immune system
The immune system is one of the most ...

extraordinary feats of Darwinian engineering on the planet. Over the past 4 billion years, as life developed from single-celled organisms to complex, multi-cellular creatures, we have been under continual attack by viruses, bacteria and other microscopic enemies that want to use our bodies for their own evil ends. As a result, every living thing has developed some type of immune system. Even bacteria themselves are attacked by viruses and have mechanisms to fight them off.

Mammals like us have a very sophisticated set of defenses against invaders. For starters, we have skin which serves to keep a lot of bad things out of our bodies. Like a moat around a castle or an electric fence around Area 51, this is our first line of defense. Unfortunately, we have to eat, breathe, and pee, so we’re forced to interact with the outside world, and any time we do, it presents an opportunity to become infected with something.

Our next line of defense is the innate immune system. Innate means “present from birth,” and all plants and animals have some type of innate immune system. If you’re a cop and you see a masked man burst out of a bank with a gun and a big white sack with a large dollar sign printed on it, well you know he’s a bad guy; he has many obvious features that make recognition easy. Similarly, many bacteria have on their outside a chemical structure called lipopolysaccharide that is never found in the human body; therefore its presence indicates a foreign invader. It is a mixture of fat and sugar, so you’d think it would be delicious, but when this material appears in the bloodstream, the immune system goes crazy. The body’s reaction is so strong that experimental animals can actually die from the intensity of their immune response if certain types of lipopolysaccharide are injected into the bloodstream. A completely different set of bacteria have another chemical on their outer coat called peptidoglycan, but again, the principle is the same. These bacteria have foreign structures on their outer walls which have been present through a billion years of evolution, and our bodies have learned to recognize them immediately as the signs of a foreign invasion and take drastic action.

We have a complete set of these so-called Pattern Recognition Receptors, or PRPs, molecules which recognize a wide variety of foreign invaders. Some are tuned to pick up the proteins in the microscopic tail of bacteria that swim around. Others pick up the DNA that is made by viruses. Some sit inside cells, while others circulate around the bloodstream. One example circulating is C-reactive protein, which we know is a measure of cardiovascular risk as well as a measure of general inflammation in the body. Many patients and clinicians think that C-reactive protein’s purpose is to rise during inflammation so that we can measure the inflammatory response in the body with a convenient blood test, but C-reactive protein actually has a day job. It binds to dead or dying human cells and certain bacteria to help remove these things from the body. The immune system can produce more of these Pattern Recognition Receptors to seek out foreign invaders when necessary, but these molecules are not highly specific. The goal from an evolutionary standpoint was to cast a broad net.

sniper stands with arms and looks forwardImmunologists call the various chemical structures we recognize as foreign by the name Pathogen Associated Molecular Patterns, or PAMPs. The result is that articles on immunology will talk about “PRPs such as CRP binding to PAMPs,” and this renders their contribution to biology rather inscrutable.

When the molecules we produce to recognize foreign invaders in a broad, nonspecific way are sitting on the surface of cells instead of floating around the bloodstream, we call them Toll-like receptors. You might think, as I did, that Toll-like receptors are named after Nestle Toll House cookies. However, Toll House cookies date to 1937 when the inventor, Ruth Wakefield, owner of the Toll House Inn in Whitman, Massachusetts, chopped up a chocolate bar to make the chips—chunks, really—for her cookies. Toll-like receptors, by contrast, are a billion years old and were named after a gene found in fruit flies. German scientists, upon discovering what messing with this gene did to the fruit fly, shouted, “Das ist ja toll!” which translates to, “That’s great!” German scientists, on eating a Toll House cookie have also been known to shout, “Das ist ja toll!”

The body has a set of cells whose job it is to eat things that are bad. We call them phagocytes, which, unfortunately, is one of those words that sounds like a bad word, but isn’t, like Uranus, Balzac, masticate, shiitake, penal, Bangkok, and Volvo. The correct pronunciation is “Phag’-Oh-Sights” and the process by which they digest bacteria and other foreign objects is phagocytosis (Phag”-Oh-Sigh’-tosis). Toll-like receptors sit on the outer membrane of these phagocytes to recognize foreign invaders.

A key feature of the innate immune system is that it is geared to recognize evolutionary conserved foreign structures. These are structures in bacteria and viruses which have not changed in millions of years, usually because they are essential to the function of the foreign organism. Here’s an analogy. All automobiles need wheels and brakes. It has been this way since the first Model A came off the assembly line in 1903. These are conserved. But paint color, body style, license plate frames, well, these things can be changed and not alter the essential function of a car. The innate immune system is recognizing the equivalent of the wheels and brakes of a car, but it is not set up to pick out a 1973 Buick Riviera, license YNG 085. Another way to think about the innate immune system is that it is like our Marines: first on the beachhead and able to deploy anywhere in the world very quickly.

You might wonder about “good bacteria” that live in our gut and on our skin and do helpful things for us. The innate immune system responds to all bacteria, good or bad, so these bacteria are distinguished by their behavior. If they stay within the intestines or on the skin, they are in a location where we have little of the innate immune system, but if they invade elsewhere into the body, the immune system is there to respond.

