Communication Pattern Changes Along With Declined IGF1 of Immune Cells in COVID-19 Patients During Disease Progression

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19) pandemic, represents a global crisis. Most patients developed mild/moderate symptoms, and the status of immune system varied in acute and regulatory stages. The crosstalk between immune cells and the dynamic changes of immune cell contact is rarely described. Here, we analyzed the features of immune response of paired peripheral blood mononuclear cell (PBMC) samples from the same patients during acute and regulatory stages. Consistent with previous reports, both myeloid and T cells turned less inflammatory and less activated at recovery phase. Additionally, the communication patterns of myeloid-T cell and T-B cell are obviously changed. The crosstalk analysis reveals that typical inflammatory cytokines and several chemokines are tightly correlated with the recovery of COVID-19. Intriguingly, the signal transduction of metabolic factor insulin-like growth factor 1 (IGF1) is altered at recovery phase. Furthermore, we confirmed that the serum levels of IGF1 and several inflammatory cytokines are apparently dampened after the negative conversion of SARS-CoV-2 RNA. Thus, these results reveal several potential detection and therapeutic targets that might be used for COVID-19 recovery.

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Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽

10.3390/v13030514 ◽

2021 ◽

Vol 13 (3) ◽

pp. 514

Author(s):

Denise Utami Putri ◽

Cheng-Hui Wang ◽

Po-Chun Tseng ◽

Wen-Sen Lee ◽

Fu-Lun Chen ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Mononuclear Cells ◽

Immune Cell ◽

Severe Disease ◽

Viral Rna ◽

Disease Course ◽

Peripheral Blood Mononuclear ◽

Peripheral Immune Cells ◽

Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

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Molecular mechanisms governing circulating immune cell heterogeneity across different species revealed by single cell sequencing

10.1101/2021.12.17.472326 ◽

2021 ◽

Author(s):

Zhibin Li ◽

chengcheng Sun ◽

Fei Wang ◽

Xiran Wang ◽

Jiacheng Zhu ◽

...

Keyword(s):

Single Cell ◽

Immune Cells ◽

Evolutionary Biology ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Immune Cell ◽

Cell Types ◽

Genetic Regulatory Networks ◽

Peripheral Blood Mononuclear

Background: Immune cells play important roles in mediating immune response and host defense against invading pathogens. However, insights into the molecular mechanisms governing circulating immune cell diversity among multiple species are limited. Methods: In this study, we compared the single-cell transcriptomes of 77 957 immune cells from 12 species using single-cell RNA-sequencing (scRNA-seq). Distinct molecular profiles were characterized for different immune cell types, including T cells, B cells, natural killer cells, monocytes, and dendritic cells. Results: The results revealed the heterogeneity and compositions of circulating immune cells among 12 different species. Additionally, we explored the conserved and divergent cellular cross-talks and genetic regulatory networks among vertebrate immune cells. Notably, the ligand and receptor pair VIM-CD44 was highly conserved among the immune cells. Conclusions: This study is the first to provide a comprehensive analysis of the cross-species single-cell atlas for peripheral blood mononuclear cells (PBMCs). This research should advance our understanding of the cellular taxonomy and fundamental functions of PBMCs, with important implications in evolutionary biology, developmental biology, and immune system disorders

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Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease

eLife ◽

10.7554/elife.60939 ◽

2020 ◽

Vol 9 ◽

Author(s):

Marlies P Noz ◽

Siroon Bekkering ◽

Laszlo Groh ◽

Tim MJ Nielen ◽

Evert JP Lamfers ◽

...

