scholarly journals Multi-layered transcriptomic analyses reveal an immunological overlap between COVID-19 and hemophagocytic lymphohistiocytosis associated with disease severity

2021 ◽  
Author(s):  
Lena F Schimke ◽  
Alexandre H Marques ◽  
Gabriela C Baiocchi ◽  
Caroline A Prado ◽  
Dennyson L Fonseca ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Plasma Proteins ◽  
Lymphocyte Subsets ◽  
Strong Association ◽  
Interconnected Network ◽  
Chemokine Signaling ◽  
Intelligence Modeling ◽  
Underlying Mechanisms ◽  
Leukocyte Populations

Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.

scholarly journals Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

2021 ◽  
Vol 9 (1) ◽  
pp. e001615
Author(s):  
Rachel A Woolaver ◽  
Xiaoguang Wang ◽  
Alexandra L Krinsky ◽  
Brittany C Waschke ◽  
Samantha M Y Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Single Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Tcr Repertoire ◽  
Underlying Mechanisms ◽  
Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

scholarly journals Mechanistic within-host models of the asexual Plasmodium falciparum infection: a review and analytical assessment

2021 ◽  
Author(s):  
Flavia Camponovo ◽  
Tamsin E Lee ◽  
Jonathan Russell ◽  
Lydia Burgert ◽  
Jaline Gerardin ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Immune Escape ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Clinical Malaria ◽  
Individual Variability ◽  
Switching Dynamics ◽  
Underlying Mechanisms ◽  
Parasite Dynamics

Background: Malaria blood-stage infection length and intensity are important drivers of disease and transmission; however, the underlying mechanisms of parasite growth and the host's immune response during infection remain largely unknown. Over the last 30 years, several mechanistic mathematical models of malaria parasite within-host dynamics have been published and used in malaria transmission models. Methods: We identified mechanistic within-host models of parasite dynamics through a review of published literature. For a subset of these, we reproduced model code and compared descriptive statistics between the models using fitted data. Through simulation and model analysis, we compare and discuss key features of the models, including assumptions on growth, immune response components, variant switching mechanisms, and inter-individual variability. Results: The assessed within-host malaria models generally replicate infection dynamics in malaria-na&iumlve individuals. However, there are substantial differences between the model dynamics after disease onset, and models do not always reproduce late infection parasitemia data used for calibration of the within host infections. Models have attempted to capture the considerable variability in parasite dynamics between individuals by including stochastic parasite multiplication rates; variant switching dynamics leading to immune escape; variable effects of the host immune responses; or via probabilistic events. For models that capture realistic length of infections, model representations of innate immunity explain early peaks in infection density that cause clinical symptoms, and model representations of antibody immune responses control the length of infection. Models differed in their assumptions concerning variant switching dynamics, reflecting uncertainty in the underlying mechanisms of variant switching revealed by recent clinical data during early infection. Overall, given the scarce availability of the biological evidence there is limited support for complex models. Conclusions: Our study suggests that much of the inter-individual variability observed in clinical malaria infections has traditionally been attributed in models to random variability, rather than mechanistic disease dynamics. Thus, we propose that newly developed models should assume simple immune dynamics that minimally capture mechanistic understandings and avoid over-parameterisation and large stochasticity which inaccurately represent unknown disease mechanisms.

scholarly journals TCR Transgenic Mice: A Valuable Tool for Studying Viral Immunopathogenesis Mechanisms

2020 ◽  
Vol 21 (24) ◽  
pp. 9690
Author(s):  
Yong-Bin Cho ◽  
In-Gu Lee ◽  
Yong-Hyun Joo ◽  
So-Hee Hong ◽  
Young-Jin Seo
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Receptor ◽  
Global Economy ◽  
Viral Infections ◽  
Cell Receptor ◽  
Cell Responses ◽  
Significant Burden ◽  
Underlying Mechanisms ◽  
Remarkable Progress

Viral infectious diseases are a significant burden on public health and the global economy, and new viral threats emerge continuously. Since CD4+ and CD8+ T cell responses are essential to eliminating viruses, it is important to understand the underlying mechanisms of anti-viral T cell-mediated immunopathogenesis during viral infections. Remarkable progress in transgenic (Tg) techniques has enabled scientists to more readily understand the mechanisms of viral pathogenesis. T cell receptor (TCR) Tg mice are extremely useful in studying T cell-mediated immune responses because the majority of T cells in these mice express specific TCRs for partner antigens. In this review, we discuss the important studies utilizing TCR Tg mice to unveil underlying mechanisms of T cell-mediated immunopathogenesis during viral infections.

scholarly journals Mycorrhizas enhance drought tolerance of citrus by altering root fatty acid compositions and their saturation levels

2019 ◽  
Vol 39 (7) ◽  
pp. 1149-1158 ◽  
Author(s):  
Qiang-Sheng Wu ◽  
Jia-Dong He ◽  
A K Srivastava ◽  
Ying-Ning Zou ◽  
Kamil Kuča
Keyword(s):  
Fatty Acid ◽  
Drought Tolerance ◽  
Strong Association ◽  
Regulation Of Gene Expression ◽  
Am Fungi ◽  
Unsaturation Index ◽  
Arbuscular Mycorrhizas ◽  
Poncirus Trifoliata ◽  
Underlying Mechanisms ◽  
Fatty Acid Compositions

