scholarly journals Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

Science ◽  
2020 ◽  
Vol 369 (6508) ◽  
pp. 1210-1220 ◽  
Author(s):  
Prabhu S. Arunachalam ◽  
Florian Wimmers ◽  
Chris Ka Pun Mok ◽  
Ranawaka A. P. M. Perera ◽  
Madeleine Scott ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Mammalian Target Of Rapamycin ◽  
Myeloid Cells ◽  
Human Leukocyte ◽  
Oncostatin M ◽  
Biological Assessment ◽  
Interferon Α ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr

Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators—including EN-RAGE, TNFSF14, and oncostatin M—which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.

scholarly journals Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2707-2715 ◽  
Author(s):  
D Cemerlic ◽  
B Dadey ◽  
T Han ◽  
L Vaickus
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Protein A ◽  
Human Leukocyte ◽  
Lymphocytic Leukemia ◽  
Target Antigen ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Hla Dr

Abstract The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.

scholarly journals Low-Dose Steroid Therapy Is Associated with Decreased IL-12 Production in PBMCs of Severe Septic Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Huang-Pin Wu ◽  
Chi-Chung Shih ◽  
Duen-Yau Chuang ◽  
Tien-Hsing Chen
Keyword(s):  
Steroid Therapy ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Human Leukocyte ◽  
Mortality Rates ◽  
Peripheral Blood Mononuclear ◽  
Leukocyte Antigen ◽  
Hla Dr ◽  
Relationship Of ◽  
The Relationship

Background.Sepsis-induced immunosuppression may result in higher mortality rates in patients.Methods. We examined the relationship of cytokine responses from stimulated peripheral blood mononuclear cells (PBMCs) and monocyte human leukocyte antigen-DR (HLA-DR) expression (days 1 and 7) with low-dose steroid therapy in 29 septic patients. Patients were treated according to the guidelines. Thirty healthy controls were enrolled for validation.Results. Eighteen patients were prescribed low-dose steroids and 11 were not. Interleukin- (IL-) 12 responses in patients without low-dose steroid therapy on days 1 and 7 were higher than those with low-dose steroid therapy. Compared to day 1, IL-12 responses significantly increased on day 7 in patients without low-dose steroid therapy. After regression analysis, the change in the IL-12 response from day 7 to day 1 was found to be independently associated with the low-dose steroid therapy. There was no difference in monocyte HLA-DR expression between patients treated with and without low-dose steroid on day 1 or 7. No change in monocyte HLA-DR expression from day 7 to day 1 was observed in patients with or without low-dose steroid therapy.Conclusion. Decreased IL-12 response was associated with the low-dose steroid therapy in PBMCs of septic patients.

scholarly journals Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2707-2715
Author(s):  
D Cemerlic ◽  
B Dadey ◽  
T Han ◽  
L Vaickus
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mononuclear Cells ◽  
Protein A ◽  
Human Leukocyte ◽  
Lymphocytic Leukemia ◽  
Target Antigen ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Hla Dr

The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.

scholarly journals Dynamic blood single-cell immune responses in patients with COVID-19

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Lulin Huang ◽  
Yi Shi ◽  
Bo Gong ◽  
Li Jiang ◽  
Zhixin Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Mitogen Activated Protein Kinase ◽  
Interferon Α ◽  
Type I ◽  
Peripheral Blood Mononuclear

AbstractThe 2019 coronavirus disease (COVID-19) outbreak caused by the SARS-CoV-2 virus is an ongoing global health emergency. However, the virus’ pathogenesis remains unclear, and there is no cure for the disease. We investigated the dynamic changes of blood immune response in patients with COVID-19 at different stages by using 5’ gene expression, T cell receptor (TCR), and B cell receptors (BCR) V(D)J transcriptome analysis at a single-cell resolution. We obtained single-cell mRNA sequencing (scRNA-seq) data of 341,420 peripheral blood mononuclear cells (PBMCs) and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies. In addition, we used three control samples. We found expansion of dendritic cells (DCs), CD14+ monocytes, and megakaryocytes progenitor cells (MP)/platelets and a reduction of naïve CD4+ T lymphocytes in patients with COVID-19, along with a significant decrease of CD8+ T lymphocytes, and natural killer cells (NKs) in patients in critical condition. The type I interferon (IFN-I), mitogen-activated protein kinase (MAPK), and ferroptosis pathways were activated while the disease was active, and recovered gradually after patient conditions improved. Consistent with this finding, the mRNA level of IFN-I signal-induced gene IFI27 was significantly increased in patients with COVID-19 compared with that of the controls in a validation cohort that included 38 patients and 35 controls. The concentration of interferon-α (IFN-α) in the serum of patients with COVID-19 increased significantly compared with that of the controls in an additional cohort of 215 patients with COVID-19 and 106 controls, further suggesting the important role of the IFN-I pathway in the immune response of COVID-19. TCR and BCR sequences analyses indicated that patients with COVID-19 developed specific immune responses against SARS-CoV-2 antigens. Our study reveals a dynamic landscape of human blood immune responses to SARS-CoV-2 infection, providing clues for therapeutic potentials in treating COVID-19.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

scholarly journals Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Clémence Marais ◽  
Caroline Claude ◽  
Nada Semaan ◽  
Ramy Charbel ◽  
Simon Barreault ◽  
...  
Keyword(s):  
Critically Ill ◽  
Host Response ◽  
Secondary Infection ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Human Leukocyte ◽  
Myeloid Derived Suppressor Cells ◽  
Phenotypic Characteristics ◽  
Leukocyte Antigen ◽  
Hla Dr

Abstract Background De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. Methods Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. Results Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5–7 and 8–10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. Conclusions Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

scholarly journals The 2′-O-methylation status of a single guanosine controls transfer RNA–mediated Toll-like receptor 7 activation or inhibition

2012 ◽  
Vol 209 (2) ◽  
pp. 235-241 ◽  
Author(s):  
Stefanie Jöckel ◽  
Gernot Nees ◽  
Romy Sommer ◽  
Yang Zhao ◽  
Dmitry Cherkasov ◽  
...  
Keyword(s):  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Thermus Thermophilus ◽  
Methylation Status ◽  
Transfer Rna ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Molecular Pattern

Foreign RNA serves as pathogen-associated molecular pattern (PAMP) and is a potent immune stimulator for innate immune receptors. However, the role of single bacterial RNA species in immune activation has not been characterized in detail. We analyzed the immunostimulatory potential of transfer RNA (tRNA) from different bacteria. Interestingly, bacterial tRNA induced type I interferon (IFN) and inflammatory cytokines in mouse dendritic cells (DCs) and human peripheral blood mononuclear cells (PBMCs). Cytokine production was TLR7 dependent because TLR7-deficient mouse DCs did not respond and TLR7 inhibitory oligonucleotides inhibited tRNA-mediated activation. However, not all bacterial tRNA induced IFN-α because tRNA from Escherichia coli Nissle 1917 and Thermus thermophilus were non-immunostimulatory. Of note, tRNA from an E. coli knockout strain for tRNA (Gm18)-2′-O-methyltransferase (trmH) regained immunostimulatory potential. Additionally, in vitro methylation of this immunostimulatory Gm18-negative tRNA with recombinant trmH from T. thermophilus abolished its IFN-α inducing potential. More importantly, Gm18-modified tRNA acted as TLR7 antagonist and blocked IFN-α induction of influenza A virus–infected PBMCs.

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