May 19, 2024

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Immunology Knowledge: Phase 2

Immunology Knowledge: Phase 2

Immunology Knowledge: Phase 2.  Human body has the third barrier of defense-the adaptive immune system.



▉ Introduction

Before introducing the defense strategy of the human innate immune system, we know that when your toe is pierced, the strongest warrior macrophages of innate immunity can programmatically recognize many of the most common invading pathogens, and the response is so Soon, the entire battle can be over in just a few days. This is why in the evening a few days later, your injured toe is intact, so you can take a hot bath again. It can be seen that the innate immune system plays an indispensable role in the process of protecting our body. In fact, about 99% of animals rely solely on physical barriers and innate immune systems to protect them. However, for vertebrates like us, there is a third barrier of defense-the adaptive immune system, and this is a powerful system that can adapt and protect the human body from almost any “invader”.



▉ Adaptive immune system

The clues to the existence of the adaptive immune system can be traced back to the 1890s, when the famous British immunologist Edwar Jenner began to use immune methods to help the British get rid of the fear of smallpox virus. In that era, smallpox was a major safety issue, so that hundreds of thousands of people died of the disease, and more people “differentiated” because of smallpox. Jenner discovered that milking women often have been infected with a disease called vaccinia, which causes some lesions on their hands that look like sores caused by the smallpox virus. At the same time Jenner also noticed that those female workers who had had cowpox seemed to never get smallpox again.


So Jenner decided to conduct a bold experiment. He collected the pus from the sores of a female worker suffering from vaccinia and inoculated it into a boy named James Phipps. Later, when the boy was vaccinated again with pus from a sore from a person with smallpox, he did not get smallpox. In Latin, the word corresponding to cow is vacca, which also explains the origin of the word vaccine. In this incident, history has portrayed Edward Jenner as a hero, but I think that boy is the real hero. Imagine what it feels like when a tall man walks towards you with a huge needle and a tube of pus in his hand! Although this will never happen again, we should still be grateful for the success of the Jenner experiment, because it opened up a whole new path for immunization, thus saving countless lives.


Immunology Knowledge: Phase 2

Smallpox is not something that humans often encounter. And Jenner’s experiment showed that if the human immune system has time to prepare, it can create weapons that protect us from “invaders”, and this “invader” can be something it has never seen before. It is worth noting that smallpox vaccination can only protect us from smallpox virus and similar viruses (such as vaccinia), so James Phipps may still get mumps, measles and other diseases. This is the typical characteristic of the adaptive immune system: it can adapt and acquire the ability to resist specific “invaders.”



▉  Antibodies and B cells

In the end, immunologists determined that the immunity against smallpox comes from some special proteins circulating in the blood of immunized individuals. These proteins are called antibodies, and the substances that induce the production of these antibodies are called antigens. (antigen). In the previous example, vaccinia is the antigen. The figure below is a schematic diagram of the structure of immunoglobulin G (IgG).

Immunology Knowledge: Phase 2

As shown in the figure, an IgG antibody molecule is composed of two different pairs of proteins, namely the heavy chain (Hc) and the light chain (Lc). It is precisely because of this structure that every molecule has two identical “grips”, namely Fab regions, which can bind to antigens. Proteins are ideal molecules for building antibodies that can “catch” an attacker, because different proteins can fold into countless complex shapes. IgG accounts for 75% of the antibodies in the blood, and there are four other antibodies, namely IgA, IgD, IgE and IgM. Each antibody is produced by B cells, and B cells are white blood cells born in the bone marrow, which can mature into plasma cells called “antibody factories”.

In addition to the “grasper” that can “grab” the antigen, each antibody molecule also has a constant region (Fc) tail that can bind to receptors on the cell membrane such as macrophages. In fact, the type of antibody is divided by the special structure of its Fc region. At the same time, the Fc region also determines which immune cell the antibody will bind to and how it will function.

The “grip” of each antibody will bind to a specific antigen, so in order to obtain antibodies that bind to many different antigens, many different antibody molecules must be made. So, if we want antibodies to protect us from any possible “aggressors,” how many different antibody molecules do we need? Rough estimates made by immunologists show that approximately 100 million antibodies would be needed.

Since the antigen binding region of each antibody molecule is composed of one heavy chain and one light chain, we can mix and pair about 10,000 different heavy chains with 10,000 different light chains, so that we can get what we need. There are hundreds of millions of different antibody molecules. However, human cells have only about 25,000 genes in total, so if each heavy chain or light chain is encoded by a different gene, then the genetic information of most B cells will be used up just to make antibodies, so this That’s the problem.


