Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
Another indirect route of SARS-CoV-2-induced NET production is platelet activation
SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
NETosis and NETs are increasingly recognized as causes of vascular injury
early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
“cytokine storm”
SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
have weakened adaptive immunity as well as a high level of inflammation
tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
NETs have also been shown to enhance macrophage pyroptosis in sepsis
facilitating an immunosuppressive microenvironment
persistent immunosuppression may result in bacterial co-infection or secondary infection
COVID-19 NETs may act as potential inducers for autoimmune responses
NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
COVID-19 also has a long-term influence on tumor progression
Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
awaken cancer cells
NETs have been shown to change the tumor microenvironment
enhance tumor progression and metastasis
vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
vitamin C may also inhibit NETosis and NET production in COVID-19
administration of low‐dose IL‐2 results in
expansion of a CD3– / CD56+ NK cell population in patients with advanced cancer
approximately 20 % will overexpress theHer2 / neu proto‐oncogene
In breast cancer, Her2 / neu overexpression is associated with a worse histologicalgrade, decreased relapse‐free
and overall survival periods, and altered sensitivity to chemotherapeutic regimens
NK cells are large granular lymphocytes that comprise approximately 10 % of circulating
lymphocytes
all human NK cells express the CD56 antigen
treatment
with various concentrations of IL‐2 in vivo may induce distinct functions within the NK cell compartment and, therefore, may
have profound effects on NK cell‐mediated cytotoxicity
CD56bright
CD56dim
We show here that ADCC conducted
by NK cells in vitro is enhanced by IL‐2 activation and is critically dependent on interactions between
FcγRIII on NK cells and Herceptin‐coated tumor targets
administration
of low‐dose IL‐2 to patients results in the marked expansion of a CD56+ population of immune effectors with the ability to lyse antibody‐coated cancer targets
NK cells represented only 7 % of lymphocytes prior to therapy but comprised over
50 % of the population after 10 weeks of low‐dose IL‐2
These data suggest that the enhanced ADCC seen following
the expansion of NK cells with low‐dose IL‐2 is likely due to an increase in the overall
number of NK cells
co‐administration of IL‐2 with rhu4D5 mAb will enhance activation of NK cell effector
functions
Stimulation of NK cells with IL‐2
resulted in a significant increase in the lysis of rhu4D5‐coated targets
We have shown that costimulation with IL‐2 plus rhu4D5 results in
significant production of IFN‐γ by NK cells with concomitant up‐regulation of cell‐surface
activation and adhesion molecules
It has been previously demonstrated that continuous
low‐dose IL‐2 can expand a CD56+ lymphocyte population, and we have now shown that this cell population is a potent
mediator of ADCC against rhu4D5 mAb‐coated Her2 / neu+ targets
These results suggest that administration of low‐dose IL‐2 can be used to
expand NK cell numbers, while higher doses may be used to enhance their cytolytic
capacity in the setting of mAb therapy
we have demonstrated that NK cell lysis of Her2 / neu+ breast cancer cell lines in the presence of rhu4D5 mAb is markedly enhanced following
stimulation with IL‐2
we have presented evidence that administration
of low‐dose IL‐2 in vivo results in the expansion of a potent NK cell effector population
Our experiments suggest that NK cells costimulated with IL‐2 and
immobilized IgG can secrete potent immunomodulatory cytokines which may serve to potentiate
the anti‐tumor immune response.