. The cellular pathology of most EBS subtypes is associated with the fragility of the intermediate filament network, cytolysis of the basal layer of the epidermis, or attenuation of hemidesmosomal/desmosomal components. Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes. Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs. Global changes in cellular signaling mainly occur in cases of severe dominant EBS mutations. The spectrum of changes initiated by phosphorylation includes the inhibition of proteasome degradation, TNF-α signaling activation, deregulated proliferation, abnormal cell migration, and impaired adherence of keratinocytes. ER stress also leads to the release of proinflammatory danger-associated molecular pattern (DAMP) molecules, which enhance avalanche-like inflammation. Many instances of positive feedback in the course of cellular stress and the development of sterile inflammation led to systemic chronic inflammation in EBS. This highlights the role of keratin in the maintenance of epidermal and immune homeostasis.
Highlights
The mechanical properties of the skin are the result of the combination of different components acting inside and outside the skin cells
The statistics for all types of epidermolysis bullosa (EB) show a prevalence of approximately 1:50,000 births in the USA, among the patients registered in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database (EBCCOD), 30.1% of whom have Epidermolysis bullosa simplex (EBS), with signs of disease present at birth in 38% of these [37]
EBS with mottled pigmentation is the fourth type of EB simplex, in which skin fragility is present at birth and, over time, brown pigmentation interspersed with spots develops on the body
Summary
The mechanical properties of the skin are the result of the combination of different components acting inside and outside the skin cells. Released play the role of immunoregulators, exerting mitomones, and neurotrophins) withneurotransmitters their specific receptors expressed by both neuronal and genic influences on KCs. Neurotrophic factors and neuropeptides are non-neuronal skin cells. Sci. 2021, 22, 12446 which could contribute to the maintenance of chronic pain and inflammation [28] This type of T-cell activation will be discussed later in connection with the pathology of EBS (see Section 9.3). The treatment of KCs with mechanical stimulation activates the secretion of inflammatory cytokines (IL-1α, IL-6, IL-23, and TNF) and chemokines (CXCL1 and CCL20) [23]. When a skin injury occurs, the wound healing (WH) process starts, which is a natural remedial process in epidermal tissue It consists of four main stages: hemostasis, inflammation, proliferation, and maturation. The wound-healing process has been well studied in rodent models, but only limited studies have been conducted with EB lesions
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