Around the time in evolution that animals developed a spine and a jaw, a new type of immune system also evolved. This is the adaptive immune system. Here, the strategy is to determine what bacteria and viruses are attacking us and then make tons of antibodies and cells directed at killing just those specific enemies.  The reason you generally only get illnesses like chicken pox or measles once is the response of the adaptive immune system. This is the branch of the immune system we exploit when patients are given vaccines. When the innate immune system responds to a threat, it often will call in the adaptive immune system in addition to fighting the bacteria or virus itself.

Adaptive immunity begins when we are in our mother’s womb. The body produces two different sets of cells with antibodies. One primarily keeps antibodies on its cell surface and the other is set up to manufacture antibodies to float around the body. What are these early antibodies directed against? Everything! There are billions of them and they are made to recognize virtually every three-dimensional molecular structure that an antibody could bind to. The two types of cells involved with these antibodies are B lymphocytes and T lymphocytes, sometimes also called B cells and T cells.

T cells are named because they grow and mature in the thymus. This is an organ which sits in the middle of the chest and is quite large in infants and children but shrinks up to nearly nothing by the time we are old. Because the antibodies on the surface of T cells are randomly generated, some are so bizarre that they could not participate in the immune response and are culled out of the population. Others, by chance misfortune, are actually directed against the tissues in our own body. Obviously, we don’t want to let those critters circulate around because then we would be attacking ourselves. Ninety-eight percent of T cells never make it out of the thymus. Unfortunately, the process is not perfect and certain diseases, such as hypothyroidism and type I diabetes, result from T cells directed against our own body escaping out into the general circulation.

Know Thy Enemy

The other family of cells which produce antibodies are the B cells or B lymphocytes. These are named for the structure in which they were first discovered in birds, called the Bursa of Fabricius. Some people think B cells are named that way because, in humans, the B cells are made in the Bone marrow. Sure, B cells are made there in humans and it is a nice way to remember that fact, but the original “B” is from the Bursa of Frabricius in birds.

Each T cell and B cell has antibodies directed against a different molecular structure. Given that we generate B and T cells to fight many millions of possible enemies, it follows that only a few cells are able to fight any particular bacteria or virus. Fortunately, when these few cells are presented with a piece of bacteria or virus bound to the specific antibody they happen to manufacture, they begin making copies of themselves and grow an army to fight that specific invader. In the case of B cells, they can recognize parts of bacteria or viruses directly and then divide rapidly to create offspring called plasma cells which pour antibodies into the circulation. T cells need foreign enemies presented to them by other cells, at which time they also divide and multiply. This is the heart of the adaptive immune response. Billions of different cells, with only a few capable of responding to any particular foreign invader, lie in wait. When part of a bad bacteria or virus binds to an antibody receptor on a cell’s surface, it causes that specific cell to divide and make millions of offspring that are all now able to fight the invader.

It follows that the innate immune system can respond more quickly to an infection but is unable to build defenses to prevent future infections, nor can it fight more forcefully against the particular infections we are encountering. The adaptive immune system, on the other hand, is slower to respond since there are initially very few B or T lymphocytes capable of attacking any given foreign invader, but after a few days or weeks, there can be many millions of cells, all specifically targeted against one bad guy. In 1939, when Hitler marched into Poland, the United States had an army of 175,000 men. In 1940, it had grown to 1.4 million, all specifically targeted to shoot Germans. This is an example of adaptive immunity.

If you want to treat

pre-cancerous lesions on your face,

you can also put Aldara there.

An example, using the virus which causes genital warts, can serve two purposes. First, it can illustrate the difference between the innate and adaptive immune systems, and second, it can gross out the reader, which I find entertaining. If you have genital warts, your body often does not generate a very vigorous immune response. However, you can try to treat these warts with a cream called imiquimod, also sold under the brand name Aldara. Imiquimod is an immune system stimulator. How does it “stimulate” the immune system? Well, this chemical looks like a bunch of viral RNA (RNA is quite similar to the DNA we have, but with one chemical substitution), and when you smear Aldara on the skin, the body thinks it has been infected by a virus and it activates the innate immune system which shows up and kills off cells infected with the wart virus. If you want to treat pre-cancerous lesions on your face, you can also put Aldara there. The nonspecific innate system will show up and start killing off pre-cancerous skin cells there.

Another approach to genital warts is to prevent them in the first place by getting a vaccine against the wart virus, sold under the brand name Gardasil. This vaccine looks like the outside shell of four very specific strains of warts, and it causes us to produce antibodies against just those strains by triggering a response from the adaptive immune system. Then, when the real virus is encountered, the body is primed and ready with tons of antibodies directed against wart viruses, and this infection can never establish itself in the skin.

The world is a dangerous place, and we are tempting, high-value targets to the billions of bacteria, viruses, fungi, and protozoans out there. Fortunately, our highly evolved immune system does a reasonably good job of keeping us safe. Supplemented with public sanitation, vaccines, and the occasional antibiotic, most of us will live out our full life spans without succumbing prematurely to an infectious disease. We have our immune system, in part, to thank for it.

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