The potential etiopathogenetic role and diagnostic utility of CD3+ CD56+ regulatory T lymphocytes in Myelodysplastic Syndromes

Serio et al. show a significant reduction of CD3+CD56+ regulatory T cells (TR3-56) in bone marrow (BM) of low-risk myelodysplastic subjects, as compared with the high-risk and the AML group; in addition, the BM frequency of mature granulocytes, a recognised marker of residual effective haematopoiesis, was observed to inversely correlate with TR3-56 in the MDS cohort. Such data are of great interest and confirm and extend, in an independent MDS cohort, the trend-increase of BM TR3-56 from very low/low risk to high/very high risk MDS and the inverse correlation with the cytotoxic T-cell (CTL) activity, likely fostering the escape of leukaemic blasts to immune-surveillance, by us recently described

Bone marrow CD3+ CD56+ regulatory T lymphocytes (TR3 -56 cells) are inversely associated with activation and expansion of bone marrow cytotoxic T cells in IPSS-R very-low/low risk MDS patients

Background Emergence of dysplastic haematopoietic precursor/s, cytopenia and variable leukaemia risk characterise myelodysplastic syndromes (MDS). Impaired immune-regulation, preferentially affecting cytotoxic T cells (CTL), has been largely observed in MDS. Recently, we described the TR3-56 T cell subset, characterised by the co-expression of CD3 and CD56, as a novel immune-regulatory population, able to modulate cytotoxic functions. Here, we address the involvement of TR3-56 cells in MDS pathogenesis/progression. Objectives To analyse the relationship between TR3-56 and CTL activation/expansion in bone marrow (BM) of very-low/low-risk MDS subjects. Methods Peripheral blood and BM specimens, obtained at disease onset in a cohort of 58 subjects, were analysed by immune-fluorescence and flow cytometry, to preserve the complexity of the biological sample. Results We observed that a trend-increase of BM TR3-56 in high/very-high MDS stage, as compared with very-low/low group, associates with a decreased activation of BM resident CTL; significant correlation of TR3-56 with BM blasts has been also revealed. In addition, in very-low/low-risk subjects the TR3-56 amount in BM inversely correlates with the presence of activated BM CTL showing a skewed V beta T-cell repertoire. Conclusions These data add TR3-56 to the immune-regulatory network involved in MDS pathogenesis/progression. Better knowledge of the immune-mediated processes associated with the disease might improve MDS clinical management

An Open Question in the COVID-19 Pandemic: Can Humans Transmit the Disease to Pets and Vice Versa?

SARS-CoV-2 infection apparently emerged in China in December 2019, causing the disease known as COVID-19,which can cause severe damage to vital organs (Ackermann et al, 2020). Spillover of SARS-CoV- 2 from bats to humans has been hypothesized (Ackermann et al, 2020). The virus spike protein is the main determinant of viral tropism because it is responsible for binding to the angiotensin converting enzyme 2 (ACE2) and subsequent entry of SARSCoV- 2 to host cells in humans and several animal species (Sun et al, 2020). Therefore, it is reasonable to hypothesize that the spike proteineACE2 receptor complex may represent evolutionary exploitation to overcome speciesbarriers to infection, thushighlighting the zoonotic origin and transmission of the virus

Pro-Inflammatory and Immunological Profile of Dogs with Myxomatous Mitral Valve Disease