Keyword(s):

Coronary Artery Disease ◽

Bone Marrow ◽

Coronary Artery ◽

Immune Cells ◽

Mononuclear Cells ◽

Immune Cell ◽

Ex Vivo ◽

Peripheral Blood Mononuclear ◽

Artery Disease ◽

Myeloid Progenitors

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

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Single cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse immune cell subtypes including T-bet+ B cells

10.1101/2020.05.05.077362 ◽

2020 ◽

Cited By ~ 1

Author(s):

Roosheel S. Patel ◽

Joy E. Tomlinson ◽

Thomas J. Divers ◽

Gerlinde R. Van de Walle ◽

Brad R. Rosenberg

Keyword(s):

B Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Model Organisms ◽

Traditional Model ◽

Cell Type ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

ABSTRACTTraditional laboratory model organisms represent a small fraction of the diversity of multicellular life, and findings in any given experimental model often do not translate to other species. Immunology research in non-traditional model organisms can be advantageous or even necessary (e.g. for host-pathogen interaction studies), but presents multiple challenges, many stemming from an incomplete understanding of potentially species-specific immune cell types, frequencies and phenotypes. Identifying and characterizing immune cells in such organisms is frequently limited by the availability of species-reactive immunophenotyping reagents for flow cytometry, and insufficient prior knowledge of cell type-defining markers. Here, we demonstrate the utility of single cell RNA sequencing (scRNA-Seq) to characterize immune cells for which traditional experimental tools are limited. Specifically, we used scRNA-Seq to comprehensively define the cellular diversity of equine peripheral blood mononuclear cells (PBMCs) from healthy horses across different breeds, ages, and sexes. We identified 30 cell type clusters partitioned into five major populations: Monocytes/Dendritic Cells, B cells, CD3+PRF1+ lymphocytes, CD3+PRF1- lymphocytes, and Basophils. Comparative analyses revealed many cell populations analogous to human PBMC, including transcriptionally heterogeneous monocytes and distinct dendritic cell subsets (cDC1, cDC2, plasmacytoid DC). Unexpectedly, we found that a majority of the equine peripheral B cell compartment is comprised of T-bet+ B cells; an immune cell subpopulation typically associated with chronic infection and inflammation in human and mouse. Taken together, our results demonstrate the potential of scRNA-Seq for cellular analyses in non-traditional model organisms, and form the basis for an immune cell atlas of horse peripheral blood.

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Analysis of human glioma-associated co-inhibitory immune checkpoints in glioma microenvironment and peripheral blood

International Journal of Immunopathology and Pharmacology ◽

10.1177/20587384211056505 ◽

2021 ◽

Vol 35 ◽

pp. 205873842110565

Author(s):

Shaoping Shen ◽

Qiyan Wu ◽

Jialin Liu ◽

Liangliang Wu ◽

Rong Zhang ◽

...

Keyword(s):

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Myeloid Cell ◽

Immune Checkpoints ◽

Human Glioma ◽

Peripheral Blood Mononuclear ◽

Glioma Microenvironment

One biomarker for a better therapeutic effect of immune checkpoint inhibitors is high expression of checkpoint in tumor microenvironment The purpose of this study is to investigate the expression of immune checkpoints in human glioma microenvironment and peripheral blood mononuclear cells. First, single-cell suspension from 20 fresh high-grade glioma (HGG) specimens were obtained, and analyzed for lymphocyte composition, then six co-inhibitory immune checkpoints were analyzed at the same time. Second, 36 PBMC specimens isolated from HGG blood samples were analyzed for the same items. In GME, there were four distinct subtypes of cells, among them, immune cells accounted for an average of 51.3%. The myeloid cell population (CD11b+) was the most common immune cell identified, accounting for 36.14% on average; the remaining were most CD3+CD4+ and CD3+/CD8−/CD4− T lymphocytes. In these cells, we detected the expression of BTLA, LAG3, Tim-3, CTLA-4, and VISTA on varying degrees. While in PBMCs, the result showed that when compared with healthy volunteers, the proportion of NK cells decreased significantly in HGG samples ( p < 0.01). Moreover, the expression of BTLA, LAG3, and Tim-3 in CD45+ immune cells in PBMC was more remarkable in glioma samples. In conclusion, the CD11b+ myeloid cells were the predominant immune cells in GME. Moreover, some immune checkpoints displayed a more remarkable expression on the immune cells in GME. And the profile of checkpoint expression in PBMC was partially consistent with that in GME.

