ABSTRACT
Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2-4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells - basophiles and eosinophils - were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory" Tfh1 cell and increased "pro-inflammatory" Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naive" and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24- plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.
ABSTRACT
Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased "regulatory” Tfh1 cell and increased "pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of "naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.
ABSTRACT
Current review presents a brief overview of the immune system dysregulation during acute COVID-19 and illustrates the main alterations in peripheral blood CD4+ T-cell (Th) subsets as well as related target cells. Effects of dendritic cell dysfunction induced by SARS-CoV-2 exhibited decreased expression of cell-surface HLA-DR, CCR7 as well as co-stimulatory molecules CD80 and CD86, suggesting reduced antigen presentation, migratory and activation capacities of peripheral blood dendritic cells. SARS-CoV-2-specific Th cells could be detected as early as days 2–4 post-symptom onset, whereas the prolonged lack of SARS-CoV-2-specific Th cells was associated with severe and/or poor COVID-19 outcome. Firstly, in acute COVID-19 the frequency of Th1 cell was comparable with control levels, but several studies have reported about upregulated inhibitory immune checkpoint receptors and exhaustion-associated molecules (TIM3, PD-1, BTLA, TIGIT etc.) on circulating CD8+ T-cells and NK-cells, whereas the macrophage count was increased in bronchoalveolar lavage (BAL) samples. Next, type 2 immune responses are mediated mainly by Th2 cells, and several studies have revealed a skewing towards dominance of Th2 cell subset in peripheral blood samples from patients with acute COVID-19. Furthermore, the decrease of circulating main Th2 target cells — basophiles and eosinophils — were associated with severe COVID-19, whereas the lung tissue was enriched with mast cells and relevant mediators released during degranulation. Moreover, the frequency of peripheral blood Th17 cells was closely linked to COVID-19 severity, so that low level of Th17 cells was observed in patients with severe COVID-19, but in BAL the relative number of Th17 cells as well as the concentrations of relevant effector cytokines were dramatically increased. It was shown that severe COVID-19 patients vs. healthy control had higher relative numbers of neutrophils if compared, and the majority of patients with COVID-19 had increased frequency and absolute number of immature neutrophils with altered ROS production. Finally, the frequency of Tfh cells was decreased during acute COVID-19 infection. Elevated count of activated Tfh were found as well as the alterations in Tfh cell subsets characterized by decreased “regulatory” Tfh1 cell and increased “pro-inflammatory” Tfh2 as well as Tfh17 cell subsets were revealed. Descriptions of peripheral blood B cells during an acute SARS-CoV-2 infection werev reported as relative B cell lymphopenia with decreased frequency of “naïve” and memory B cell subsets, as well as increased level of CD27hiCD38hiCD24– plasma cell precursors and atypical CD21low B cells. Thus, the emerging evidence suggests that functional alterations occur in all Th cell subsets being linked with loss-of-functions of main Th cell subsets target cells. Furthermore, recovered individuals could suffer from long-term immune dysregulation and other persistent symptoms lasting for many months even after SARS-CoV-2 elimination, a condition referred to as post-acute COVID-19 syndrome.
ABSTRACT
Coronary artery disease (CAD) is widely considered a chronic inflammatory disorder, and dysfunction of epicardial adipose tissue could be an important source of the inflammation. Amino-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) is a known marker of cardiovascular disorders of cardiac origin. Recent studies show that inflammatory stimuli may influence its secretion. Our purpose was to evaluate NT-proBNP serum concentration in relation to immune cell ratios in epicardial adipose tissue (EAT), and cytokine levels in the patients with stable CAD. Patients with stable CAD and heart failure classified into classes II-III, according to the New York Heart Association (NYHA) scale, scheduled for the coronary artery bypass graft (CABG) surgery, were recruited into the study (n = 10;59.5 (53.0-65.0) y. o.;50% males). The EAT and subcutaneous adipose tissue (SAT) specimens were harvested in the course of CABG surgery. Immunostaining with anti-CD68, anti-CD45, anti-IL-1β and anti-TNFα monoclonal antibodies was performed to evaluate cell composition by differential counts per ten fields (400 magnification). Fasting venous blood was obtained from patients before CABG. Blood was centrifuged at 1500g, aliquots were collected and stored frozen at -40 °С until final analysis. Concentrations of NT-proBNP, IL-1β, IL-6, IL-10, TNFα were determined in serum samples by enzyme-linked immunosorbent assay (ELISA). We have found increased production of IL-1β and TNFα cytokines in EAT compared to SAT. Concentrations of NT-proBNP exceeded 125 pg/ml in 4 patients, and correlations between the CD68+ macrophage counts in both EAT and SAT samples (rs = 0.762;p = 0.010 and rs = 0.835;p = 0.003, respectively). NT-proBNP levels showed positive relations with CD45+ leukocyte counts (rs = 0.799;p = 0.006), and with IL-1β+ cell numbers (rs = 0.705;p = 0.023) in EAT samples only. As for the serum biomarkers, NT-proBNP levels showed negative correlation with fasting glucose levels (rs = -0.684;p = 0.029), and positive correlation with serum IL-6 concentrations (rs = 0.891;p = 0.001). Increased serum concentrations of NT-proBNP in CAD patients correlate with accumulation of macrophages in EAT, which is associated with increased production of IL-1β in EAT and correlates with some metabolic parameters.
