Peripheral Inflammatory Cytokines and Lymphocyte Subset Features of Deceased COVID-19 Patients

Objective. To compare the difference of inflammatory cytokines and lymphocyte subsets between deceased patients and survivors with COVID-19. Methods. This retrospective study included 254 confirmed patients from 10 January to 11 March, 2020, at Tongji Hospital of Wuhan, China. Laboratory and immunologic features were collected and analyzed, and the main outcomes focused on inflammatory cytokines and lymphocyte subsets. Results. A trend of markedly higher levels of inflammatory cytokines as well as lower lymphocyte subset levels in deceased patients was observed compared with survivors. ROC curve analyses indicated that inflammatory cytokines and the decrease levels of T cell, Th (helper T cells) cell, Ts (suppressor T cells) cell, B cell, and NK cell along with Th/Ts ratio increase could be used to predict the death of COVID-19. Multivariate analyses showed that higher levels of IL-6, IL-8, and IL-10 remained significantly correlated with shorter survival time and that the amount of Ts cells was negatively associated with the possibility of death in COVID-19 patients. In conclusion, SARS-CoV-2 would cause lymphopenia and result in decreased lymphocyte subset cells, particularly in Ts cell counts, which further induces hyperinflammatory response and cytokine storm. IL-6, IL-8, IL-10, and Ts cell might be independent predictors for the poor outcome of COVID-19.

From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases.

Dynamic Changes in the Immune Response Correlate with Disease Severity and Outcomes During Infection with SARS-CoV-2

Background:Little is known about the dynamic changes in the patient immune responses to SARS-CoV-2, and how different responses are correlated with disease severity and outcomes.Method:A total of 74 patients with confirmed COVID-19 were included from January 29th to February 15th 2020. Clinical characteristics and dynamic changes in immune response were analyzed and compared between severe and non-severe patients. ResultsOf the 74 patients, 17 suffered from severe disease and 57 from non-severe disease. Patients with severe disease tended be older (65.29 ± 12.33 years vs. 45.37 ± 18.66 years), and had a greater degree of underlying disease (41.18% vs. 24.56%) , lower lymphocytes counts (0.69 ± 0.36 × 10⁹ vs. 1.46 ± 0.75 × 10⁹) , higher neutrophil-lymphocyte-ratios (NLRs; 3.76 (3.15–5.51) vs. 2.07 (1.48–2.93)) and lower eosinophil counts (0.01 ± 0.01 × 10⁹ vs. 0.05 ± 0.07 × 10⁹), than that in non-severe patients. The number of immune cell subtypes, including helper T cells, suppressor T cells, B cells, and natural killer cells was significantly decreased in severe cases compared to that in non-severe cases (335.47 vs. 666.46/mL; 158 vs. 334/mL; 95 vs. 210/mL; 52 vs. 122/mL, respectively). As the condition of the patients improved, the number of neutrophils decreased significantly in the severe patients. All patients who recovered exhibited a gradual and persistent increase in eosinophil counts and lymphocyte counts, including helper T cells, suppressor T cells, and natural killer cells. In addition, the levels of most of inflammatory cytokines, including IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A, and TNF–α generally decreased as the patients gradually recovered.ConclusionsCollectively, our study provides novel information on the kinetics of the immune responses to COVID-19. Furthermore, our study indicates that both innate and adaptive immune responses correlate with better clinical outcomes.

Orally Administered Exosomes Suppress Mouse Delayed-Type Hypersensitivity by Delivering miRNA-150 to Antigen-Primed Macrophage APC Targeted by Exosome-Surface Anti-Peptide Antibody Light Chains

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies are aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes similarly induced CD3+CD8+ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced an exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration.

Orally Administered Exosomes Alleviate Mouse Contact Dermatitis through Delivering miRNA-150 to Antigen-Primed Macrophages Targeted by Exosome-Surface Antibody Light Chains

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes induced CD3+CD8+ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral administration. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides, suggesting that exosome-coating FLC target APCs by binding to Ag-major histocompatibility complexes. This renders APCs able to inhibit DTH effector T cells. Thus, our studies described a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that are particularly effective after oral administration.