For new coronavirus pneumonia, too many hopes are pinned on antibodies, but antibodies are not as simple as generally understood, that is, as long as the body has antibodies, it can clear the virus.
We need to know enough about the complexity of antibodies and even the worsening side of the disease.
Huang Bo, professor of the Department of Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, explained the complexity of antibodies. Here is an article he posted on BioArt:
New coronavirus infection has caused more than 60,000 people to develop infectious pneumonia, and thousands of patients have lost their lives.
Whether it is government departments, scientific research teams, or the general public, everyone is looking forward to the emergence of antibody drugs, and the practice of directly collecting sera from cured patients during SARS to treat critically ill patients directly reflects the importance of antibodies for the treatment of such infectious diseases.
It is true that antibodies are one of the most important weapons for the body to fight against viral infections. Once the virus's neutralizing antibodies are produced, they are not only large in quantity but also durable, thus blocking the virus from entering the cells highly effectively.
If the virus cannot enter the cell, it cannot reproduce and expand, and the virus outside the cell will gradually decompose itself. This is the magic of antibodies.
If inactivated virus particles are directly injected into the body, the body will produce antibodies against the virus, which is a traditional vaccine that produces the effect of vaccination. The current development of vaccines for new crown virus also follows this basic principle.
However, as long as the body produces antibodies, it can control the virus. This idea may be only an illusion. The actual situation is far from this. Some antibodies can even promote the development of new coronary pneumonia.
So, is this alarmist, or is it scientific?
One fact is that many antibodies have been produced in many patients with severe neonatal pneumonia. Why can't these antibodies control the virus?
This is due to the complexity of the antibody.
Same virus and multiple antibodies
There are 20 kinds of amino acids in the body. Chemical covalent bonds link the amino acids one by one to form a long chain. This is commonly known as a protein. An antibody is a protein molecule that presents a branch-like Y-shaped structure, and the branch part recognizes and binds to the antigen (usually a foreign protein).
There are various heterologous proteins in nature. To recognize them, the branches of the branches are also various (biologically called the variable regions of antibodies), and even various Antibodies, but the trunk part of these different antibodies is basically the same (the constant region of the antibody is called biologically).
The nucleic acid substance RNA of the new coronavirus is located at the core and is enveloped by a nucleocapsid protein. The envelope is covered with spike protein (like a nail after amplification), envelope protein, envelope protein, and membrane protein. protein.
In addition to these proteins that maintain the structure of the virus, the genetic material of the nucleic acid of the virus can also direct the production of other viral proteins that are not involved in the structure of the virus (these viral proteins are present in the infected cells, not in the virus particles).
All these viral proteins are foreign proteins. For any foreign protein, the body may produce antibodies specific to it.
As a result, individuals infected with the new coronavirus can produce a variety of different antibodies against the virus.
Most antibodies lack antiviral effects
Now that the body has produced a variety of antibodies against the virus, does each antibody play an antiviral protective role? the answer is negative.
Antibodies need to play an antiviral role, provided that the antibodies recognize and bind to viral particles.
However, non-structural viral proteins do not exist in the virus particles (in the infected cells), so antibodies against this large class of viral proteins have no antiviral effect.
So, if the antibody targets the protein that is present in the virus particles (the so-called targeting, in general, it is a radish and a pit, this antibody specifically binds this protein), does it have an antiviral effect?
The answer is that only antibodies against viral surface proteins can produce antiviral effects. The surface of the new coronavirus is an envelope. The antibodies to the viral protein inside the envelope cannot be contacted. Therefore, this part of the antibody does not have antiviral effects.
In short, after the virus particles infect the body, a variety of different antibodies against viral proteins can be produced in the body, but most antibodies do not have an antiviral effect. Only antibodies that recognize the protein on the surface of the virus particle can have an antiviral effect.
Mode of action of effective antibody antiviral
(Block diagram of ACE2 antibody. Picture from: https://www.rndsystems.com)
Antibodies that recognize proteins on the surface of virus particles can produce antiviral effects, so how do these antibodies work?
Coronavirus is caused by the spike protein (nail protein) on the surface of the virus particle and a protein called angiotensin-converting enzyme 2 (ACE2) on the surface of lung epithelial cells.
ACE2 subsequently undergoes a change in shape and structure, causing the virus to enter the cell, and uses the cell's own amino acid molecules, nucleotide molecules and lipid molecules to synthesize new virus particles through chemical reactions. These new virus particles are released outside the cell. In the same way, the surrounding normal cells are infected.
Antibodies to spike proteins, which bind to spike proteins on the surface of virus particles, block the binding of spike proteins to ACE2, which also blocks the virus from entering cells. The antibodies against spike proteins are so-called neutralizing antibodies.
Neutralizing antibodies play a protective role by preventing viruses from invading cells, which is the main force for antibodies to exert antiviral effects.
There are also envelope proteins and membrane proteins on the surface of the coronavirus, but these two proteins may not mediate the entry of the virus into the cell. Therefore, the binding of the antibody to the envelope protein or membrane protein may not affect the entry of the virus into the cell.
However, if this binding affects the conformation (three-dimensional space structure) of spike protein and prevents spike protein from binding well with ACE2, it can prevent the virus from entering the cell (the probability of this situation is low).
Antibodies to envelope proteins or membrane proteins, after binding to the corresponding proteins on the surface of the virus, even though spike protein does not affect the virus to enter the lung epithelial cells, it can mediate the phagocytosis of virus particles by the immune cells of the body.
This is due to the presence of specific proteins on the surface of phagocytic cells (called Fc receptors) that are able to recognize the trunk part of the antibody, the constant region.
In this way, the antibody binds to the virus through its variable region and binds to phagocytes through its constant region, which greatly promotes the phagocytosis of virus particles by the phagocytic cells, and the phagocytosed virus is decomposed and eliminated in the phagocytic cells.