▉ Modular design produces antibody diversity

In 1977, Susumu Tonegawa solved the mystery of how B cells make 100 million different antibodies, and he won the Nobel Prize for this. When Tonegawa set out to study this problem, the accepted theorem was that the DNA in every cell is the same. This is proved by facts, because when an egg cell is fertilized, the DNA in the fertilized egg will be copied and passed equally to the daughter cell, and the DNA in the daughter cell will be copied again and passed equally to the next generation. Cell, and keep going like this. Therefore, except for the errors in the process of replication, every cell in our body has the same DNA as the original fertilized egg. However, Tonegawa assumes that although the above process is generally correct, there may be exceptions. He believes that all our B cells start from the same DNA, but during the maturation of these cells, the genes encoding antibodies may have changed, and these changes may be enough to make B cells produce the 100 million different kinds we need. Of antibodies.

Tonegawa decided to verify his conjecture by comparing the DNA sequence encoding the antibody light chain in mature B cells and immature B cells. Indeed, he found that these two sequences are different, and the genes encoding antibodies in mature B cells were obtained through modular design.

In each B cell, there are 4 DNA modules (gene fragments) on the chromosome encoding the heavy chain of the antibody, namely V, D, J and C, and each module has many copies, the same module There are slight differences between the different copies of. For example, in human genes, there are about 40 different V modules, 25 different D modules, and 6 different J modules. B cells select one (more or less, random) copies of each gene module and splice them together as shown in the figure below to assemble a mature B cell antibody heavy chain gene .

We have seen this “mix and match” strategy used to generate diversity before. For example, our cells use 20 different amino acids to mix and match to produce a huge number of different proteins. In terms of genetic diversity, the chromosomes that a person inherits from Ta’s parents are mixed and matched to produce a set of chromosomes that eventually enter the sperm or egg cell. Once nature has an exquisite design, it will continue to reuse it, and modular design is one of nature’s most exquisite designs.

The DNA encoding the antibody light chain is also assembled by selecting gene fragments and then splicing them together. It is precisely because there are so many different gene fragments that can be used to mix and match, this strategy can produce about 10 million different antibodies, which seems not enough. Therefore, in order to further increase the diversity of antibodies, when these genes are combined, there will be additional base insertions or deletions. Coupled with this junctional diversity, it is no problem to make 100 million different B cells and make corresponding different antibodies. The magic of this strategy is that through modular design and connection diversity, only very little genetic information is required to create incredible antibody diversity.



▉  Clone selection

In the human blood, there are about 3 billion B cells in total. This may seem like a lot, but if it contains 100 million different B cells to produce the 100 million antibodies needed to protect us, it means that on average there are only 30 B cells of each type. In other words, although there are B cells in our “arsenal” that can fight against any potential “aggressor”, the number of any kind of B cell is very small. Therefore, when we are attacked by “invaders”, we need to create more suitable B cells. Indeed, B cells are made on demand. But how does the immune system know which B cells to make? The answer to this question is one of the most concise principles in immunology—the principle of clonal selection.

After B cells mix and match the modules required to form antibodies and splice them together, a small amount of antibodies called “antibody detectors” are produced, called B cell receptors (BCR). These “antibody detectors” will be transported to the surface of B cells, and then anchored on the cell membrane with the antigen-binding region outward. Each B cell has about 100,000 BCRs anchored on the membrane, and the BCR on the same B cell can only recognize the same antigen.

The BCR on the surface of B cells is like a “bait”, and what they are looking for is a molecule that can be “caught” by virtue of the correct shape of the Fab region—cognate antigen. Unfortunately, most B cell searches are futile. For example, most of us may not be infected with SARS or HIV in our lifetime. Therefore, the B cells in our body that can make antibodies to recognize these viruses will never find molecules that pair with them. Most B cells must be very frustrating, because they have been searching all their lives, but they have found nothing.

Sometimes, however, B cells can indeed search for what they want. When the BCR of a B cell binds to its cognate antigen, that B cell will be activated, increase in size and divide into two daughter cells, and this process is called proliferation. The two daughter cells once again increased in size and divided into four cells, and so on. Each cycle of cell growth and division takes about 12 hours, and this period of proliferation lasts about a week. So in the end, about 20,000 identical B cell clones will be created, and the BCR on their membranes will all recognize the same antigen. This way we have enough B cells to form a strong defense.

