Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment.

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.

T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review.

T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: "T cell immunoglobulin and mucin-domain containing-3", "TIM-3" and/or "Immunocheckpoint inhibitors" in combination with "malignant melanoma" or "human malignant melanoma" or "cutaneous melanoma". The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of 'pleiotropism' is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

Immune disturbance leads to pulmonary embolism in COVID-19 more than classical risk factors: a clinical and histological study.

COVID-19 induces endotheliitis and one of the main complications is enhanced coagulation. The incidence of pulmonary embolism (PE) in COVID-19 (CPE) has increased and clinical features for a rigorous analysis still need to be determined. Thus, we evaluated the clinical characteristics in CPE and the immune infiltration that occurred. Between January 1 and December 31, 2021, 38 patients were affected by CPE (9 ICU, 19 males/19 females, 70.18 ± 11.24 years) out of 459 COVID-19 cases. Controls were subjects who were evaluated for PE between January 1 2015, and December 31, 2019 (92 patients, 9 ICU, 48 males/45 females, 69.55 ± 16.59 years). All patients underwent complete physical examination, pulmonary computed tomography, laboratory tests, D-dimer, and blood gas analysis. There were no differences in laboratory tests or D-dimer. In patients with CPE, pO2, alveolar-arterial oxygen difference (A-aDO2), oxygen saturation %, and the ratio between arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2), P/F, were significantly increased. There were no differences in PaCO2. Platelet count was inversely correlated to P/F (r = - 0.389, p = 0.02) but directly to A-aDO2 (r = 0.699, p = 0.001) only in patients with CPE. Histology of lung biopsies (7 CPE/7 controls) of patients with CPE showed an increase in CD15+ cells, HMGB1, and extracellular MPO as a marker of NETosis, while no significant differences were found in CD3+, CD4+, CD8+, and intracellular MPO. Overall, data suggest that CPE has a different clinical setting. Reduced oxygen content and saturation described in Patients with CPE should not be considered a trustworthy sign of disease. Increased A-aDO2 may indicate that CPE involves the smallest vessels as compared to classical PE. The significant difference in NETosis may suggest the mechanism related to thrombi formation.

Nutritional impairment of neonates with epidermolysis bullosa: a retrospective study.

BACKGROUND: Epidermolysis bullosa (EB) is a highly invalidating genodermatosis characterized by skin and mucosa fragility and blister-formation caused by mutations of genes encoding components of the cutaneous basement membrane zone. Nutritional impairment is one of the main complications of all forms of EB, having a huge impact on growth, pubertal development, wound healing, resistance to infections and quality of life. METHODS: In our study we have retrospectively evaluated 17 children with EB to define whether nutritional impairment in those patients is already present in the neonatal period. As secondary outcomes we considered nutritional status differences among EB subtypes and relative percentages of underweight infants at birth, first and third month. Moreover, information concerning feeding modality, possible complications were also collected, as well as cutaneous or systemic infections and duration of hospital stay. RESULTS: Our study demonstrated that nutritional impairment of neonates with EB has an early onset since as at first month 35% of patients were below 5th centile for weight-for-age, and 94% were below the 50th percentile. Moreover, the number of infants at one month of life <5th centile for weight-for-age was significantly higher compared to birth. The nutritional status is also heavily related to the occurrence of complications, in particular infections; therefore, the prevention of these complications must play a central role in the treatment of these infants, also to avoid any nutritional impairment. CONCLUSIONS: Nutritional status of neonates with EB seems to be compromised already during the first month of life and it is heavily related to the occurrence of infections; therefore, the prevention of these complications must play a central role in the treatment of these infants, also to avoid any nutritional impairment.

Immune Disregulation in Cutaneous Squamous Cell Carcinoma of Patients with Recessive Dystrophic Epidermolysis Bullosa: A Single Pilot Study.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most devastating complications of recessive dystrophic epidermolysis bullosa (RDEB). We recently demonstrated a reduction in immune cell peritumoral infiltration in RDEB patients with cSCC, together with a reduction in CD3+, CD4+, CD68+ and CD20 lymphocytes as compared to primary and secondary cSCC in patients without RDEB. Recently, new molecules, such as high mobility group box 1 (HMGB1), T cell immunoglobulin, mucin domain 3 (TIM-3) and Heme oxygenase-1 (HO-1), have been shown to play a role in antitumoral immunity. OBJECTIVE: Patients with RDEB are known to be at increased risk of developing skin cancers, including the dreaded squamous cell carcinoma of the. Tendentially, cSCCs that arise in the context of EBDR are more aggressive and lead to statistically significant bad outcomes compared to cSCCs developed on the skin of patients without EBDR. In an attempt to study the microenvironment of these lesions, we conducted an immunohistochemical analysis study of proteins that could be actively involved in the genesis of this type of malignant neoplasms. METHODS: In this retrospective study, the OH1-HMGB1-TIM3 activation axis, as correlated to the T lymphocytes cell count, was assessed in biopsy samples from 31 consecutive cases consisting of 12 RDEB patients with cSCC, 12 patients with primary cSCC and 7 RDEB patients with pseudoepitheliomatous cutaneous hyperplasia. Parametric Student's t-test was applied for normally distributed values, such as CD4+ and CD8+, and non-parametric Mann-Whitney test for non-normally distributed values, such as HMGB-1, TIM-3 and HO-1. RESULTS: In RDEB patients with cSCC and with pseudoepitheliomatous hyperplasia, the expression of CD4 T helper lymphocytes was lower than in the peritumoral infiltrate found in primary cSCC. CD8 cytotoxic T lymphocytes were increased in primary cSCC compared to the other two groups. An increased HMGB1 expression was evident in both primary and RDEB cSCC. TIM3 expression was higher in RDEB patients with cSCC compared to the other two groups. A significantly reduced immunohistochemical expression of HO-1 was evident in the tumoral microenvironment of cSCC-RDEB as compared to primary cSCC. CONCLUSIONS: These data suggest that a reduced immune cell peritumoral infiltration in RDEB patients could be responsible, in the complexity of the mechanisms of carcinogenesis and host response, of the particular aggressiveness of the cSCC of RDEB patients, creating a substrate for greater local immunosuppression, which, potentially, can "open the doors" to development and eventual metastasis by this malignant neoplasm.

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19.

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.

Skin Manifestation of SARS-CoV-2: The Italian Experience.

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.

HMGB1-TIM3-HO1: A New Pathway of Inflammation in Skin of SARS-CoV-2 Patients? A Retrospective Pilot Study.

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.