The 2019 Coronavirus Disease (COVID-19) pandemic affected hundreds of millions of people around the world and killed more than 4.5 million people. The most prominent part of the outbreak is the fact that the majority of infected people show mild or no symptoms, while a significant minority develop severe or serious illness.
Several studies are investigating the immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and trying to understand what causes the severity of the disease and what the risk factors are. .. These provide an overview of the innate and adaptive immune responses.
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Innate immunity to the virus
Cytokines are cell signaling molecules that mediate many biological and immunological actions. One of these is interleukin-6 (IL-6), a pleiotropic cytokine that mediates both innate and adaptive immunity. It not only induces immune cell differentiation, but also helps warn of invading pathogens and ischemic damage.
IL-6 also mediates the proliferation of plasma cells and the production of immunoglobulin antibodies. High levels of IL-6 expression found in autoimmune or autoinflammatory disorders also play a role in these conditions. Similarly, in COVID-19, IL-6 is persistently expressed at high levels after the virus has invaded the lung epithelium.
SARS-CoV-2 activates alveolar and circulating macrophages, Cytokine storm As a result of high IL-6 secretion. This in turn leads to endothelial cell damage and dysfunction, highly permeable capillaries, and blockage of the alveoli by exudate and cells. This is the underlying mechanism of acute respiratory distress syndrome (ARDS).
This suggests the use of tocilizumab, an IL-6 receptor inhibitor monoclonal antibody, to regulate the severity of ARDS.
Multiple symptoms of severe COVID-19 pneumonia may be due to complement activation at the systemic level. They include ARDS and hypercoagulability. Elevated IL-6 levels in these pneumonia patients activate complement via the C5a-C5a receptor (C5aR) axis.
With the severity of the symptoms, all inflammatory markers also gradually increase from asymptomatic to severe COVID-19. Multiple pathways of complement activation are involved, and classical and alternative pathways may be associated with the strongest phenotype. These pathways are activated by the IgG viral immune complex.
Inhibition of the C5a / C5aR1 axis can block the release of inflammatory markers and lung damage, thus benefiting these patients. In addition, patients with COVID-19 pneumonia often develop coagulation due to intense activation of the complement system. Therefore, this can also be prevented by blocking the activation of complement.
Another complement activation pathway may be responsible for the development of ARDS in patients infected with this virus. Here, C1 esterase inhibitors (C1-INH) act through multiple pathways to regulate the endogenous complement pathway. It may be useful in treating patients with COVID-19 pneumonia and suppresses crosstalk between innate immunity and the coagulation pathway.
This arm of the immune response handles the coordinated B and T cell responses to the virus. The initial antibody reaction involves IgM and IgA, and within 10 days more IgG is secreted. This immune response is thought to prevent viral infections and provide high-affinity IgG memory B cells.
Antibodies to the receptor binding domain (RBD) are important and preferred prognostic markers in the defense response to the virus. Antibodies that are effective in preventing infection are those that target RBD and bind to spike trimers.
First, T-follicular cells activate naive B cells, which mature into activated B cells. These give rise to B memory cells and IgG-producing cells or plasmablasts. These changes occur in the germinal center of the follicle. Plasmablasts have a short lifespan and end this stage of antibody reaction. Reinfection then reactivates memory B cells and long-lived plasma cells in the bone marrow, triggering a specific antibody response to RBD.
Because T cell memory retains the ability to respond to viral antigens, direct cytotoxic T cell activity eliminates the virus and promotes B cell responses.
Nevertheless, antibody titers vary from individual to individual and peak in 50-60 days. They can remain at protection levels for up to 10 months. If the IgG antibody’s response to the virus is too high, it can cause severe cytokine release, leading to systemic inflammation, multiple organ failure, and even death.
Adaptive immunity – T cells
CD4T cells that target spikes are found in more than 80% of SARS-CoV-2 infected individuals, but also in the blood of more than 1 in 3 healthy donors. In the latter case, these cells responded to the C-terminal domain epitope of the peplomer. These cells also cross-react with the human-specific coronavirus 229E and OC43 peplomers.
This may mean that the reactive T cells found in these donors were induced by a previous seasonal coronavirus infection. If so, they may explain why children and young adults are less likely to develop symptomatic infections. This discovery Neutralizing antibody To human coronavirus, which is very specific to the inducing strain. Therefore, CD4 T cells are key to an effective and durable cross-reactive response to human coronavirus infections, including SARS-CoV-2.
The interferon alpha (IFN-α) response is found in most COVID-19 patients. Patients with moderate symptoms who successfully recover show several types of CD4 and CD8 effector T cells and natural killer cells. The latter interacts with the FcγRIIIb receptor.
T cells also respond to many viral proteins other than spikes, namely membrane (M) and nucleoprotein (N) antigens, which are more than one-third and nearly half of patients, respectively. This not only suggests a profile that characterizes protective immunity, but may also mean that future vaccines need to contain additional immune-dominant T cell-reactive peptides, as well as peplomer. I have.
Conversely, severe illness was associated with an abnormally strong and persistent immune response. Sustained secretion of IFN-α caused widespread expansion of T cells without activation of NK cells, as well as T cell depletion and an abnormal T cell receptor repertoire. The latter is an important sign of the inability to eliminate the virus via antibody-dependent cellular cytotoxicity (ADCC).
The rapid increase in the number of cells secreting IFN-α in patients with COVID-19 pneumonia indicates that this drug should be avoided in these cases.
Patients with the highest severity of the disease have the highest response of CD4 and CD8 T cells to multiple SARS-CoV-2 antigens. However, both central and effector memory CD8 T cells that respond to non-peplomer proteins have been identified in COVID-19 patients. These are probably cross-reactive, indicating the presence of permanent immunity.
Presumably, these cells reside in the respiratory tract and encounter the newly invading SARS-CoV-2 virus, which rapidly expands and triggers an effective immune response. While antibody production can ensure rapid bactericidal immunity when an antigen is encountered, T cells must present the antigen and initiate a memory response to initiate the process of virus removal. This also means that not only does the phenotype of the resulting disease change, but individuals without symptomatic infections can carry and infect the virus until it is cleared by a cellular and humoral response. To do.
People with immunodeficiency
Some scientists have found an association between the risk of severe illness and human leukocyte antigen (HLA) DQB1 * 06. This may help detect the presence of immunocompromised people, who are superspreaders who cannot cope with the virus but are at risk of diminished immune response to the virus and vaccines.
In people with immunodeficiency, such as those taking chemotherapy or immunosuppressive drugs, viral shedding can last up to two months after infection. A quarter of kidney transplant patients also developed antibodies that lasted for at least two months, but showed sustained viral shedding. The presence of viral particles in the blood indicates a poor prognosis.
Real-time assessment of adaptive immune response in patient samples showed that anti-spiked IgG and anti-RBD IgG were detectable 5 months after infection. However, a smooth curve was not obtained, indicating that the response to SARS-CoV-2 is diverse.
Importantly, memory B cell responses and memory central T cells appear to persist indefinitely and increase up to 5 months after infection. If this is confirmed, it means that the virus elicits a highly durable and specific B cell and IgG response. Some viruses, such as the 1918 influenza H1N1 virus and the smallpox vaccine 60 years ago, continue to induce B memory cells until 90 years after infection.
New therapies need to be developed based on these findings so that the pandemic can be controlled. Such studies are the best way to understand the immunology of SARS-CoV-2 and develop better vaccines.
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