ABSTRACT
Rationale: Angiotensin-converting enzyme 2 (ACE2) is a vasoactive enzyme involved in regulation of vascular tone and blood pressure by reducing angiotensin II and increasing ang(1-7). It is also implicated in the pathogenesis of coronaviruses including SARS-CoV-2. Epidemiological reports differ in implicating cigarette smoking as a risk factor for SARS-CoV-2 infection (COVID-19). Previous studies have been conflicting regarding the implications of cigarette smoke exposure on ACE2 signaling. We hypothesized that cigarette smoke exposure will increase ACE2 expression and impair endothelial cell function. Methods: Female 8-week-old A/J mice were randomly assigned to either air exposure or 48 minutes per day, 5 days per week of cigarette smoke exposure. Mainstream whole-body cigarette smoke exposure was delivered by the SCIREQ “InExpose” smoking system with standard 3R4F research cigarettes. Mouse were sacrificed at 1 and 12 weeks of smoke exposure, and lungs were homogenized and subjected to ACE2 ELISA (Abcam). To investigate the effect of smoking on ACE2 expression and endothelial barrier function, serum starved human pulmonary microvascular endothelial cells (PMVECs) were exposed to cigarette smoke extract (CSE). CSE was prepared at a concentration of 1 cigarette/5 ml in serumfree DMEM and quiescent PMVECs were treated with 1% CSE, 3% CSE or vehicle. Cells were processed for real-time RT-PCR and ELISA 4 hours later, assessment of apoptosis, or underwent TEER to assess endothelial cell barrier function. Results: Lung tissue ACE2 levels were significantly elevated following 1-week of cigarette smoke-exposure. This increase was accompanied by increased macrophage count in bronchoalveolar lavage. Interestingly, at 12-weeks of cigarette smoke-exposure, lung ACE2 was reduced by 15% response. Chronic cigarette smoke-exposure was accompanied by increased right ventricular systolic pressure and Fulton index. In PMVEC models, CSE dose-dependently increased ACE2 mRNA and protein expression. This was accompanied by altered EC barrier function and EC apoptosis. Conclusions: The dose and duration of cigarette smoke exposure affects ACE2 signaling, leading to altered apoptosis and endothelial cell barrier function. These findings have implications for SARS-CoV-2 pathogenesis as well as for furthering our understanding of the effects of smoking on vascular health.
ABSTRACT
Background: Angiotensin-converting enzyme 2, the target cellular receptor of SARS-CoV-2, is known to be present in adipose tissue. SARS-CoV-2 could enter the heart via the epicardium because the myocardium and the epicardium share the same microcirculation and are not separated from one another by a fascial layer. Previous studies demonstrated that macrophages play an important role in inflammation in adipose, including epicardial, tissue. In this study, we explore two hypotheses: a) there is no significant difference between the density of macrophages in the epicardium of patients who died with Covid-19 infection and those who died with non-Covid-19 acute lung injury, and b) the density of macrophages in the epicardium does not correlate with histological evidence of focal myocyte necrosis in patients who die of Covid-19 infection. Design: We compared the density of macrophages in the epicardium of 10 patients who died of complications of Covid-19 infection to that in a control group of 10 decedents with non-Covid related acute lung injury. Further, macrophage densities of those with and without histological evidence of focal myocardial damage were compared within the Covid-19 group. Three blocks were routinely sampled from each case (right ventricle, left ventricle and septum). All the sections were stained with CD68 as a macrophage marker. The density of CD68-positive cells in the epicardium was determined by counting the number of cells in five hot spot regions (each 3 mm2) at 100x. Quantification was performed using imageJ and is expressed as cells/mm2. The densities of CD68- positive macrophage were compared using T-test. The clinical characteristics between the groups were compared using Fischer exact test. P-value < 0.05 is significant. Results: The density of CD68-positive macrophages in the epicardium is significantly higher in Covid-19 patients compared to the control group. The CD68-macrophage count is also significantly higher in hearts of Covid-19 decedents with histological evidence of focal myocyte necrosis than those with no evidence of myocyte necrosis. There are no significant differences in other characteristics between the groups (Table, Figure). Conclusions: Contrary to our hypotheses, the density of CD68-positive macrophages is strongly correlated with Covid-19 infection and Covid-19 related myocyte necrosis. Further studies are needed to understand the pathophysiologic relationship between epicardial inflammation and myocyte necrosis.