Impaired function and delayed regeneration of dendritic cells in COVID-19

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DC) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute disease to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage- HLADR+ cells lacking DC markers. Increased frequency of the recently discovered CD163+ CD14+ DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of PD-L1 in conventional DC (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naive CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.

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Impaired function and delayed regeneration of dendritic cells in COVID-19

PLoS Pathogens ◽

10.1371/journal.ppat.1009742 ◽

2021 ◽

Vol 17 (10) ◽

pp. e1009742

Author(s):

Elena Winheim ◽

Linus Rinke ◽

Konstantin Lutz ◽

Anna Reischer ◽

Alexandra Leutbecher ◽

...

Keyword(s):

Dendritic Cells ◽

Severe Disease ◽

Innate Immune ◽

Severe Illness ◽

Adaptive Immune ◽

Follicular Helper ◽

Secondary Infections ◽

Programmed Death ◽

Classical Monocytes ◽

Antibody Secreting Cells

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage−HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.

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Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children

Nature Communications ◽

10.1038/s41467-021-21414-x ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 6

Author(s):

Melanie R. Neeland ◽

Samantha Bannister ◽

Vanessa Clifford ◽

Kate Dohle ◽

Kim Mulholland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Acute Phase ◽

Innate Immune ◽

Low Density ◽

Innate Immune Responses ◽

Immunological Mechanisms ◽

Activated Neutrophils ◽

Classical Monocytes

AbstractChildren have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.

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Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽

10.3390/genes11030323 ◽

2020 ◽

Vol 11 (3) ◽

pp. 323 ◽

Cited By ~ 1

Author(s):

Guoying Wang ◽

Xianghui Li ◽

Lei Zhang ◽

Abualgasim Elgaili Abdalla ◽

Tieshan Teng ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Th2 Responses ◽

Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

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Inflammation and Immune Response in COPD: Where Do We Stand?

Mediators of Inflammation ◽

10.1155/2013/413735 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 73

Author(s):

Nikoletta Rovina ◽

Antonia Koutsoukou ◽

Nikolaos G. Koulouris

Keyword(s):

Immune Responses ◽

Bacterial Infections ◽

Severe Disease ◽

Critical Role ◽

Specific Pattern ◽

Innate Immune ◽

Danger Signal ◽

Cd4 Cells ◽

Adaptive Immune ◽

Molecular Patterns

Increasing evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD. Recent data provide evidence for a role in the NLRP3 inflammasome in the airway inflammation observed in COPD. Cigarette smoke activates innate immune cells by triggering pattern recognition receptors (PRRs) to release “danger signal”. These signals act as ligands to Toll-like receptors (TLRs), triggering the production of cytokines and inducing innate inflammation. In smokers who develop COPD there appears to be a specific pattern of inflammation in the airways and parenchyma as a result of both innate and adaptive immune responses, with the predominance of CD8+ and CD4+ cells, and in the more severe disease, with the presence of lymphoid follicles containing B lymphocytes and T cells. Furthermore, viral and bacterial infections interfere with the chronic inflammation seen in stable COPD and exacerbations via pathogen-associated molecular patterns (PAMPs). Finally, autoimmunity is another novel aspect that may play a critical role in the pathogenesis of COPD. This review is un update of the currently discussed roles of inflammatory and immune responses in the pathogenesis of COPD.

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Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22063090 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3090

Author(s):

Toshimasa Shimizu ◽

Hideki Nakamura ◽

Atsushi Kawakami

Keyword(s):

Immune Responses ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Adaptive Immune ◽

Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

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Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22105386 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5386

Author(s):

Maria Namwanje ◽

Bijay Bisunke ◽

Thomas V. Rousselle ◽

Gene G. Lamanilao ◽

Venkatadri S. Sunder ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Therapeutic Potential ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Graft Loss ◽

Kidney Injury ◽

Adaptive Immune ◽

Consumption Rates ◽

Regulatory Phenotype

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

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