Abstract Arbuscular mycorrhizas (AMs) have the ability to enhance drought tolerance of citrus, but the underlying mechanisms have not been clearly elucidated. Considering the strong association of cell membrane fatty acid (FA) unsaturation with plant drought tolerance, the present study hypothesized that AM fungi (AMF) modulated the composition and unsaturation of FAs to enhance drought tolerance of host plants. Drought-sensitive citrus rootstocks, trifoliate orange (Poncirus trifoliata) seedlings, were inoculated with AMF (Funneliformis mosseae) for 3 months and were subsequently exposed to drought stress (DS) for 8 weeks. Mycorrhizal seedlings exhibited better plant growth performance, higher leaf water potential and lower root abscisic acid concentrations under both well-watered (WW) and DS conditions. Arbuscular mycorrhiza fungus inoculation considerably increased root methyl oleate (C18:1), methyl linoleate (C18:2) and methyl linolenate (C18:3N3) concentrations under both WW and DS conditions, and root methyl palmitoleate (C16:1) concentrations under WW, while it decreased root methyl stearate (C18:0) levels under both WW and DS. These changes in the composition of FAs of mycorrhized roots resulted in higher unsaturation index of root FAs, which later aided in reducing the oxidative damage on account of lower concentration of malondialdehyde and superoxide radicals. The changes of these FAs were a result of AMF-up-regulating root FA desaturase 2 (PtFAD2), FA desaturase 6 (PtFAD6) and Δ9 FA desaturase (PtΔ9) genes under WW and PtFAD2, PtFAD6 and Δ15 FA desaturase (PtΔ15) genes under DS conditions. Our results confirmed that mycorrhization brought significant changes in root FA compositions, in addition to regulation of gene expression responsible for increasing the unsaturation level of FAs, a predisposing physiological event for better drought tolerance of citrus.

Modified Vaccinia Ankara Virus (MVA) Induces a Th1-Polarized Immune Response in Antigen-Presenting Cells (APCs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4650-4650
Author(s):  
Christin Flechsig ◽  
Yasemin Suezer ◽  
Markus Kapp ◽  
Gerd Sutter ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Fluorescent Protein ◽  
Conflicts Of Interest ◽  
Human Peripheral Blood ◽  
Cell Transplant ◽  
Peripheral Blood Mononuclear ◽  
Leukocyte Populations

Abstract Abstract 4650 Introduction MVA is one of the most promising vaccine candidates for infectious diseases as well as for malignancies. Astonishingly, little information exists about the mechanism by which immune responses to MVA are generated. It was shown that among leukocytes - which are essential for the generation of cellular and humoral immune responses - APCs like dendritic cells, monocytes and B cells are preferentially infected. But little is known about the effects on APCs. Therefore we wanted to analyze in more detail the general effects of MVA infections on different immune cells. Methods Primary human peripheral blood mononuclear cells (PBMCs) and isolated leukocyte populations in particular monocyte derived DCs, monocytes and B cells were infected with (wildtype) wtMVA or MVA-gfp (green fluorescent protein) to verify the infection. Subsequently changes in surface markers and cytokine expression were assessed. Results Among PBMCs and specific isolated leukocyte populations, monocytes, DCs and B cells were most susceptible to MVA infection. NK cells showed a lower and T cells a very low infection rate. Surprisingly, selected monocytes were less susceptible to MVA as compared to unselected ones. This phenomenon is due to phagocytosis of other infected PBMCs by monocytes. Furthermore we could show that MVA causes a downregulation of CD14 on iDCs and monocytes as well as of CD25, CD80, and CD86 on B cells. Furthermore, there was a slight downregulation of CD1a on iDCs and mDCs and of CD80 on iDCs. On the other hand MVA caused an upregulation of HLA-DR on monocytes and additionally a slight upregulation of CD40 on iDCs. Moreover, MVA evoked a slight upregulation of CD83 on iDCs but a slight downregulation on mDCs. Above all, we could demonstrate that MVA induces an upregulation of CXCL10 in iDCs, mDCs, monocytes, and B cells, and an upregulation of TNFα, IL-6, and IL-12p70 in iDCs, mDCs, and monocytes. In addition, we revealed a downregulation of CXCL8 in monocytes as well as of IL-β in B cells. Conclusions These results suggest that MVA induces a Th1-polarized immune response in APCs. Thus, MVA seems to be an appropriate vaccine vector for antiviral immunotherapy of stem cell transplant recipients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Probing the Unknowns in Cytokinin-Mediated Immune Defense in Arabidopsis with Systems Biology Approaches

2014 ◽  
Vol 8 ◽  
pp. BBI.S13462 ◽  
Author(s):  
Muhammad Naseem ◽  
Meik Kunz ◽  
Thomas Dandekar
Keyword(s):  
Systems Biology ◽  
Immune Responses ◽  
Protein Interactions ◽  
Immune Defense ◽  
Immune Functions ◽  
Protein Protein Interactions ◽  
Cytokinin Signaling ◽  
Host Immune Responses ◽  
Arabidopsis Protein ◽  
Underlying Mechanisms

