How the Immune System Works

LECTURE 1
An Overview

Immunology is a difficult subject to study for several reasons. First, there are lots of details, and sometimes these details get in the way of understanding the concepts. To get around this problem, we’re going to concentrate on the big picture. It will be easy for you to find the details somewhere else. A second difficulty in learning immunology is that there is an exception to every rule. Immunologists love these exceptions, because they give clues as to how the immune system functions. But for now, we’re just going to learn the rules. Oh, sure, we’ll come upon exceptions from time to time, but we won’t dwell on them. Our goal is to examine the immune system, stripped to its essence. The third difficulty in studying immunology is that our knowledge of the immune system is still evolving. As you’ll see, there are many unanswered questions, and some of the things that seem true today will be proven false tomorrow. I’ll try to give you a feeling for the way things stand now, and from time to time I’ll discuss what immunologists speculate may be true. But keep in mind that although I’ll try to be straight with you, some of the things I’ll tell you will change in the future (maybe even by the time you read this!).

I think the main reason immunology is such a tough subject, however, is that the immune system is a “team effort” that involves many different players interacting with each other. Imagine you’re watching a football game on TV, and the camera is isolated on one player, say, the tight end. You see him run at full speed down the field, and then stop. It doesn’t seem to make any sense. Later, however, you see the same play on the big screen, and now you understand: that tight end took two defenders with him down the field, leaving the running back uncovered to catch the pass and run for a touchdown. The immune system is just like a football team. It’s a network of players who cooperate to get things done, and just looking at one player doesn’t make much sense. You need an overall view. That’s the purpose of this first lecture, which you might call “turbo immunology.” Here, I’m going to take you on a quick tour of the immune system, so you can get a feeling for how it all fits together. Then in the next lectures, we’ll go back and take a closer look at the players and their interactions.

PHYSICAL BARRIERS

Our first line of defense against invaders consists of physical barriers, and to cause real trouble, viruses, bacteria, parasites, and fungi must first penetrate these shields. Although we tend to think of our skin as the main barrier, the area covered by our skin is only about two square meters. In contrast, the area covered by the mucous membranes that line our digestive, respiratory, and reproductive tracts measures about 400 square meters – an area about as big as two tennis courts. The main point here is that there is a large perimeter which must be defended.

THE INNATE IMMUNE SYSTEM

Any invader that breaches the physical barrier of skin or mucosa is greeted by the innate immune system – our second line of defense. Immunologists call this system “innate” because it is a defense that all animals just naturally seem to have. Indeed, some of the weapons of the innate immune system have been around for more than 500 million years. Let me give you an example of how this amazing innate system works.

Imagine you are getting out of your hot tub, and as you step onto the deck, you get a large splinter in your big toe. On that splinter are many bacteria, and within a few hours you’ll notice (unless you had a lot to drink in that hot tub!) that the area around where the splinter entered is red and swollen. These are indications that your innate immune system has kicked in. In your tissues are roving bands of white blood cells that defend you against attack. To us, tissue looks pretty solid, but that’s because we’re so big. To a cell, tissue looks somewhat like a sponge with holes through which individual cells can move rather freely. One of the defender cells that is stationed in your tissues is the most famous innate immune system player of them all: the macrophage. If you are a bacterium, a macrophage is the last cell you want to see after your ride on that splinter. Here is an electron micrograph showing a macrophage about to devour a bacterium:

You will notice that this macrophage isn’t just waiting until it bumps into the bacterium, purely by chance. No, this macrophage actually has sensed the presence of the bacterium, and is reaching out a “foot” to grab it. But how does a macrophage know that a bacterium is out there? The answer is that macrophages have antennae (receptors) on their surfaces which are tuned to recognize “danger molecules” characteristic of common microbial invaders. For example, the walls that surround bacteria are made up of fats and carbohydrates that normally are not found in the human body. These foreign molecules represent “find me and eat me” signals for macrophages. Indeed, when macrophages detect danger molecules, they begin to crawl toward the microbe which is emitting the foreign molecule.

When it encounters a bacterium, a macrophage first engulfs it in a pouch (vesicle) called a phagosome. This vesicle is then taken inside the macrophage, where it fuses with another vesicle termed a lysosome. Lysosomes contain powerful chemicals and enzymes which can destroy bacteria. In fact, these agents are so destructive that they would kill the macrophage itself if they were released inside it. That’s why they are kept in pouches. Using this clever strategy, the macrophage can destroy an invader without “shooting itself in the foot.” This whole process is called phagocytosis, and this series of snapshots shows how it happens:

Macrophages have been around for a very long time. In fact, the ingestion technique macrophages employ is simply a refinement of the strategy that amoebas use to feed themselves – and amoebas have roamed the earth for about 2.5 billion years. Why is this creature called a macrophage, you may be wondering. “Macro,” of course, means large – and a macrophage is a large cell. Phage comes from a Greek word meaning “to eat.” So a macrophage is a big eater. In fact, in addition to defending against invaders, the macrophage functions as a garbage collector. It will eat almost anything. Immunologists take advantage of this appetite by feeding macrophages iron filings. Then, using a small magnet, they can separate macrophages from other cells in a cell mixture. Really!

Where do macrophages come from? Macrophages and all the other blood cells in your body are made in the bone marrow, where they descend from self-renewing cells called stem cells – the cells from which all the blood cells “stem.” By self-renewing, I mean that when a stem cell grows and divides into two daughter cells, it does a “one for me, one for you” thing in which some of the daughter cells go back to being stem cells, and some of the daughters go on to become mature blood cells. This strategy of continuous self-renewal insures that there will always be blood stem cells in reserve to carry on the process of making mature blood cells.

As each daughter cell matures, it has to make choices that determine which type of blood cell it will be when it grows up. As you can imagine, these choices are not random, but are carefully controlled to make sure you have enough of each kind of blood cell. For example, some daughter cells become red blood cells, which capture oxygen in the lungs, and transport it to all parts of the body. Indeed, our stem cell “factories” must turn out more than two million new red blood cells each second to replace those lost due to normal wear and tear. Other descendants of a stem cell may become macrophages, neutrophils, or other types of “white” blood cells. Just as white wine really isn’t white, these cells aren’t white either. They are colorless, but biologists use the term “white” just to indicate that they lack hemoglobin, and therefore are not red. Here is a figure showing some of the many different kinds of blood cells a stem cell can become:

When the cells which will mature into macrophages first exit the bone marrow and enter the blood stream, they are called monocytes. All in all you have about two billion of these cells circulating in your blood at any one time. This may seem a little creepy, but you can be very glad they are there. Without them, you’d be in deep trouble. Monocytes remain in the blood for an average of about three days. During this time they travel to the capillaries, which represent the “end of the line” as far as blood vessels go, looking for a crack between the endothelial cells that line the capillaries. These cells are shaped like shingles, and by sticking a foot between them, a monocyte can leave the blood, enter the tissues, and mature into a macrophage. Once in the tissues, most macrophages just hang out, do their garbage collecting thing, and wait for you to get that splinter so they can do some real work.

When macrophages eat the bacteria on that splinter in your foot, they give off chemicals which increase the flow of blood to the vicinity of the wound. The build-up of blood in this area is what makes your toe red. Some of these chemicals also cause the cells that line the blood vessels to contract, leaving spaces between them so that fluid from the capillaries can leak out into the tissues. It is this fluid which causes the swelling. In addition, chemicals released by...