Simple Summary Myxomatous mitral valve disease (MMVD) is the most commonly acquired cardiac disease in dogs and is responsible for congestive heart failure. In this research, some inflammatory, immunological, and echocardiographic parameters were evaluated in dogs affected by MMVD in order to assess the involvement of additional pathophysiological mechanisms during the disease. The main results revealed that inflammation parameters increased according to the severity of the disease and suggested that inflammatory activation may play an important role in cardiac remodeling associated with the progressive volumetric overload in MMVD. Also, a relative increase in Treg cells was detected, suggesting that they could represent a regulatory mechanism for limiting the inflammatory immune response. Myxomatous mitral valve disease (MMVD) is a very frequently acquired cardiac disease in dog breeds and is responsible for congestive heart failure (CHF). The involvement of the immune system and pro-inflammatory cytokines in dogs with CHF due to mitral valve disease has not yet been extensively investigated. Here, we investigate the role of pro-inflammatory cytokines and the dysfunction of the immune system in dogs with different stages of severity through the blood assessment of CD4(+)FoxP3(+)regulatory T cells (Treg) cells, leptin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 pro-inflammatory cytokines, and immunological and echocardiographic parameters. A total of 36 cardiopathic dogs, 14 females and 22 males, with MMVD were included. Mean age and body weight (BW) at the time of enrollment were 10.7 +/- 2.77 years and 10.9 +/- 6.69 kg, respectively. For the comparison of the pro-inflammatory and immunological parameters, two groups of healthy dogs were also established. Control group 1 consisted of young animals (n. 11; 6 females and 5 males), whose age and mean weight were 4.1 +/- 0.82 years and 13.8 +/- 4.30 kg, respectively. Control group 2 consisted of elderly dogs (n. 12; 6 females and 6 males), whose age and BW were 9.6 +/- 0.98 years and 14.8 +/- 6.15 kg, respectively. Of particular interest, an increase in Treg cells was observed in the cohort of MMVD dogs, as compared to the healthy dogs, as Treg cells are involved in the maintenance of peripheral tolerance, and they are involved in etiopathogenetic and pathophysiological mechanisms in the dog. On the other hand, TNF-alpha, IL-1 beta, and IL-6 significantly increased according to the severity of the disease in MMVD dogs. Furthermore, the positive correlation between IL-6 and the left ventricle diastolic volume suggests that inflammatory activation may be involved in cardiac remodeling associated with the progressive volumetric overload in MMVD

Superoxide Dismutase-1 intracellular content in T lymphocytes associates with increased Regulatory T Cell level in Multiple Sclerosis subjects undergoing immune-modulating treatment.

Reactive oxygen species (ROS) participate in the T-cell activation processes. ROS-dependent regulatory networks are usually mediated by peroxides, which are more stable and able to freely migrate inside cells. Superoxide dismutase (SOD)-1 represents the major physiological intracellular source of peroxides. We found that antigen-dependent activation represents a triggering element for SOD-1 production and secretion by human T lymphocytes. A deranged T-cell proinflammatory response characterizes the pathogenesis of multiple sclerosis (MS). We previously observed a decreased SOD-1 intracellular content in leukocytes of MS individuals at diagnosis, with increasing amounts of such enzyme after interferon (IFN)-b 1b treatment. Here, we analyzed in depth SOD-1 intracellular content in T cells in a cohort of MS individuals undergoing immune-modulating treatment. Higher amounts of the enzyme were associated with increased availability of regulatory T cells (Treg) preferentially expressing Foxp3-exon 2 (Foxp3-E2), as described for effective Treg. In vitro administration of recombinant human SOD-1 to activated T cells, significantly increased their IL-17 production, while SOD-1 molecules lacking dismutase activity were unable to interfere with cytokine production by activated T cells in vitro. Furthermore, hydrogen peroxide addition was observed to mimic, in vitro, the SOD-1 effect on IL-17 production. These data add SOD-1 to the molecules involved in the molecular pathways contributing to re-shaping the T-cell cytokine profile and Treg differentiation

Adaptive and Innate Cytotoxic Effectors in Chronic Lymphocytic Leukaemia (CLL) Subjects with Stable Disease

Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL progression and prognosis. The involvement of immune-mediated mechanisms in CLL control needs to be investigated. We analyse the activation profile of innate and adaptive cytotoxic immune effectors in a cohort of 26 CLL patients with stable disease, as key elements for immune-mediated control of cancer progression. We observed an increase in CD54 expression and interferon (IFN)-γ production by cytotoxic T cells (CTL). CTL ability to recognise tumour-targets depends on human leukocyte antigens (HLA)-class I expression. We observed a decreased expression of HLA-A and HLA-BC on B cells of CLL subjects, associated with a significant reduction in intracellular calnexin that is relevant for HLA surface expression. Natural killer (NK) cells and CTL from CLL subjects show an increased expression of the activating receptor KIR2DS2 and a reduction of 3DL1 and NKG2A inhibiting molecules. Therefore, an activation profile characterises CTL and NK cells of CLL subjects with stable disease. This profile is conceivable with the functional involvement of cytotoxic effectors in CLL control

Breast cancer and communication: monocentric experience of a self-assessment questionnaire

