To Learn Immunology Well: Section 2

  • Categories:Academic Research
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-02
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(Summary description)

To Learn Immunology Well: Section 2

(Summary description)

  • Categories:Academic Research
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-02
  • Views:0

▉ Introduction

The previous section briefly introduced the defense strategies of the innate immune system. The innate response involves warriors such as macrophages, which are programmed to recognize many common invaders, so after your toe gets punctured, your innate immune system usually responds so quickly that the battle is over in just a few days. That's why your injured toe will be intact a few days later, and you can take a hot bath again that night. It can be seen that the innate immune system plays an indispensable role in protecting our body. In fact, about 99% of all animals get along just fine with only natural barriers and the innate immune system to protect them. However, vertebrates like us have a third level of defense: the adaptive immune system. This is a defense system which actually can adapt to protect us against almost any invader.


Figure 1: Macrophage


▉ Adaptive immune system

One of the first clues that the adaptive immune system existed came back in the 1790s when Edward Jenner began to use immune methods to help British people get rid of the fear of smallpox virus. In those days, smallpox was a major health problem. Hundreds of thousands of people died from this disease, and many more were horribly disfigured. What Jenner observed was that milkmaids frequently contracted a disease called cowpox, which caused lesions on their hands that looked similar to the sores caused by the smallpox virus. Jenner also noted that milkmaids who had contracted cowpox almost never got smallpox.


Figure 2: Edward Jenner


So Jenner decided to conduct a daring experiment. He collected pus from the sores of a milkmaid who had cowpox, and used it to inoculate a little boy named James Phipps. Later, when Phipps was re-inoculated with pus from the sores of a person infected with smallpox, he did not contract that disease. In Latin, the word for cow is vacca – which explains where we get the word vaccine. History makes out the hero in this affair to be Edward Jenner, but I think the real hero that day was the young boy. Imagine having this big man approach you with a large needle and a tube full of pus! Although this isn't the sort of thing that could be done today, we can be thankful that Jenner's experiment was a success, because it paved the way for vaccinations that have saved countless lives.


Figure 3: Vaccine


▉ Antibodies and B cells

Eventually, immunologists determined that immunity to smallpox was conferred by special proteins that circulated in the blood of immunized individuals. These proteins were named antibodies, and the agent that caused the antibodies to be made was called an antigen. In this case, the antigen is the cowpox virus. Here's a sketch that shows the prototype antibody, immunoglobulin G (IgG).


Figure 4: IgG


As you can see, an IgG antibody molecule is made up of two pairs of two different proteins, the heavy chain (Hc)and the light chain (Lc). Because of this structure, each molecule has two identical "hands" (Fab regions) that can bind to antigens. Proteins are the ideal molecules to use for constructing antibodies that can grasp attackers because different proteins can fold up into a myriad of complex shapes. IgG makes up about 75% of the antibodies in the blood, but there are four other classes of antibodies: IgA, IgD, IgE, and IgM. Each kind of antibody is produced by B cells – white blood cells that are born in the bone marrow, and which can mature to become antibody factories called plasma cells.


Figure 5: Plasma cells


In addition to having hands that can bind to an antigen, an antibody molecule also has a constant region (Fc)"tail" which can bind to receptors (Fc receptors) on the surface of cells such as macrophages. In fact, it is the special structure of the antibody Fc region that determines its class (e.g., IgG vs. IgA), which immune system cells it will bind to, and how it will function.

The hands of each antibody bind to a specific antigen, so in order to have antibodies available that can bind to many different antigens, many different antibody molecules are required. Now, if we want antibodies to protect us from every possible invader, how many different antibodies would we need? Well, immunologists estimate that about 100 million should do the trick. Since each antigen-binding region of an antibody is composed of a heavy chain and a light chain, we could mix and match about 10,000 different heavy chains with 10,000 different light chains to get the 100 million different antibodies we need. However, human cells only have about 25,000 genes in all, so if each heavy or light chain protein were encoded by a different gene, most of a human's genetic information would be used up just to make antibodies. You see the problem.