After the selected B cells proliferate to form a huge “clone force”, most of them will start to make antibodies. The difference between the antibodies produced by these B cells and the BCR originally displayed on the cell membrane is that there is no “anchor” that will fix them on the surface of the B cell. Therefore, these antibodies will be transported out of B cells and into the blood. When a B cell is working at full capacity, it can secrete about 2,000 antibody molecules per second. After exerting great power, most B cells will die within about a week after working as an “antibody factory”.

When you think about this whole process, you will find that this is really an amazing strategy. First of all, because B cells use the idea of ​​modular design, enough different kinds of antibodies can be made with only a few genes to identify all possible “invaders.” Secondly, B cells are manufactured on demand, so we will not make too many useless B cells to fill our body, but start with a few B cells and select those useful for the existing “invaders” B cells.

Once selected, B-cells proliferate rapidly to form a huge “clone army”, and the antibodies of each B-cell fighter in the army are effective against that specific “invader”. Third, after these B cell clones grow up, the large logarithm will become an “antibody factory”, producing antibodies that can resist “invaders” in batches. Finally, when the “invaders” are eliminated, most B cells will die. Therefore, our bodies will not be filled with B cells that are used to deal with yesterday’s “invaders” and will have no effect on the “enemy” that will attack us tomorrow.



▉  Function of antibodies

It is very interesting that although antibodies play a very important role in defending against “invaders”, antibodies do not kill anything. Their task is to leave a “kiss of death” on the “invaders”. , Which gives the invading pathogen a mark of elimination. If you go to a very luxurious wedding, you will often pass by a welcome line before you are allowed to enjoy champagne and cake.

One of the duties of the welcoming team is to introduce everyone to the bride and groom, and the other is to ensure that outsiders do not enter the wedding celebration. As you walk through the welcome line, you will be seen by someone who is familiar with all the invited people.

If he finds that you do not belong to this wedding, then he will call a bodyguard and let you leave. His job is to identify those who are not welcome, not to drive them out. The same goes for antibodies: they identify “intruders” and then let other characters do the “dirty work.” All people are here to bless the bride and groom.

The most frequently encountered “invaders” are bacteria and viruses, and antibodies can combine with the two and mark them for elimination. Immunologists like to call them the “antibody opsonize” these “invaders.” The word “conditioning” comes from German, and its original meaning is “to prepare for eating”. When antibodies opsonize bacteria or viruses, they use Fab regions to bind to “invaders”, and Fc regions can bind to Fc receptors on the surface of cells such as macrophages. Through this strategy, the antibody builds a bridge between the “invader” and the phagocytic cell, bringing the “invader” to the vicinity of the phagocytic cell and handing it to the phagocytic cell.

In fact, the more ingenious part is that when the Fc receptor of macrophages binds to the antibody that modulates the “invader”, the “appetite” of the macrophages will greatly increase, making it more phagocytic. The surface of macrophages has proteins that can directly bind to common “invaders”, but the bridge function of antibodies increases the types of enemies that macrophages can swallow. As long as they are marked by antibodies, no matter whether the “invaders” are common or not, Phagocytes can swallow them. In fact, antibodies allow macrophages to focus on “invaders”, and if there is no such effect, then some uncommon “invaders” may be ignored.

Under the attack of viruses, antibodies have some other important functions. Viruses enter our cells by binding to specific receptors on our cell membranes. Of course, those receptors are not set up specifically for viruses to invade. They are also normal receptors, just like Fc receptors, which have normal physiological functions, but viruses have learned to use these receptors for their own use. Once the virus binds to the receptor and enters the cell, it can use the cell’s synthetic machinery to replicate many of itself. These newly born progeny viruses will destroy cells and sometimes even kill cells to continue to infect other neighboring cells.

The antibody can bind to the virus before it enters the cell, thereby preventing the virus from entering the cell or proliferating after entering the cell. Antibodies with such functions are called neutralizing antibodies. For example, some neutralizing antibodies can bind to specific sites where the virus binds to cell receptors, thereby blocking the “parking” of the virus on the cell surface. When this phenomenon occurs, the virus is “aired” outside the cell, conditioned by the antibody and ready to be phagocytosed by macrophages.



▉ Summary

This issue mainly introduces the immune response mediated by B cells and antibodies in the adaptive immune system, which further strengthens the defense capabilities of our defense system on the basis of the innate immune system. So, if “invaders” like viruses have entered our cells, what can the immune system do to eliminate those viruses? We will tell you in future articles, please wait!




(source:internet, reference only)

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