To Learn Immunology Well: Section 4

  • Categories:Academic Research
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-22
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(Summary description)

To Learn Immunology Well: Section 4

(Summary description)

  • Categories:Academic Research
  • Origin:WeChat official account -- Quick View of Pharmacy
  • Time of issue:2021-02-22
  • Views:0


In the previous section, we introduced the classification of T cells, the process of antigen presentation, and the process of activation of the adaptive immune system, providing a further understanding of humoral and cellular immunity in the adaptive immune system. In addition, through the figurative example of buying shoes, we can intuitively feel the difference and connection between the innate and adaptive immune systems, as well as their different roles. Starting from this section, we will return to the innate immune system and dissect it in more details to understand certain knowledge that has not been presented in detail in the previous sections.


The innate immune system rules

Immunologists used to believe that the only function of the innate system was to provide a rapid defense which would deal with invaders while the adaptive immune system was getting cranked up. However, it is now clear that the innate system does much more than that.

The adaptive immune system's antigen receptors (BCRs and TCRs) are so diverse that they can probably recognize any protein molecule in the universe. However, the adaptive system is clueless as to which of these molecules is dangerous and which is not. So how does the adaptive system distinguish friend from foe? The answer is that it relies on the judgment of the innate system.

Compared to the antigen receptors of the adaptive immune system, the receptors of the innate system are precisely tuned to detect the presence of the common pathogens (disease-causing agents) we encounter in daily life – viruses, bacteria, fungi, and parasites.In addition, the innate system has receptors that can detect when "uncommon" pathogens kill human cells. Consequently, it is the innate system which is responsible for evaluating the danger and for activating the adaptive immune system. In a real sense, the innate system gives "permission" to the adaptive system to respond to an invasion. But it's even better than that, because the innate system does more than just turn the adaptive system on. Actually, the innate system actually integrates all the information it collects about an invader and formulates a plan of action.This "game plan," which the innate system delivers to the adaptive immune system, tells which weapons must be mobilized (e.g., B cells or killer T cells) and exactly where in the body these weapons should be deployed. So if we think of the helper T cell as the quarterback of the adaptive immune system team, we should consider the innate immune system to be the "coach" – for it is the innate system that "scouts" the opponents, designs the game plan, and sends in the plays for the quarterback to call.


Figure 1: Coach deploying tactics


The importance of the innate immune system

For years, immunologists didn't pay much attention to the innate system – , because the adaptive system seemed more interesting. However, studies of the adaptive immune system have led to a new appreciation of the role that the innate system plays, not only as a lightning-fast second line of defense, but also as an activator and a controller of the adaptive immune system.

It's easy to understand the importance of the innate system's quick response to common invaders if you think about what could happen in an uncontrolled bacterial infection. Imagine that the splinter from your hot tub deck introduced just one bacterium into your tissues. As you know, bacteria multiply very quickly. In fact, a single bacterium doubling in number every 30 minutes could give rise to roughly 100 trillion bacteria in one day.If you've ever worked with bacterial cultures, you know that a 1-liter culture containing one trillion bacteria is so dense you can't see through it. So, a single bacterium proliferating for one day could yield a dense culture of about 100 liters. Now remember that your total blood volume is only about 5 liters, and you can appreciate what an unchecked bacterial infection could do to a human! Without the quick-acting innate immune system to defend us, we would clearly be in big trouble.

The innate system team includes the complement system of proteins, the professional phagocytes, and natural killer cells. This section begins with the complement system of proteins.


Figure 2: Bacteria


The complement system

The complement system is composed of about 20 different proteins that work together to destroy invaders and to signal other immune system players that the attack is on! The complement system is very old. Even sea urchins, which evolved about 700 million years ago, have a complement system. In humans, complement proteins start being made during the fi rst trimester of fetal development, so this important system is ready to go well before a child is born. Indeed, those rare humans born with a defect in one of the major complement proteins usually do not live long before succumbing to infection.

As with just about everything else in the immune defense, the complement system must be activated before it can function, and there are three ways this can happen. The first, the so-called "classical" pathway, depends on antibodies for activation, so we'll save that for a later lecture. Here we focus on the alternative pathway and the lectin activation pathway. It should be noted that the function of complement has nothing to do with its activation pathway.


Figure 3: The complement System


The alternative pathway

The second way the complement system can be activated is called the alternative pathway. Although the alternative pathway certainly evolved before the classical pathway. Immunologists call antibody-dependent activation "classical," simply because it happened to have been discovered first.

The proteins that make up the complement system are produced mainly by the liver, and are present at high concentrations in blood and tissues. The most abundant complement protein is called C3, and in the human body, C3 molecules are continually being broken into two smaller proteins. One of the protein fragments created by this "spontaneous" cleavage, C3b, is very reactive, and can bind to either of two common chemical groups (amino or hydroxyl groups). Because many of the proteins and carbohydrates that make up the surfaces of invaders (e.g., bacterial cells) have amino or hydroxyl groups, there are lots of targets for these little C3b "grenades."