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Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

10.1101/2020.05.08.082628 ◽

2020 ◽

Author(s):

Priscilla Do ◽

Lacey A Perdue ◽

Andrew Chyong ◽

Rae Hunter ◽

Jodi Dougan ◽

...

Keyword(s):

T Cell ◽

Immune Cells ◽

Immune Cell ◽

Ex Vivo ◽

Leukemia Cell ◽

Lytic Activity ◽

Cell Contact ◽

Specific Cell ◽

Wide Range ◽

Parallel Assembly

ABSTRACTTherapies that bind with immune cells and redirect their cytotoxic activity towards diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells towards leukemic B cells and simultaneously co-targets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bi-specific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of structure-function relationships. Using this approach, we identified CD19 × CD3 × IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.

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Immunotherapy in Aplastic Anemia Using a Biotherapeutic Approach.

Blood ◽

10.1182/blood.v104.11.4214.4214 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4214-4214

Author(s):

Weiwei Liu ◽

Jiayu Chen ◽

Yangqiu Li ◽

Demao Yang

Keyword(s):

Aplastic Anemia ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Severe Disease ◽

Calcium Ionophore ◽

Cell Contact ◽

Target Cells ◽

Peripheral Blood Mononuclear

Abstract We have developed a cell-based immunotherapy and successfully treated some patients with benzene-induced and idiopathic aplastic anemia (AA). Autologous and/or allogeneic peripheral blood mononuclear cells were cultured in vitro with a combination of cytokines and calcium ionophore for 2 days before given to patients via intravenous infusion--initially with patients with mild or modest disease. However, these patients had been treated with conventional immune suppression plus growth factors for 6 months to 1.5 years. During this rather prolonged time, they did not recover spontaneously, and one or more lineages (mostly platelet) of their peripheral blood counts had never been normal. The frequency of the treatment was once a week and patients stopped receiving any other therapy. Encouraged by the fact that these patients had strong and rapid recovery of blood counts after receiving a number of cycles of the therapy, we then treated patients with more severe disease. This immunotherapy is very powerful in that no patients, among total 29 we have treated so far, even with the most severe form of benzene-induced AA, have failed therapy in our hospitals. It was found that severe disease requires more aggressive and prolonged therapy, the longest period of time we have performed the therapy for such patients is one year. The first group of patients we treated were followed up to 2.5 years and no secondary clonal disorders were found. It was found in our ongoing studies that infusion of large numbers of allogeneic immune cells is even more effective than infusion of small numbers of autologous cells for patients with severe disease. We have used 2–5x108 allogeneic immune cells per infusion per day for 5 consecutive days, followed by small numbers of autologous infusions (1 to 10 million from 50 ml of peripheral blood, depending on the severity of the disease). This cycle of therapy is repeated once a month for as long as the neutrophil count is more than 0.5x109/L. The efficacy of the therapy seems to correlate well with the number of cells infused and the frequency of infusion. The mechanism by which our immunotherapy works is not completely clear to us, and we are currently trying to understand it better by performing various animal experiments to see how stem cells benefit from the therapy. Because allogeneic cells work well for patients with AA, we speculate that our immunotherapy has little to do with HLA-mediated specific immune responses but rather affects target cells, tissues, and organs through cytokines produced by both infused and target cells and cell contact. Analysis of patients’ thymus function indicates improvement in T-cell differentiation and maturation. Finally, we are using the same therapy to treat 6 patients with severe idiopathic AA and have found that the therapy is also effective for these patients. One patient had a complete response after 3 months of therapy and the other 5 have had dramatic improvements in bone marrow histology, reduced blood transfusion, and increased neutrophil, leukocyte and reticulocyte counts after several months of therapy. We found, in general, that idiopathic AA is much more difficult and requires an even longer period of time to cure than benzene-induced AA using this immunotherapy and also that cure of this terrible disease using biotherapeutic approachs may become possible. This simple but very effective immunotherapy may have more potential in treatment of other hematopoietic disorders.