Background: The communication of the diagnosis of breast cancer induces to the patient a strong psychological trauma. Radiologists are at the forefront of communicating, either for a biopsy or the probable diagnosis of malignancy. This is a complex task, which requires the knowledge and application of correct "communicative models", among which the SPIKES protocol represents a fundamental reference. Design and methods: 110 patients, with a history of breast cancer, filled out a questionnaire consisting of six questions: five aimed at defining communication compliance with the SPIKES protocol, the sixth, consisting of six feelings, aimed at the knowledge of the next emotional state. Results: Regarding compliance with various "strategic points" of the SPIKES protocol, questionnaires show that 70% of patients reported no omissions, while the remaining 30% reported omissions relatively to perception (56%), emotions (23%), setting (13%), knowledge (6%) and invitation (2%). The results showed the existence of a correlation between the final emotional state and the correct application of the SPIKES protocol; in fact, patients who reacted with a positive final emotional state-reported greater adherence to the strategic points of the SPIKES protocol. Conclusions: In healthcare, knowing the communicative compliance of a team in giving "bad news" is fundamental, especially in breast cancer. The SPIKES protocol is recognized by the Literature as a fundamental reference able to affect "positively" the emotional state of patients. The proposed questionnaire is a valid tool to identify the weak points of communication and related criticalities, to improve clinical practice

An Open Question: Is It Rational to Inhibit the mTor-Dependent Pathway as COVID-19 Therapy?

In December 2019, a novel coronavirus infection appeared in China (Wuhan City and Hubei Province), causing the first cases of abnormal severe pneumonia. Since then, the SARS-Cov2 infection has become pandemic and the correlated coronavirus disease (COVID-19) has been showing a plethora of pathophysiological manifestations that do not exclusively reduce COVID-19 to the occurrence of severe acute respiratory distress. Although the immunological responses against SARS-Cov2 remain poorly defined it is of note that the critical phase of COVID-19 currently appears, at least in some critical pathophysiological aspects, as a sort of autoimmune disease or as immune response hypersensitivity. Consequently, many authors have proposed various therapeutic approaches based on the modulation/inhibition of abnormal immune response in COVID-19. Recently, the effects of Tocilizumab administration has seemed to indicate that inhibition of the Interleukin (IL)-6 receptor (IL-6R) may result in the recovery of critical COVID-19 patients in the advanced post-alveolitic phase, when extensive pulmonary fibrosis is accompanied by a diffuse interstitial inflammation apparently sustained by a described exacerbated cytokine storm. Such evidence highlights the critical relevance of controlling the IL-6/IL-6R pro-inflammatory pathway in the pathophysiology of COVID-19 in order to mitigate the adverse immune response that is a determinant of the most serious and undesirable phase of SARS-Cov2 infection.In particular, hyper-reactivity was described as a major feature of the critical phase of COVID-19, broadly due to the hyperacute inflammatory context that leads to pulmonary interstitial disease and severe acute respiratory distress

Early patello-femoral condropathy assessment through quantitative analyses via T2 mapping magnetic resonance after anterior cruciate ligament reconstruction

Background: Patellar femoral chondropathy (FPC) is a common problem in patients undergoing anterior cruciate ligament reconstruction (ACL-R) surgery, which, if left untreated, predisposes to arthrosis. Magnetic resonance imaging (MRI) is the non-invasive gold standard for morphological evaluation of cartilage, while in recent years advanced MRI techniques (such as T2 mapping) have been developed to detect early cartilage biochemical changes. This study evaluates the different onset of early PFC between B-TP-B and HT through T2 mapping. Secondly, it aims to assess the presence of any concordance between self-reported questionnaires and qualitative MRI. Materials and methods: 19 patients enrolled were divided into two groups based on the type of intervention: B-PT-B and HT. After a median time of 54 months from surgery, patients were subjected to conventional MRI, T2 mapping, and clinical-functional evaluation through three self-reported questionnaires: Knee Injury and Osteoarthritis index (KOOS); Tegner Lysholm Knee Scoring Scale; International Knee Documentation Committee (IKDC). Results: There is not statistically significant difference in the comparison between the two MRI techniques and the two reconstructive techniques. KOOS and Tegner Lysholm scales showed significant agreement with MRI results on the grading of chondropathy. Conclusions: There are no differences between B-TP-B and HT techniques in the early development of PFC detectable through non-invasive methods. Due to the large reduction in the frequency of physical activity following ACL-R and the finding of mild PFC (grade I and II) in a substantial proportion of patients, after a relatively short period from ACL-R, all patients should undergo conservative treatment