▉ Generating antibody diversity by modular design

The riddle of how B cells could produce the 100 million different antibodies required to protect us was solved in 1977 by Susumu Tonegawa, who received the Nobel Prize for his discovery. When Tonegawa started working on this problem, the dogma was that the DNA in every cell in the body was the same. This made perfect sense, because after an egg is fertilized, the DNA in the egg is copied. These copies are then evenly passed down to the daughter cells, where they are copied again, and evenly passed down to their daughters – and so on. Therefore, barring errors in copying, each of our cells should end up with the same DNA as the original, fertilized egg. Tonegawa, however, hypothesized that although this is probably true in general, there might be exceptions. His idea was that all of our B cells might start out with the same DNA, but that as these cells mature, the DNA that makes up the antibody genes might change – and these changes might be enough to generate the 100 million different antibodies we need.

Tonegawa decided to test this hypothesis by comparing the DNA sequence of the light chain from a mature B cell with the DNA sequence of the light chain from an immature B cell. Sure enough, he found that these two sequences were different. And the genes encoding antibody in mature B cells are made by modular design.

In every B cell, on the chromosomes that encode the antibody heavy chain there are multiple copies of four types of DNA modules (gene segments) called V, D, J, and C. Each copy of a given module is slightly different from the other copies of that module. For example, in humans there are about 40 different V segments, about 25 different D segments, 6 different J segments, and so on. To assemble a mature heavy chain gene, each B cell chooses (more or less at random) one of each kind of gene segment, and pastes them together as shown in the following image.


Figure 6: Modular design


You have seen this kind of mix-and-match strategy used before to create diversity. For example, 20 different amino acids are mixed and matched to create the huge number of different proteins that our cells produce. And to create genetic diversity, the chromosomes you inherited from your mother and father are mixed and matched to make the set of chromosomes that goes into your egg or sperm cells. Once Mother Nature gets a good idea, she uses it over and over – and modular design is one of her very best ideas.

The DNA that encodes the light chain of the antibody molecule is also assembled by picking gene segments and pasting them together. Because there are so many different gene segments that can be mixed and matched, this scheme can be used to create about 10 million different antibodies – not quite enough. So, to make things even more diverse, when the gene segments are joined together, additional DNA bases are added or deleted. When this junctional diversity is included, there is no problem creating 100 million B cells, each with the ability to make a different antibody The magic of this scheme is that by using modular design and junctional diversity, only a small amount of genetic information is required to create incredible antibody diversity.


▉ Clonal selection

In the human blood stream there is a total of about three billion B cells. This seems like a lot, but if there are 100 million different kinds of B cells (to produce the 100 million different kinds of antibodies we need for protection), this means that, on average, there will only be about 30 B cells in the blood that can produce an antibody which will bind to a given antigen. Said another way, although we have B cells in our arsenal that can deal with essentially any invader, we don't have a lot of any one kind of B cell. As a result, when we are attacked, more of the appropriate B cells must be made. Indeed, B cells are made "on demand." But how does the immune system know which B cells to make more of? The solution to this problem is one of the most elegant in all of immunology: the principle of clonal selection.


Figure 7: B cell


After B cells do their mix-and-match thing and paste together the modules required, a relatively small number of proteins is made – a "test batch" of antibody molecules. These tester antibodies are called B cell receptors (BCRs). These tester antibodies are transported to the surface of the B cell and are tethered there with their antigen-binding regions facing out. Each B cell has roughly 100,000 BCRs anchored on its surface, and all the BCRs on a given B cell recognize the same antigen.

The B cell receptors on the surface of a B cell act like "bait." What they are "fishing for" is the molecule which their Fab regions have the right shape to grasp – their cognate antigen. Sadly, the vast majority of B cells fish in vain. For example, most of us will never be infected with the SARS virus or the AIDS virus. Consequently, those B cells in our body which could make antibodies that recognize these viruses never will find their match. It must be very frustrating for most B cells. They fish all their lives, and never catch anything!

On occasion, however, a B cell does make a catch. And when a B cell's receptors bind to its cognate antigen, that B cell is triggered to double in size and divide into two daughter cells – a process immunologists call proliferation. Both daughter cells then double in size and divide to produce a total of four cells, and so forth. Each cycle of cell growth and division takes about 12 hours to complete, and this period of proliferation usually lasts about a week. At the end of this time, a "clone" of roughly 20,000 identical B cells will have been produced, all of which have receptors on their surface that can recognize the same antigen. Now there are enough B cells to mount a real defense!


