Thursday, 10 December 2020

С(Ц)ИЕСТА СО ХУСЕИН ХАДЕИБА: Неколку работи што треба да ги знаете за имунитетот и КОВИД-19

Хусеин Хадеиба, по потекло од Босна и Херцеговина, е истражувач на Универзитетот Стенфорд во областа на имунологијата, чиј фокус на интерес е како специјализираните клетки-гласници наречени дендрични клетки ја регулираат имунолошката реакција. На една од последните С(ц)иести како гостин тој се обиде на наједноставен можен начин да објасни како функционира имунитетот, што е тоа клеточен имунитет (или имунитет на Т-клетките) и што сè треба да знаеме за нив во контекст на борбата на едно тело и на целиот свет против коронавирусот.
Дискусијата беше на англиски јазик и текстот што произлезе од неа, ви го пренесуваме исто на англиски:


Husein Hadeiba, originally from Bosnia and Herzegovina, is a Stanford University immunology researcher focusing on how specialized messenger cells of the immune system called dendritic cells, regulate the immune response. As a guest at one of the last S(c)iestas, he tried to explain in the simplest possible way how immunity works: what is cellular immunity (or T-cell immunity) and what we need to know about it in the context of the body’s immune system and the fight against coronavirus.

1. What exactly is immunity?

The immune system is the body's army with the task to protect us from foreign dangerous invaders. If the army fails to distinguish “foreign” invaders from your own (“self”) tissues, it can lead to a state of civil war, or autoimmune disease, with the potential to turn the human body into a bag of pus over a period of several hours if it completely loses control.

When it comes to immunity, lymphocytes are key to the body's defense. Red and white blood cells, including lymphocytes, present in the blood are produced in the bone marrow by stem cells. Lymphocytes come in different flavors: B-lymphocytes and T-lymphocytes. B-lymphocytes mature in the bone marrow (hence the designation “B”) and then enter the bloodstream where they produce sticky proteins called antibodies that bind to foreign invaders and prevent them from causing damage. T cell precursors on the other hand, enter the bloodstream, but continue their journey to the thymus (hence the designation “T”) where they undergo further education, similar to a military academy. There they learn to distinguish self from foreign. The principle is simple: everything that the thymus presents to them during their development is considered "self" and these T lymphocytes with specialized receptors to "self" are eliminated. The remaining T lymphocytes do not recognize "self" and are therefore useful to the body. T cells then leave the thymus and enter the blood stream to perform two key functions because they come in two flavors: The T helper cells produce short range immune hormones or cytokines that orchestrate the activation and proliferation of many important immune cells, in order to sustain a robust immune response. The T killer cells, recognize cells that are either infected or mutated and then proceed to kill and eliminate the “unhealthy” cells.

Interestingly, if your body encounters something for the first time, such as the novel coronavirus, the primary adaptive immune response is gradual: cytokines are produced that orchestrate B cells to produce antibodies and killer T cells to kill virally infected cells. However, in some deadly situations the immune system can slide out of control and a cytokine storm occurs, which contributes to sepsis and potentially thrombosis that can kill the patient. In most patients, T- and B-cell proliferation is brought under control by triggering T and B cell death after activation. After most die, those that survive develop into two types: (i) memory cells that respond much faster to a secondary infection and (ii) immunosuppressive regulatory cells that prevent chronic inflammation to the infectious trigger. It is the memory cells that give us “immunity” to re-infection because these cells are programmed to step into action much faster and more vigorously, preventing the infectious agent to setup camp in the body.

In general, recurrent viral infections of any type have an important contribution to the health of our immune system. Frequent illness is important because it triggers the production of memory cells and a healthy immunoregulatory network.

2. What is T-cell immunity?

In addition to antibodies, each of us has also cellular immunity, because we all have T cells. The immune response is divided into two stages. First, we have the innate immune response, which is the first line of defense found in the tissue. Cells such as macrophages or neutrophils come in and eat the virus, producing innate cytokines that orchestrate the arrival of more potent adaptive immune cells, predominantly lymphocytes, involved in the second phase of the immune response. Critical messenger cells (called Dendritic cells studied by Husein), scan the tissue environment and travel from the tissues via the lymph to the lymph nodes. Here the messenger cells communicate with the lymphocytes and thus activate the second stage of the immune response, the so-called adaptive immune response. When the messenger cells reach the lymph nodes, they promote T cell proliferation (that causes lymph nodes to swell) and mobilize the killer T cells to leave the lymph node and travel via the bloodstream to the tissues to kill infected cells. The activated T helper cells on the other hand stimulate the B cells in the lymph nodes, via cytokines, to produce a vast amount of antibodies that are released into the bloodstream. Thus, antibodies produced by B cells neutralize any virus that lives outside the cell, whereas killer T cells kill virally infected cells. The orchestrator of both B and killer T cell responses is the helper T cells, which is akin to an army general that orchestrates the army incursion via short-range immune hormones or cytokines. The HIV virus in AIDS for example, infects and destroys the helper T cell, or immune general and therefore has a very potent impact on the immune response. AIDS patients always die of opportunistic infections and rare cancers that do not occur in healthy individuals. 

