scholarly journals Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients

2021 ◽  
Vol 7 ◽  
Author(s):  
Caroline Ruetsch ◽  
Vesna Brglez ◽  
Marion Crémoni ◽  
Kévin Zorzi ◽  
Céline Fernandez ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Type I ◽  
Type Ii ◽  
Systemic Complications ◽  
Adaptive Immune ◽  
Functional Exhaustion ◽  
Cytokine Levels ◽  
Stimulation Of

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines.

Disparate cytokine regulation of ICAM-1 in rat alveolar epithelial cells and pulmonary endothelial cells in vitro

1995 ◽  
Vol 269 (1) ◽  
pp. L127-L135 ◽  
Author(s):  
W. W. Barton ◽  
S. Wilcoxen ◽  
P. J. Christensen ◽  
R. Paine
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Inflammatory Cytokines ◽  
Alveolar Epithelial Cells ◽  
Normal Lung ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Epithelial

Intercellular adhesion molecule-1 (ICAM-1) is expressed at high levels on type I alveolar epithelial cells in the normal lung and is induced in vitro as type II cells spread in primary culture. In contrast, in most nonhematopoetic cells ICAM-1 expression is induced in response to inflammatory cytokines. We have formed the hypothesis that the signals that control ICAM-1 expression in alveolar epithelial cells are fundamentally different from those controlling expression in most other cells. To test this hypothesis, we have investigated the influence of inflammatory cytokines on ICAM-1 expression in isolated type II cells that have spread in culture and compared this response to that of rat pulmonary artery endothelial cells (RPAEC). ICAM-1 protein, determined both by a cell-based enzyme-linked immunosorbent assay and by Western blot analysis, and mRNA were minimally expressed in unstimulated RPAEC but were significantly induced in a time- and dose-dependent manner by treatment with tumor necrosis factor-alpha, interleukin-1 beta, or interferon-gamma. In contrast, these cytokines did not influence the constitutive high level ICAM-1 protein expression in alveolar epithelial cells and only minimally affected steady-state mRNA levels. ICAM-1 mRNA half-life, measured in the presence of actinomycin D, was relatively long at 7 h in alveolar epithelial cells and 4 h in RPAEC. The striking lack of response of ICAM-1 expression by alveolar epithelial cells to inflammatory cytokines is in contrast to virtually all other epithelial cells studied to date and supports the hypothesis that ICAM-1 expression by these cells is a function of cellular differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Efferent Synaptic Transmission at the Vestibular Type II Hair Cell Synapse

2020 ◽  
Author(s):  
Zhou Yu ◽  
J. Michael McIntosh ◽  
Soroush Sadeghi ◽  
Elisabeth Glowatzki
Keyword(s):  
Hair Cells ◽  
Nerve Fibers ◽  
Repetitive Stimulation ◽  
Vestibular Nerve ◽  
Type I ◽  
Type Ii ◽  
Optogenetic Stimulation ◽  
Vestibular Afferents ◽  
Stimulation Of

ABSTRACTIn the vestibular peripheral organs, type I and type II hair cells (HCs) transmit incoming signals via glutamatergic quantal transmission onto afferent nerve fibers. Additionally, type I HCs transmit via ‘non-quantal’ transmission to calyx afferent fibers, by accumulation of glutamate and potassium in the synaptic cleft. Vestibular efferent inputs originating in the brainstem contact type II HCs and vestibular afferents. Here, we aimed at characterizing the synaptic efferent inputs to type II HCs using electrical and optogenetic stimulation of efferent fibers combined with in vitro whole-cell patch clamp recording from type II HCs in the rodent vestibular crista. Properties of efferent synaptic currents in type II HCs were similar to those found in cochlear hair cells and mediated by activation of α9/α10 nicotinic acetylcholine receptors (AChRs) and SK potassium channels. While efferents showed a low probability of release at low frequencies of stimulation, repetitive stimulation resulted in facilitation and increased probability of release. Notably, the membrane potential of type II HCs measured during optogenetic stimulation of efferents showed a strong hyperpolarization even in response to single pulses and was further enhanced by repetitive stimulation. Such efferent-mediated inhibition of type II HCs can provide a mechanism to adjust the contribution of signals from type I and type II HCs to vestibular nerve fibers. As a result, the relative input of type I hair cells to vestibular afferents will be strengthened, emphasizing the phasic properties of the incoming signal that are transmitted via fast non-quantal transmission.New and NoteworthyType II vestibular hair cells (HCs) receive inputs from efferent fibers originating in the brainstem. We used in vitro optogenetic and electrical stimulation of efferent fibers to study their synaptic inputs to type II HCs. Efferent inputs inhibited type II HCs, similar to cochlear efferent effects. We propose that efferent inputs adjust the contribution of signals from type I and type II HCs that report different components of the incoming signal to vestibular nerve fibers.