Figure 4: Spontaneously clipped C3


If C3b doesn't find one of these chemical groups to react with within about 60 microseconds, it is neutralized by binding to a water molecule, and the game is over. This means that the spontaneously clipped C3 molecule has to be right up close to the surface of the invading cell in order for the complement cascade to continue. Once C3b is stabilized by reacting with a molecule on the cell surface, another complement protein, B, binds to C3b. Then complement protein D comes along and clips off part of B to yield C3bBb.


Figure 5: C3 clipped by D after binding to B


Once a bacterium has this C3bBb molecule glued to its surface, the fun really begins, because C3bBb acts like a "chain saw" that can cut other C3 proteins and convert them to C3b.  Consequently, C3 molecules that are in the neighborhood don't have to wait for spontaneous clipping events to convert them to C3b – the C3bBb molecule (called a convertase) can do the job very efficiently. And once another C3 molecule has been clipped, it too can bind to an amino or hydroxyl group on the surface of the bacterium.


Figure 6: C3 clipped by C3bBb


This process can continue, and pretty soon there are lots of C3b molecules attached to the surface of the target bacterium – , each of which can form a C3bBb convertase – which can then cut even more C3 molecules. All this attaching and cutting sets up a positive feedback loop, and the whole process just snowballs.


Figure 7: Positive feedback loop


Once C3b is bound to the surface of a bacterium, the complement cascade can proceed further. The C3bBb chain saw can bind to another molecule of C3b, and together they can clip a complement protein, C5, into two pieces. One of these pieces, C5b, can then combine with other complement proteins (C6, C7, C8, and C9) to make a membrane attack complex (MAC). To form this structure, C5b, C6, C7, and C8 form a "stalk" that anchors the complex in the bacterial cell membrane. Then C9 proteins are added to make a channel that opens up a hole in the surface of the bacterium. And once a bacterium has a hole in its surface, it's toast!


Figure 8: Assembly of C5b, C6, C7, C8, and C9


In the previous sections, I have used a bacterium as our "model pathogen," but the complement system also can defend against other invaders such as parasites and even some viruses. Now, you may be thinking: With these grenades going off all over the place, why doesn't the complement system form membrane attack complexes on the surface of our own cells? The answer is that human cells are equipped with many safeguards to keep this from happening. In fact, there are about as many proteins devoted to controlling the complement system as there are proteins in the system itself! For instance, the complement fragment, C3b, can be clipped to an inactive form by proteins in the blood, and this clipping is accelerated by an enzyme (MCP) that is present on the surface of human cells. There is also a protein on human cells called decay accelerating factor (DAF), which accelerates the destruction of the convertase, C3bBb, by other blood proteins. This can keep the positive feedback loop from getting started. And yet another cell-surface protein, CD59 (also called protectin), prevents the incorporation of C9 molecules into nascent MACs.


Figure 9


Below an interesting story is used to illustrate why these safeguards are so important. Transplant surgeons don't have enough human organs to satisfy the demand for transplantation, so they are considering using organs from animals. One of the hot candidates for an organ donor is the pig, because pigs are cheap to raise and some of their organs are about the same size as those of humans. As a warm-up for human transplantation, surgeons decided to transplant a pig organ into a baboon. This experiment was not a big success! Almost immediately, the baboon's immune system began to attack the organ, and within minutes the transplanted organ was a bloody pulp.  The culprit? The complement system. It turns out that the pig versions of DAF and CD59 don't work to control primate complement, so the unprotected pig organ was vulnerable to attack by the baboon's complement system.

This story highlights two important features of the complement system. First, the complement system works very fast. Complement proteins are present at high concentrations in blood and in tissues, and they are ready to go against any invader that has a surface with a spare hydroxyl or amino group. A second characteristic of this system is that if a cell surface is not protected, it will be attacked by complement. In fact, the picture you should have is that the complement system is continually dropping these little grenades, and any unprotected surface will be a target. In this system, the default option is death!


Figure 10: Organ transplantation


This section mainly introduces the complement system in the innate immune system and one of its activation pathways, the alternative pathway. Understanding the activation pathway of the complement system has become very simple through figurative metaphors such as "chain saw" and "grenade". In addition, we have also learned that the innate immune system does not only play a role in the initial stage of the immune response, but also acts as a commander. In the next section, we will continue to introduce the content of the lectin activation pathway of complement activation and the professional phagocytes. Please pay attention and stay tuned!



Figure 1, 2, 3, 9, 10:

Figure 4,5,6,7,8: How the Immune System Works

Bibliography: How the Immune System Works




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