Abstract
Systemic sclerosis (SSc) is a connective tissue disease secondary to three cardinal pathological features: immune-system alterations, diffuse microangiopathy, and fibrosis involving the skin and internal organs. The etiology of SSc remains quite obscure; it may encompass multiple host genetic and environmental -infectious/chemical-factors.The present review focused on the potential role of environmental agents in the etiopathogenesis of SSc based on epidemiological, clinical, and laboratory investigations previously published in the world literature.Among infectious agents, some viruses that may persist and reactivate in infected individuals, namely human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and parvovirus B19 (B19V), and retroviruses have been proposed as potential causative agents of SSc. These viruses share a number of biological activities and consequent pathological alterations, such as endothelial dysfunction and/or fibroblast activation.Moreover, the acute worsening of pre-existing interstitial lung involvement observed in SSc patients with symptomatic SARS-CoV-2 infection might suggest a potential role of this virus in the overall disease outcome.A variety of chemical/occupational agents might be regarded as putative etiological factors of SSc. In this setting, the SSc complicating silica dust exposure represents one of the most promising models of study. Considering the complexity of SSc pathogenesis, none of suggested causative factors may explain the appearance of the whole SSc; it is likely that the disease is the result of a multifactorial and multistep pathogenetic process. A variable combination of potential etiological factors may modulate the appearance of different clinical phenotypes detectable in individual scleroderma patients.The in-deep investigations on the SSc etiopathogenesis may provide useful insights in the broad field of human diseases characterized by diffuse microangiopathy or altered fibrogenesis.
Highlights
Systemic sclerosis (SSc) can be counted among the most represen tative models of complex disease, involving the whole organism, from the skin to most of systems and internal organs [1,2,3]; it represents an open challenge for the physicians [1,2,3,4]
The present review focused on the potential role of environmental infectious/toxic agents in the etiopathogenesis of SSc evidenced throughout a careful search of epidemiological, clinical, and laboratory investigations reported in the world literature at June 2021 (PubMed, Embase, Scopus, and Web of Science)
More recent data have highlighted a relevant role of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) in the induction of cell fibrosis and apoptosis at the tissue level, showing that both viruses significantly modified the expression of several pro-fibrotic and pro-apoptotic factors in in vitro infected human dermal fibroblasts [72]
Summary
Systemic sclerosis (SSc) can be counted among the most represen tative models of complex disease, involving the whole organism, from the skin to most of systems and internal organs [1,2,3]; it represents an open challenge for the physicians [1,2,3,4]. Classified among connective tissue diseases, SSc is characterized by multiple pathogenetic mechanisms, mainly immune system alterations, diffuse micro angiopathy, and excessive production/deposition of extracellular matrix by altered fibroblasts [1,2]. All together, these pathological alterations may be responsible for both ischemic and fibrotic tissue damages causing cutaneous sclerosis, digital ulcers, pulmonary, cardiac,. Antibodies directed against UL94/Recognition of membrane receptors of dermal fibroblasts (NAG2) with activation of fibroblasts and subsequent expression of genes functionally associated with clinical signs of SSc (molecular mimicry mechanism) Increased expression of profibrotic factors/Fibrosis induction in fibroblasts [50] [72]. The present review focused on the potential role of environmental infectious/toxic agents in the etiopathogenesis of SSc evidenced throughout a careful search of epidemiological, clinical, and laboratory investigations reported in the world literature at June 2021 (PubMed, Embase, Scopus, and Web of Science)
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