Figure 8: Plasma cell


After the selected B cells proliferate to form this large clone, most of them begin to make antibodies. The antibodies produced by these selected B cells are slightly different from the antibody molecules displayed on their surface in that there is no "anchor" to attach them to the B cell's surface. As a result, these antibodies are transported out of the B cell and into the blood stream. One B cell, working at full capacity, can pump out about 2,000 antibody molecules per second. After making this heroic effort, most of these B cells die, having worked for only about a week as antibody factories.


Figure 9: Plasma cell


When you think about it, this is a marvelous strategy. First, because they employ modular design, B cells use relatively few genes to create enough different antibody molecules to recognize any possible invader. Second, B cells are made on demand. So instead of filling up our bodies with a huge number of B cells which may never be used, we begin with a relatively small number of B cells, and then select the particular B cells that will be useful against the "invader du jour." Once selected, the B cells proliferate rapidly to produce a large clone of B cells whose antibodies are guaranteed to be useful against the invader Third, after the clone of B cells has grown sufficiently large, most of these cells become antibody factories which manufacture huge quantities of the very antibodies that are right to defend against the invader. Finally, when the intruder has been conquered, most of the B cells die. As a result, we don't fill up with B cells that are appropriate to defend against yesterday's invader, but which would be useless against the enemy that attacks us tomorrow.


▉ What antibodies do

Interestingly, although antibodies are very important in the defense against invaders, they really don't kill anything. Their job is to plant the "kiss of death" on an invader – to tag it for destruction. If you go to a fancy wedding, you'll usually pass through a receiving line before you are allowed to enjoy the champagne and cake. One of the functions of this receiving line is to introduce everyone to the bride and groom, while the other function is to be sure no outsiders are admitted to the celebration. As you pass through the line, you will be screened by someone who is familiar with all the invited guests. If she finds that you don't belong there, she will call the bouncer and have you removed. Her role is to identify undesirables, not to show them to the door. And it's the same with antibodies: They identify invaders, and let other players do the dirty work. All people are here to bless the bride and groom.


Figure 10


The invaders we encounter most frequently are bacteria and viruses. Antibodies can bind to both types of invaders and tag them for destruction. Immunologists like to say that antibodies can opsonizethese invaders. This term "opsonize" comes from a German word that means "to prepare for eating." When antibodies opsonize bacteria or viruses, they do so by binding to the invader with their Fab regions, leaving their Fc tails available to bind to Fc receptors on the surface of cells such as macrophages. Using this strategy, antibodies can form a bridge between the invader and the phagocyte, bringing the invader in close, and preparing it for phagocytosis.


Figure 11: Opsonizing


In fact, it's even better than this. When a phagocyte's Fc receptors bind to antibodies that are opsonizing an invader, the appetite of the phagocyte increases, making it even more phagocytic. Macrophages have proteins on their surface that can bind directly to many common invaders. However, the ability of antibodies to form a bridge between a macrophage and an invader allows a macrophage to increase its catalog of enemies to include any invader to which an antibody can bind, common or uncommon. In effect, antibodies focus a macrophage's attention on invaders, some of which (the uncommon ones) a macrophage would otherwise ignore.

During a viral attack, antibodies can do something else that is very important. Viruses enter our cells by binding to certain receptor molecules on a cell's surface. Of course these receptors are not placed there for the convenience of the virus. They are normal receptors, such as the Fc receptor, that have quite legitimate functions, but which the virus has learned to use to its own advantage. Once it has bound to these receptors and entered a cell, a virus then uses the cell's machinery to make many copies of itself. These newly made viruses burst out of the cell, sometimes killing it, and go on to infect neighboring cells. Antibodies can actually bind to a virus while it is still outside of a cell, and can keep the virus either from entering the cell or from reproducing once it has entered. Antibodies with these special properties are called neutralizing antibodies. For example, some neutralizing antibodies can prevent a virus from "docking" on the surface of a cell by binding to the part of the virus that normally would plug into the cellular receptor. When this happens, the virus is "hung out to dry," opsonized and ready to be eaten by phagocytes!


Figure 12: Neutralizing


▉ Summary

This section mainly introduces the immune response mediated by B cells and antibodies in the adaptive immune system, which further strengthens our defense system's capabilities on the basis of the innate immune system. So, if invaders like viruses have entered our cells, how can the immune system destory those viruses? Let's see what will happen in the next section!





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Figure 4, 6, 11: How the Immune System Works

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