scholarly journals Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

2021 ◽  
Vol 17 (9) ◽  
pp. e1009878
Author(s):  
Martina Severa ◽  
Roberta A. Diotti ◽  
Marilena P. Etna ◽  
Fabiana Rizzo ◽  
Stefano Fiore ◽  
...  
Keyword(s):  
Viral Replication ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Lung Epithelial Cells ◽  
Interferon Response ◽  
Cell Surface Expression ◽  
Cell Phenotype ◽  
Type I ◽  
Type I Ifn

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

scholarly journals Efferent synaptic transmission at the vestibular type II hair cell synapse

2020 ◽  
Vol 124 (2) ◽  
pp. 360-374 ◽  
Author(s):  
Zhou Yu ◽  
J. Michael McIntosh ◽  
Soroush G. Sadeghi ◽  
Elisabeth Glowatzki
Keyword(s):  
Hair Cells ◽  
Nerve Fibers ◽  
Type I ◽  
Type Ii ◽  
Vestibular Hair Cells ◽  
Efferent Neurons ◽  
The Brain ◽  
Cell Synapse ◽  
Stimulation Of

Type II vestibular hair cells (HCs) receive inputs from efferent neurons in the brain stem. We used in vitro optogenetic and electrical stimulation of vestibular efferent fibers to study their synaptic inputs to type II HCs. Stimulation of efferents inhibited type II HCs, similar to efferent effects on cochlear HCs. We propose that efferent inputs adjust the contribution of signals from type I and II HCs to vestibular nerve fibers.

IL-36 Receptor Antagonist with Special Emphasis on IL-38

2013 ◽  
Vol 26 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Y. Shaik ◽  
G. Sabatino ◽  
G. Maccauro ◽  
G. Varvara ◽  
G. Murmura ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Immune Cells ◽  
Biological Effect ◽  
Inflammatory Diseases ◽  
Biological Effects ◽  
Adaptive Immune Response ◽  
Type I ◽  
Adaptive Immune

IL-36 is another family member of IL-1 and induces the production of proinflammatory cytokines and activates MAPK and NFκB pathways. IL-36 is a common mediator of innate and adaptive immune response and is inhibited by IL-36 receptor antagonist (RA). IL-36RA acts on IL-36 receptor ligand which exerts proinflammatory effect in vivo and in vitro. IL-38 binds to IL-36 receptor as does IL-36RA and has similar biological effects on immune cells. IL-38 is also a member of IL-1 cytokine and shares some characteristics of IL-1RA, binding the same IL-1 receptor type I. IL-38 plays a role in the pathogenesis of inflammatory diseases, exerting protective effect in some autoimmune diseases. Both IL-38 and IL-36RA have an anti-inflammatory biological effect, however in some cases have contrary effects.

scholarly journals Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

2021 ◽  
Author(s):  
Martina Severa ◽  
Roberta Antonina Diotti ◽  
Marilena Paola Etna ◽  
Fabiana Rizzo ◽  
Stefano Fiore ◽  
...  
Keyword(s):  
Viral Replication ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Lung Epithelial Cells ◽  
Interferon Response ◽  
Cell Surface Expression ◽  
Cell Phenotype ◽  
Type I ◽  
Type I Ifn

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

scholarly journals Establishment of a New Device for Electrical Stimulation of Non-Degenerative Cartilage Cells In Vitro

2021 ◽  
Vol 22 (1) ◽  
pp. 394
Author(s):  
Simone Krueger ◽  
Alexander Riess ◽  
Anika Jonitz-Heincke ◽  
Alina Weizel ◽  
Anika Seyfarth ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Electric Fields ◽  
Cartilage Tissue ◽  
Type I ◽  
Dependent Manner ◽  
New Device ◽  
Alternating Electric Fields ◽  
Cartilage Cells ◽  
Stimulation Of

In cell-based therapies for cartilage lesions, the main problem is still the formation of fibrous cartilage, caused by underlying de-differentiation processes ex vivo. Biophysical stimulation is a promising approach to optimize cell-based procedures and to adapt them more closely to physiological conditions. The occurrence of mechano-electrical transduction phenomena within cartilage tissue is physiological and based on streaming and diffusion potentials. The application of exogenous electric fields can be used to mimic endogenous fields and, thus, support the differentiation of chondrocytes in vitro. For this purpose, we have developed a new device for electrical stimulation of chondrocytes, which operates on the basis of capacitive coupling of alternating electric fields. The reusable and sterilizable stimulation device allows the simultaneous use of 12 cavities with independently applicable fields using only one main supply. The first parameter settings for the stimulation of human non-degenerative chondrocytes, seeded on collagen type I elastin-based scaffolds, were derived from numerical electric field simulations. Our first results suggest that applied alternating electric fields induce chondrogenic re-differentiation at the gene and especially at the protein level of human de-differentiated chondrocytes in a frequency-dependent manner. In future studies, further parameter optimizations will be performed to improve the differentiation capacity of human cartilage cells.