In summary, the ways in which antibodies work are divided into two categories: neutral surface antibodies bind to the virus to prevent the virus from entering the cell (protecting the enemy from outside the country); non-neutral surface antibodies bind to the virus, and mediate the phagocytosis and elimination of immune cells Viruses (kill the enemy within the country).
The disadvantages of antibodies against viruses
Non-neutralizing surface antibodies bind to viruses and mediate the phagocytosis of immune cells, which are mainly macrophages (full-time phagocytic cells in the human body).
After the macrophages swallow the virus, the virus particles are wrapped in a vesicle called an endosome, and the endosome then moves away from the cell surface and moves towards the center of the cell. In the process, it interacts with a type called a lysosome. The vesicles are fused, and the lysosome contains a variety of hydrolytic enzymes that can hydrolyze the virus, thereby eliminating the virus.
But while the immune system has evolved such an anti-virus mechanism, the virus is also evolving, using all means to escape the swallowing and killing.
One of these mechanisms is that the virus escapes from the endosome before the endosome is fused with the lysosome. How to escape?
After the endosomes envelop the virus, the fluid in the endocytic body's cyst cavity is gradually acidified (the pH value decreases). The virus can remove the outer envelope by acidification to expose the viral nucleic acid, and take the viral nucleic acid from the endosome. In the cytoplasm, viral nucleic acids can be replicated to form new viral particles and released outside the cell.
In this way, the virus uses surface antibodies to transform immune cells into virus intermediates to escape immune killing.
The virus's intracellular expansion in macrophages may not be the worst thing. Worse still, the virus may promote the inflammatory storm through macrophages.
Damage to lung cells by new coronaviruses generally does not directly lead to death of patients. The main cause of patient death is the excessive activation of non-specific immune cells, which release a large number of pro-inflammatory factors, such as interleukin-1 and leukocyte Interleukin-6, tumor necrosis factor, etc. form a so-called cytokine storm, which is scientifically called cytokine release syndrome (CRS).
The pathological damage of CRS is mainly manifested in capillaries. The capillary tube wall is arranged by a single layer of vascular endothelial cells. The gap between the endothelial cells is small only 1-2 nanometers, and the big one is only 5-8 nanometers. This is because the endothelial cells border the endothelial cells. There are numerous connexins on the surface, which are closely connected to each other, resulting in such a small gap.
However, the above-mentioned pro-inflammatory factors act on capillary endothelial cells in lung tissue, so that the surface of endothelial cells is no longer expressed or the amount of connexin is greatly reduced. In this way, the gap between endothelial cells suddenly becomes very large and the blood in the capillary It flows out from the enlarged gap and fills the alveoli. This is the inflammation storm.
So, what kind of immune cells are the cytokines that trigger the inflammatory storm? Macrophages are the culprit. Macrophages are important first-line defense cells in the body, with a large number.
Virus infection of macrophages can quickly activate macrophages and induce macrophages to release pro-inflammatory factors, but when the virus multiplies in macrophages, the activation of macrophages is particularly strong and can release excess pro-inflammatory Factor, triggering a cytokine storm.
The effect of non-neutralizing surface antibodies depends on the phase
Since the virus multiplies in macrophages, and there is a risk of causing great harm to the body, isn't the non-neutralizing surface antibody completely bad?
The answer is not yes, it depends on the time. In the early stages of viral infection, macrophages are functional in all aspects, phagocytosing antibody-mediated viruses, and more often hydrolyzing them in lysosomes. Even if some viruses escape to the cytoplasm, macrophages interfere with startup The protein signaling pathway can also effectively inhibit virus replication and amplification.
In the middle and late stages of virus infection, macrophages not only sense the signals of the virus, but also the signals of various cytokines. The function of the macrophages changes, and the virus can take advantage of it.
On the one hand, it escapes to the cytoplasm, on the other hand, a large number of viruses are amplified, which in turn forces macrophages to be strongly activated, which in turn releases excessive amounts of pro-inflammatory factors, causing damage to lung tissue.
Therefore, against virus surface proteins, neutralizing antibodies always play a protective role by preventing the virus from entering the lung epithelial cells, but non-neutralizing antibodies mainly mediate the virus into macrophages and play an antiviral role in the early stages, but in In the middle and late stages, it may be mainly caused by lung immune damage.
The body clears the virus and ultimately relies on T cells
Neutralizing antibodies are outside the cell, but they are powerless for viruses that have entered the cell. At the same time, neutralizing antibodies can only prevent most of the virus from invading the cell, and a small part or part of the virus will still enter the cell. .
For viruses that hide inside cells, the ultimate killing depends on T cells in the human body. The virus is in the epithelial cells of the lung, and the information of the viral protein is expressed on the surface of the infected cell.
The T cells can recognize the virus protein information on the surface of the infected cells, thus launching an attack on the infected cells and killing them. The end result is that the infected cells die, and the viruses hiding inside are also degraded. fate.
Therefore, even if it is a neutralizing antibody, it is not a panacea, but it can remove obstacles well and allow T cells to play their final role.
In short, for new coronary pneumonia, too many hopes are pinned on antibodies, but antibodies are not generally understood as simple, that is, as long as the body has antibodies, it can clear the virus.
We need to know enough about the complexity of antibodies and even the worsening side of the disease. At the same time, this also has important guiding significance for vaccine development, because the purpose of vaccination is to let the body produce antibodies, in fact, to produce neutralizing antibodies against the surface proteins of virus particles.
It is easy to vaccinate the body to produce antibodies, but it is not easy to produce such protective neutralizing antibodies, which poses a huge challenge to vaccine development. We should take a cautious attitude and carry out in-depth and detailed work.