A virus in general, is genetic information (such as DNA or RNA) wrapped in a protein core that cannot multiply outside the cell, it must infect the cell and thus instruct the cellular machinery to make new viral copies. Antibodies are only useful in neutralizing viruses present outside cells, because they cannot enter the cell. They are useless in targeting infected cells packed with viral particles and viral genetic information. As a result, the immune system evolved the killer T cell that can detect changes in the cell, via specialized detector molecules on its cell surface called T-cell receptors. If the cell has been altered from its healthy state and becomes either virally infected or mutated, killer T cells are activated and latch onto the infected or altered cell and induce its killing and shredding of any genetic information present in the cell. This mechanism ensures that the sick cell and any viral particles present inside the cell get destroyed.

3. Vaccines and antibody therapy

If you want to achieve protection to the corona virus for example, you can either inject the patient with preformed antibodies to the virus (passive immunity) or by active immunization to either a viral component (e.g. protein) or a dead or inactivated virus (active immunity).

In passive immunity, antibodies from convalescent plasma (blood fluid from patients who’ve recovered from illness) are injected into patients with the hope that the antibodies will immediately bind to the virus and prevent them from attaching to and infecting other cells. After binding to their viral targets, the antibodies can signal innate immune cells to eat them up more easily.  However, these antibodies or other antibody therapies, like those from Regeneron for example, may also trigger a more systemic or widespread immune response that may contribute to a dangerous cytokine storm in the body which may worsen the patient's condition. This therapy therefore seems to be appropriate and effective in the early stages of infection, when viral levels are low, and not too much antibodies trigger an immune response.

In active immunity, it is very dangerous to infect someone with a live virus or a weak/attenuated form of the virus in general, as it might cause disease especially in immunocompromised individuals. Medical researchers have successfully created killed or severely compromised viral vaccines by isolating the virus and inactivating them with formaldehyde or other chemicals. Most viral vaccines today use viral components (such as proteins or killed virus) mixed with immune stimulators. These vaccines generate a successful antibody response to the viral component without making you sick, including the generation of memory cells as we discussed previously. Upon infection with the real virus, the antibodies are already present in the blood stream at sufficient levels to immediately neutralize the virus before it creates any havoc.  The problem is that a dead virus (or a protein component) cannot trigger potent cellular immunity, because it cannot infect a cell to induce effective killer T cell memory.

Therefore, effective vaccines involve isolating a protein from the virus, and mixing it with immunostimulants. The protein alone may not trigger an immune response, but mixed with certain types of nonspecific immunostimulants, will trigger an antibody response. However, in certain viral infections, cellular immunity is critical and highly desired since antibodies alone are not sufficient for effective immunity. In these cases, either live but weakened viral preparations are given, or viral genetic information is introduced into the cell, with the aim of altering a healthy cell into an infected cell. For example, with the new COVID-19 vaccine (the mRNA vaccine from Pfizer and Moderna), the genetic viral code in the form of mRNA is injected so that cells can take up the viral genes and make viral proteins inside the cell that will trigger cellular immunity, in addition to antibody production.

The somewhat comforting news as this COVID pandemic progresses, is that medical doctors and researchers are learning more about how to deal with the nasty side effects of viral infection, such as an overactive immune response and cytokine storm leading to complications from pneumonia and thrombosis usually in the elderly.  Current therapies to mitigate the effects of the virus, include treatment with immunosuppressants such as Dexamethasone and others as well as treatment with anti-coagulant agents to reduce blood clots as a potential result of an excessive immune response. Additional treatment modalities include anti-viral agents like Remdesivir.  These results are very encouraging.  The arrival of the Pfizer, Moderna and Astra-Zeneca vaccines will put an end to this pandemic by quickly establishing herd immunity, which can be achieved if 60-70% of a particular population have established immunity to the virus.

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