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17β-Estradiol Promotes Proinflammatory and Procoagulatory Phenotype of Innate Immune Cells in the Presence of Antiphospholipid Antibodies

Biomedicines ◽

10.3390/biomedicines8060162 ◽

2020 ◽

Vol 8 (6) ◽

pp. 162

Author(s):

Gayane Manukyan ◽

Anush Martirosyan ◽

Ludek Slavik ◽

Jana Ulehlova ◽

Martin Dihel ◽

...

Keyword(s):

Immune Cells ◽

Antiphospholipid Antibodies ◽

Mononuclear Cells ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cells ◽

Cytokine Release ◽

Peripheral Blood Mononuclear ◽

17Β Estradiol ◽

Acquired Thrombophilia

Antiphospholipid syndrome (APS) is the most common cause of acquired thrombophilia and recurrent spontaneous miscarriages associated with extended persistence of antiphospholipid antibodies (aPL). How circulating aPL and high-17β-estradiol (E2) environment contribute to the pregnancy complications in APS is poorly defined. Therefore, we aimed to analyse whether E2 could be responsible for the immune cell hyperactivation in aPL- positive (lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein) in women. For this, peripheral blood mononuclear cells (PBMCs) from 14 aPL- positive and 13 aPL- negative women were cultured in the presence or absence of E2, LPS or E2+LPS and cell immunophenotype and cytokine release were analysed. In the aPL+ group, E2 presence markedly increased the percentage of NK cells positive for CD69 (p < 0.05), monocytes positive for tissue factor (TF, CD142) (p < 0.05), and B cells expressing PD-L1 (p < 0.05), as well as the elevated production of IL-1β comparing to aPL- women (p < 0.01). Regardless of aPL positivity, E2 augmented the procoagulatory response elicited by LPS in monocytes. Our findings show the ability of E2 to promote proinflammatory and procoagulatory phenotype of innate immune cells in individuals with aPL positivity. Our data highlights the significant impact of female hormones on the activation of immune cells in the presence of aPL.

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Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma

Blood ◽

10.1182/blood-2010-04-279893 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3227-3237 ◽

Cited By ~ 145

Author(s):

Güllü Görgün ◽

Elisabetta Calabrese ◽

Ender Soydan ◽

Teru Hideshima ◽

Giulia Perrone ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Natural Killer ◽

Immune Cells ◽

Immune Cell ◽

Interleukin 2 ◽

Cytokine Signaling ◽

Accessory Cell ◽

Cell Contact ◽

Effector Cells

Abstract The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing–MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.

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Hemoglobin drives inflammation and initiates antigen spread and nephritis in lupus

10.1101/2020.11.27.399501 ◽

2020 ◽

Author(s):

Hritika Sharma ◽

Anjali Bose ◽

Uma Kumar ◽

Rahul Pal

Keyword(s):

T Cells ◽

B Cells ◽

Inflammatory Cytokines ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Immune Cell ◽

Cell Types ◽

Peripheral Blood Mononuclear ◽

Autoantibody Production

AbstractHemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during conditions of erythrocyte lysis, a condition that may occur in systemic lupus erythematosus. Whether Hb is preferentially inflammatory in lupus and additionally induces autoreactivity against prominent autoantigens was assessed. Peripheral blood mononuclear cells derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with Hb, effects negated by haptoglobin. Hb (more particularly, ferric Hb) triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from aging NZM2410 mice, and also had mitogenic effects on B cells. Ferric Hb activated multiple signaling pathways which were differentially responsible for the generation of specific cytokines; inflammatory signaling also appeared to be cell-context dependent. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures which contain packaged autoantigens, believed to trigger lupus autoreactivity) revealed synergies (in terms of cytokine release and autoantibody production in vitro) that were also restricted to the lupus genotype. Infusion of ferric Hb into NZM2410 mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies, and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, in concert with lupus-associated autoantigens, elicits the generation of inflammatory cytokines from multiple immune cell types and stimulates the generation of potentially pathogenic autoantibodies, neutralization of Hb could have beneficial effects.

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