The immune system is one of the most successful mechanisms of human evolution. Globally, the immune system is ready to go to war, and the word is not too weak as it fights against anything that does not belong to our body, like the Coronavirus. So, how does it work?
Borders between self and non-self
Except for red blood cells, all cells in an organism contain so-called Type I histocompatibility molecules (MHC). These molecules present fragments of proteins known as peptides in the extracellular environment. These peptides, composed of 9 amino acids, are generated from our proteins, which allow us to be ourselves. These protein fragments represent the self. You could compare this presentation on the cell surface to an aircraft’s cockades to determine whether it is a friendly or enemy plane. The non-self is everything else; in other words, all the proteins we cannot synthesize from our DNA.
The first line of defense
Just like the army, the immune system is organized into two principal ranks, soldiers and officers. Macrophages and dendritic cells are the soldiers of an immune response. They specifically kill anything that does not have the same histocompatibility molecule as the individual from which they come (such as bacteria). For killing, they emit small molecules, called cytokines, which create holes in the cell’s membrane. Once “pierced”, the invader is absorbed (phagocytosis) by macrophage or dendritic cells. A cell recovers the invader’s proteins through phagocytosis and presents the peptides from the non-self on the type II histocompatibility molecules’ surface.
The mixture of cytokines and presentation of non-self molecules on macrophages and dendritic cells alerts the officers, otherwise known as T- and B-lymphocytes. These cells are the climax of evolution. Before being stored in the spleen and our lymph nodes, testing these cells ensures that they do not recognize the self’s peptides, leading to autoimmune diseases. Once the first line of defense activates in the infected organs, they migrate to the nearest lymph node, the specific immune response’s headquarters. The officers will take it in turns to check whether they recognize non-self peptides and if so, they will mobilize. To do this, they will proliferate and move towards the combat zone. In the case of COVID-19, they will migrate to the lungs. The activation of lymphocytes is accompanied by proliferation and cytokines that amplify the immune response and control it.
During an immune response, the nature of antibodies (produced after activation of B-lymphocytes) varies, but their mode of recognizing the non-self is identical. Why change something that works perfectly? There are five main types of antibodies, and these antibodies all have a basic Y-shaped pattern which can be repeated depending on the type of antibody. The upper part of the Y is complementary to the non-self peptide. The lower part of the Y will allow the binding with the first line immune system and ensure the destruction of the infected cell; this is also called a fatal attraction. In an anti-viral response, it is mainly IgM and then IgG that are involved and can be detected, depending on the test’s sensitivity, a few days after the onset of symptoms. These antibodies have a limited lifespan, which is not the case with the B-lymphocytes that produce them.
Peptide 616 is a protein fragment of the non-self against which the upper Y part of the antibodies interacts in Covid-19 infection. Presently, serological tests are mainly directed against only three non-self peptides. This virus is a small virus with 29 proteins and can produce one or more non-self peptides. To have tested positive for Coronavirus but negative in serological tests does not mean that you aren’t contaminated; it means that you have not developed antibodies against the conditions we currently know. The identification of antigens usually takes several years of research as the mechanism is so complex to ensure an adequate immune response. It is, therefore, rather a lack of knowledge that limits our detection methods. The current tests are not new, and we developed these tests already during the previous coronavirus epidemic, e.g., SARS, in 2002.
Coronavirus is an RNA virus that requires viral proteins specific to these viruses to replicate in a human cell. We don’t consider a virus to be a living being in its entirety because it cannot reproduce without a host cell. As evolution is always a simple process, there are proteins common to other viruses. Therefore, other viruses such as the virus responsible for SARS or other RNA viruses such as measles can share these proteins. Of the 29 proteins encoded by the RNA of COVID-19, only one seems to find no known equivalence. The lack of knowledge leads us to believe that this immune response does not exist. COVID-19 does not have a different mode of functioning from other viruses.
The kiss of death – cell immunity
The other actor in the immune response but not talked about is the immune response led by T-cells. Not that it is less effective or efficient. On the contrary, it is just more challenging to detect. Unlike the B lymphocyte, the T lymphocytes go directly to the front. If the T lymphocyte recognizes a peptide from the non-self on a histocompatibility molecule, it releases needle-like proteins (granzyme), inducing the death of the cell it has identified. We talk about death kisses. Such cells are tricky because not only do they not circulate in the blood, but they are found either in the ganglia or on the battlefield, and given their tremendous efficiency, they are not many of them. To detect them, not only would they have to be found at the front, we need to amplify them in vitro for at least seven days. Another difficulty is that the peptides they recognize are not necessarily the same as B lymphocytes, and the world of detection is quite different. Finding T-lymphocytes is like looking for a needle in a haystack. Note that as with antibodies, T-cells destroy the cells that have the peptide of the non-self. In massive infection cases, the destruction can be more damaging than the infection itself, hence the need for strict control.
Lessons from previous wars or the memory response
A vaccine’s power lies in its ability to create a memory that induces an immune response that we can control and allows us to be better equipped when ‘war’ breaks out. Once the first attack has passed, the T and B lymphocytes turn into memory lymphocytes. When the non-self is present again, it is not one cell that will have to be activated, but hundreds of cells are already seasoned veterans. Although difficult to detect, they are present because why lose what you have acquired?
Even though Covid-19 is restricting our movement and lives, we have to believe in the power of our immune system. There are two promising avenues in the war against Covid-19, vaccination and the administration of antibodies. Stay safe while we look for ways to help your war machinery!
Blog by Celine Powis de Tenbossche