COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.

Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.

At the end of December 2019, a new coronavirus denominated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in Wuhan, Hubei province, China. Less than three months later, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19) to be a global pandemic. Growing numbers of clinical, histopathological, and molecular findings were subsequently reported, among which a particular interest in skin manifestations during the course of the disease was evinced. Today, about one year after the development of the first major infectious foci in Italy, various large case series of patients with COVID-19-related skin manifestations have focused on skin specimens. However, few are supported by histopathological, immunohistochemical, and polymerase chain reaction (PCR) data on skin specimens. Here, we present nine cases of COVID-positive patients, confirmed by histological, immunophenotypical, and PCR findings, who underwent skin biopsy. A review of the literature in Italian cases with COVID-related skin manifestations is then provided.

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real “sentinel signal” to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds.

Background Recessive dystrophic epidermolysis bullosa is a highly disabling genodermatosis characterized by skin and mucosal fragility and blistering. Cutaneous squamous cell carcinoma (cSCC) is one of the most devastating complications, having a high morbidity and mortality rate. Patients with recessive dystrophic epidermolysis bullosa were reported to have up to a 70-fold higher risk of developing cSCC than unaffected individuals. Immune cells play a role in cancer evolution. Objective The aim of our study was to evaluate immunohistological differences between cSCC in patients with and without recessive dystrophic epidermolysis bullosa. Methods A retrospective study of 25 consecutive cases was performed; five were biopsies of cSCC taken from five patients with recessive dystrophic epidermolysis bullosa; as controls we analysed 10 cSCC in subjects without recessive dystrophic epidermolysis bullosa (5 primitive, 3 postburns and 2 postradiotherapy), 5 cSCC in renal transplant recipients and 5 cutaneous pseudoepitheliomatous hyperplasia in patients with recessive dystrophic epidermolysis bullosa. Results A significant reduction of CD3+, CD4+ and CD68+ between the cSCC in patients with recessive dystrophic epidermolysis bullosa compared to primary cSCC and a significant reduction of CD3+, CD4+, CD8+ and CD20+ were observed in cSCC in patients with recessive dystrophic epidermolysis bullosa compared to secondary cSCC. On the contrary, there was no difference in CD3+, CD8+, CD20+ and CD68+ expression when comparing cSCC in patients with recessive dystrophic epidermolysis bullosa to cSCC in renal transplant recipients. No significant difference was found in size, histopathology, grading, number of mitoses and EGFR expression between the different groups. Conclusions Our data show a reduction in immune cell peritumoral infiltration. Considering the well-known evolution of cSCC in patients with recessive dystrophic epidermolysis bullosa, as well as the younger age at diagnosis, it can be assumed that immune dysfunction might contribute to the cSCC aggressiveness in these patients.