Hailey-Hailey's disease (HHD) is a skin disease linked to mutations in ATP2C1 gene encoding Ca2+/Mn2+ ATPase localized on the Golgi; deregulations of this protein function are responsible for defects in the control of cytoplasmatic calcium concentrations leading to alterations of the desmosomic junctions and to the loss of adhesion between epidermal keratinocytes. The disorder is manifested as blistering skin lesions that do not heal and susceptible to microbial infections. While a strong relationship exists between mutations in ATP2C1 gene and HHD, the precise mechanism through which mutations induce skin lesions is unknown. We need to expand our understandings on the role of ATP2C1 in skin biology, in order to delineate how its loss may contribute to HHD. Oxidative stress plays an important role in HHD manifestation; in particular, it was found that ATP2C1 defective keratinocytes are characterized by massive ROS production and alterated Notch 1 signaling. Notch 1 signaling influences many aspects of the skin homeostasis including differentiation and wound repair. The understandings of the relevant pathways influenced by oxidative-stress would provide perspectives for future novel pharmacological targets. HHD skin lesions do not heal and show recurrent infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. The success of wound healing process depends on growth factors, cytokines and chemokines involved in cellular processes. HHD lesions are characterized by deregulated cytokine expression and decreased repair properties and, moreover, HHD patients have an increased susceptibility to skin infections. It could be important investigate the influence of deregulated cytokines on ATP2C1-defective keratinocytes proliferation, differentiation and wound repair mechanisms also in order to understand if the persistent bacterial colonization is a consequence of an attenuated immune response.
Hailey-Hailey disease (HHD) is an autosomal dominant blistering skin disorder, manifesting in the 3rd to 4th decades of life. The overall incidence and prevalence of HHD is unknown, although some authors have reported an incidence between 1:40,000 and 1:50,00. The genetics and pathophysiology of this skin disorder have been linked to mutations in the ATP2C1 gene. The gene, located on the long arm of chromosome 3, encodes the human secretory pathway Ca2+/Mn2+ ATPase, hSPCA. The lack of ATP2C1 in keratinocytes leads to the loss of cell-to-cell adhesion (acantholysis) among the cells of the suprabasal layer of epidermis probably due to a retraction of keratin intermediate filaments from the desmosomal plaques. Although ATP2C1 mutations are 100% penetrant, currently there is no treatment known to be effective in reducing the cutaneous manifestations of HHD. The Standard of Care (SOC) treatment consists in either topical or oral administration of corticosteroids often used in combination with topical/systemic antimicrobial agents. However, prolonged treatment course of steroids is limited due to their side effects, most commonly skin atrophy. This last aspect must be carefully considered because in HHD-patients lesion development is associated with the simply friction of the skin and we found that HHD-keratinocytes are characterized by wound defect. Additionally, patients develop lesions refractory to corticosteroids. The development of causal treatment strategies (i.e. molecular therapy based) is highly desirable and could be reached through intensified efforts to elucidate the various molecular mechanisms underlying the disorder. The oxidative stress represents a hallmarks of the keratinocytes derived from the lesions of HHD patients; moreover, increased ROS production both in primary keratinocytes and HaCaT cells treated with siATP2C1 determines Notch1 signaling activation. Notch1 signaling influences many aspects of the skin homeostasis including differentiation and wound repair. In our preliminary results we found that Notch1 hyper-activation, ADAM17-mediated, in ATP2C1 defective keratinocytes is implicated in the inability of keratinocytes to repair cutaneous wounds leading to premature keratinocytes differentiation that would impair the wound healing processes. A broader understanding of the molecular mechanisms responsible for the deregulated activation of Notch1 could be important means to try to reduce not only Notch1 responsiveness but also ADAM17 targets potentially involved in HHD manifestation, such as adhesion molecules. Moreover, it has been reported that Notch1 transcriptional activity can regulate also cytokines gene expression. HHD-derived keratinocytes are characterized by deregulated cytokines production and decreased repair properties. Greater understanding of the immunological aspects of HHD, such as the role of deregulated cytokines on skin physiological processes and on the immune cell activation, may help to design treatment strategies to improve wound healing and microbial infection regression in HHD patients.