Plant hormones involving salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and auxin, gibberellins, and abscisic acid (ABA) are known to regulate host immune responses. However, plant hormone cytokinin has the potential to modulate defense signaling including SA and JA. It promotes plant pathogen and herbivore resistance; underlying mechanisms are still unknown. Using systems biology approaches, we unravel hub points of immune interaction mediated by cytokinin signaling in Arabidopsis. High-confidence Arabidopsis protein—protein interactions (PPI) are coupled to changes in cytokinin-mediated gene expression. Nodes of the cellular interactome that are enriched in immune functions also reconstitute sub-networks. Topological analyses and their specific immunological relevance lead to the identification of functional hubs in cellular interactome. We discuss our identified immune hubs in light of an emerging model of cytokinin-mediated immune defense against pathogen infection in plants.

Lymphocyte subsets and T h 1/T h 2 immune responses in patients with adenocarcinoma of the oesophagus or oesophagogastric junction: relation to pTNM stage and clinical outcome

2003 ◽  
Vol 52 (10) ◽  
pp. 617-624 ◽  
Author(s):  
Johanna W. van Sandick ◽  
Marja A. Boermeester ◽  
Suzanne S. Gisbertz ◽  
Ineke J. M. ten Berge ◽  
Theo A. Out ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Responses ◽  
Lymphocyte Subsets ◽  
Ptnm Stage ◽  
Oesophagogastric Junction

scholarly journals Adipocytes Are the Control Tower That Manages Adipose Tissue Immunity by Regulating Lipid Metabolism

2021 ◽  
Vol 11 ◽  
Author(s):  
Jeu Park ◽  
Jee Hyung Sohn ◽  
Sang Mun Han ◽  
Yoon Jeong Park ◽  
Jin Young Huh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Immune Responses ◽  
Immune Cells ◽  
Adipose Stem Cells ◽  
Cellular Interactions ◽  
Multiple Impacts ◽  
Lipid Antigens ◽  
Lipid Metabolites ◽  
Underlying Mechanisms

Accumulating evidence reveals that adipose tissue is an immunologically active organ that exerts multiple impacts on the regulation of systemic energy metabolism. Adipose tissue immunity is modulated by the interactions between adipocytes and various immune cells. Nevertheless, the underlying mechanisms that control inter-cellular interactions between adipocytes and immune cells in adipose tissue have not been thoroughly elucidated. Recently, it has been demonstrated that adipocytes utilize lipid metabolites as a key mediator to initiate and mediate diverse adipose tissue immune responses. Adipocytes present lipid antigens and secrete lipid metabolites to determine adipose immune tones. In addition, the interactions between adipocytes and adipose immune cells are engaged in the control of adipocyte fate and functions upon metabolic stimuli. In this review, we discuss an integrated view of how adipocytes communicate with adipose immune cells using lipid metabolites. Also, we briefly discuss the newly discovered roles of adipose stem cells in the regulation of adipose tissue immunity.

scholarly journals How to Prevent and Mitigate Hypersensitivity Reactions to Biologicals Induced by Anti-Drug Antibodies?

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandra Vultaggio ◽  
Margherita Perlato ◽  
Francesca Nencini ◽  
Emanuele Vivarelli ◽  
Enrico Maggi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cytokine Production ◽  
Inflammatory Diseases ◽  
Immunosuppressive Treatment ◽  
Complex Structures ◽  
Hypersensitivity Reactions ◽  
Immediate Hypersensitivity ◽  
Rheumatologic Diseases ◽  
Ige Mediated ◽  
Underlying Mechanisms

Biologicals are widely used therapeutic agents for rheumatologic diseases, cancers, and other chronic inflammatory diseases. They are characterized by complex structures and content of variable amounts of foreign regions, which may lead to anti-drug antibodies (ADA) development. ADA onset may limit the clinical usage of biologicals because they may decrease their safety. In fact they are mainly associated with immediate hypersensitivity reactions (HSRs). Development of ADAs is reduced by concomitant immunosuppressive treatment, while it is increased by longer intervals between drug administrations; thus, regular infusion regimens should be preferred to reduce HSRs. Once ADAs have formed, some procedures can be implemented to reduce the risk of HSRs. ADAs may belong to different isotype; the detection of IgE ADA is advisable to be assessed when high and early ADAs are detected, in order to reduce the risk of severe HRs. In patients who need to reintroduce the biological culprit, as alternative therapies are not available, drug desensitization (DD) may be applied. Desensitization should be conceptually dedicated to patients with an IgE-mediated HSR; however, it can be performed also in patients who had developed non-IgE-mediated HSRs. Although the underlying mechanisms behind successful DD has not been fully clarified, the DD procedure is associated with the inhibition of mast cell degranulation and cytokine production. Additionally, some data are emerging about the inhibition of drug-specific immune responses during DD.

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