Modeling Endoleaks and Collateral Reperfusion following Endovascular AAA Exclusion

2003 ◽  
Vol 10 (3) ◽  
pp. 424-432 ◽  
Author(s):  
Chuh K. Chong ◽  
Thien V. How ◽  
Geoffrey L. Gilling-Smith ◽  
Peter L. Harris
Keyword(s):  
Stent Graft ◽  
Aortic Pressure ◽  
Type I ◽  
Type Ii ◽  
Pump System ◽  
Type Ii Endoleak ◽  
Type I Endoleak ◽  
The Impact ◽  
Mean Aortic Pressure

Purpose: To investigate the effect on intrasac pressure of stent-graft deployment within a life-size silicone rubber model of an abdominal aortic aneurysm (AAA) maintained under physiological conditions of pressure and flow. Methods: A commercial bifurcated device with the polyester fabric preclotted with gelatin was deployed in the AAA model. A pump system generated physiological flow. Mean and pulse aortic and intrasac pressures were measured simultaneously using pressure transducers. To simulate a type I endoleak, plastic tubing was placed between the aortic wall and the stent-graft at the proximal anchoring site. Type II endoleak was simulated by means of side branches with set inflow and outflow pressures and perfusion rates. Type IV endoleak was replicated by removal of gelatin from the graft fabric. Results: With no endoleak, the coated graft reduced the mean and pulse sac pressures to negligible values. When a type I endoleak was present, mean sac pressure reached a value similar to mean aortic pressure. When net flow through the sac due to a type II endoleak was present, mean sac pressure was a function of the inlet pressure, while pulse pressure in the sac was dependent on both inlet and outlet pressures. As perfusion rates increased, both mean and pulse sac pressures decreased. When there was no outflow, mean sac pressure was similar to mean aortic pressure. In the presence of both type I and type II endoleaks, mean sac pressure reached mean aortic pressure when the net perfusion rate was low. Conclusions: In vitro studies are useful in gaining an understanding of the impact of different types of endoleaks, in isolation and in combination, on intrasac pressure after aortic stent-graft deployment.

Type VI collagen expression is upregulated in the early events of chondrocyte differentiation

Development ◽  
1993 ◽  
Vol 117 (1) ◽  
pp. 245-251
Author(s):  
R. Quarto ◽  
B. Dozin ◽  
P. Bonaldo ◽  
R. Cancedda ◽  
A. Colombatti
Keyword(s):  
Suspension Culture ◽  
Type I Collagen ◽  
Type Ii Collagen ◽  
Type I ◽  
Type Ii ◽  
Type Vi Collagen ◽  
Full Spectrum ◽  
Collagen Expression ◽  
Hypertrophic Chondrocyte

Dedifferentiated chondrocytes cultured adherent to the substratum proliferate and synthesize large amounts of type I collagen but when transferred to suspension culture they decrease proliferation, resume the chondrogenic phenotype and the synthesis of type II collagen, and continue their maturation to hypertrophic chondrocyte (Castagnola et al., 1986, J. Cell Biol. 102, 2310–2317). In this report, we describe the developmentally regulated expression of type VI collagen in vitro in differentiating avian chondrocytes. Type VI collagen mRNA is barely detectable in dedifferentiated chondrocytes as long as the attachment to the substratum is maintained, but increases very rapidly upon passage of the cells into suspension culture reaching a peak after 48 hours and declining after 5–6 days of suspension culture. The first evidence of a rise in the mRNA steady-state levels is obtained already at 6 hours for the alpha 3(VI) chain. Immunoprecipitation of metabolically labeled cells with type VI collagen antibodies reveals that the early mRNA rise is paralleled by an increased secretion of type VI collagen in cell media. Induction of type VI collagen is not the consequence of trypsin treatment of dedifferentiated cells since exposure to the actin-disrupting drug cytochalasin or detachment of the cells by mechanical procedures has similar effects. In 13-day-old chicken embryo tibiae, where the full spectrum of the chondrogenic differentiation process is represented, expression of type VI collagen is restricted to the articular cartilage where chondrocytes developmental stage is comparable to stage I (high levels of type II collagen expression).(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital Dyserythropoietic Anemia

PEDIATRICS ◽  
1973 ◽  
Vol 51 (5) ◽  
pp. 957-958
Author(s):  
G. Bennett Humphrey ◽  
Bahaod-Din Mojab ◽  
Ingomar Mutz
Keyword(s):  
Carbohydrate Metabolism ◽  
Morphological Characteristics ◽  
Type I ◽  
Type Ii ◽  
Congenital Dyserythropoietic Anemia ◽  
The 1950S ◽  
Deja Vu ◽  
Déjà Vu ◽  
Excellent Article

Reading the excellent article by Drs. Murphy and Oski, "Congenital Dyserythropoietic Anemia (CDA)",1 which further defines type II, produced a sense of deja vu. In the 1950s, nonspherocytic, hemolytic anemias (HNHA) were categorized as type I and II based on the in vitro autohemolysis test.2 This group of anemias has subsequently been demonstrated to be due to a series of enzymatic abnormalities in carbohydrate metabolism.3 In CDA, the morphological characteristics which define types I, II, and III probably reflect nuclear rather than cytoplasmic abnormalities.

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