The immune response in a human’s immune system is remarkably complex, very efficient, and profoundly fascinating. Let’s investigate.
There are many characteristics of the immune system that are absolutely critical, starting with the fact that your immune system is very, very specific in trying to recognize a stranger. You can call it stranger danger, you can call it other, or non-self; these are all terms we use in referring to what the immune system responds to, but it’s anything that is not the person or the unit.
Your immune system has a very long-term memory for a recurring event. This means that over time (which can be your lifetime) your immune system can stay poised and up-regulated so that when it sees the same attacker again, the response will be much, much faster the second time or the third time around. The immune system also has a characteristic that is called being inducible. This means that we can get the immune system to wake up and get moving with inoculation on purpose. We can do this by vaccination—giving it something to respond to—or it can have natural exposure. Either of these things will induce the immune system to go to work.
The immune system is going to respond to any foreign invader that has not been previously recognized through the time that the organism went through embryogenesis. This means from conception until birth, anything seen by your immune system will think it is part of yourself. You introduce any foreign tissue, any infecting organism into an embryo, and that embryo’s immune system is going to be tolerant. This is called immune tolerance; it only happens one time in our lives. After the birth everything else is seen as foreign or stranger.
The immune system is going to respond to any foreign invader that has not been previously recognized through the time that the organism went through embryogenesis.
Your immune system kicks in after the external barriers such as skin are breached and after the inflammatory response has been activated and starts to subside; that’s when it’s building up. It’s working all the time. It’s sitting there, it’s on the lookout, and even when you have your eyes closed and your head’s lolling and a little drool coming out of the corner of your mouth, your immune system is wide awake. It’s there. It’s alert. It’s there while you’re sleeping. It’s there when you’re in a coma. It never stops looking for “stranger danger.”
There are several responses to this “stranger danger,” including the humoral response and the cell-mediated response. The name “humoral response” comes from an old-fashioned medical concept of the evil humors that cause disease. Humoral, in this case, simply means “circulating in the blood.”
The immune system basically has two kinds of cells, the T lymphocyte and the B lymphocyte. When you look at a lymphocyte under a microscope, you have no idea whether it is a B or a T lymphocyte. We have to distinguish them by using laboratory immunological techniques. The B lymphocytes mature in the bone marrow; that’s why they’re called B lymphocytes. The T lymphocytes come out of the bone and mature in the thymus, which is a gland that sits just under the collarbone, behind the sternum, and actually is quite big at birth and shrivels up and atrophies. This is physiologic atrophy; it’s quite normal as life goes on.
Most foreign invaders carry surface substances called antigens—complex molecules that are recognized by the body as strangers, as non-self.
Most foreign invaders carry surface substances called antigens—complex molecules that are recognized by the body as strangers, as non-self. Antigens can include micro-organisms, pollens, foods, venoms from various stinging creatures, transplanted tissue from anybody but your identical twin, drugs, and vaccines, which are introduced on purpose. Antigens are recognized by the immune system and evoke a response that, in the humoral system, is called the antibody response. An antibody is defined as something that’s responding to an antigen, and an antigen is defined as something that calls for an antibody—a rather circular definition.
In response to an antigen, an antibody will be produced that is specifically structured to fit that particular antigen. Antibodies tend to react with antigens in different ways. The complex that is bound together—the antigen–antibody complex—might have the effect of neutralizing the toxin, precipitating it so it falls out of solution, and getting rid of it. Or, a virus might carry surface antigens. These are usually proteins on the coat of the virus that stimulate a different antibody. Here, antibodies might get on to the surface of the virus and prevent it from entering a cell (which a virus has to do to multiply.) They call this agglutination, or clumping together. The molecules may number hundreds of thousands.
Antigens can be anything that’s not self. They tend to be literally very geometric, which is critical. If you change the geometry of the antigen at all, you need a whole new antibody. It’s the lock and key analogy to make it fit.
So, the first response is humoral. Once these cells are called out into the system they enter the circulation, and when a challenge is seen, when a foreign body is recognized, the determinants on the outside of these cells will recognize the presence of this challenge. It will be helped by what’s called a helper T cell and activated by a series of chemicals.
B Lymphocytes Morph into Plasma Cells
The B cells, the B lymphocytes, morph into plasma cells. Plasma cells are cells that produce and secrete the antibodies of just the right shape and geometry to attack the invader. They enter the system, they circulate, and they find and destroy the invader completely.
Plasma cells are generally short-lived cells except for a very few of them, perhaps 1 percent or 2 percent of them, which will become memory cells—very important cells. Those cells are going to go dormant and hide out somewhere in the lymphatic system, maybe in the spleen, in the bone marrow, or in the lymphatics. If ever the invader is seen again, it’s going to be released immediately because of the memory. If at some point later—a few weeks or a lifetime later in some cases—you get a second exposure, your memory cells are already there. They don’t have to go through the process of getting activated, and you get an immediate response called the anamnestic response. This is an accelerated response, which in many cases will wipe out the invader before you even develop a symptom. That’s the humoral-mediated response, the antibody response.
In the humoral-mediated response, the actual molecules are called immunoglobulins. They are globulins because they are big, complex protein molecules in the immune system. They are complex glycoprotein, sugar and protein, and they’re produced by the plasma cell.
Five Types of Immunoglobulins
IgG—Represents 80% of antibodies, and can cross the placental barrier
IgA—Synthesized in the surface of the lining of your intestine
IgD—A surface antibody on the B lymphocytes
IgE—The responder for allergies and parasites
IgM—The first antibody synthesized by babies
They’re all designated with an Ig name, and the first one that’s very important is called IgG. It represents most of the circulating antibodies in the body, roughly 80 percent. It is a neutralizing antibody for bacterial toxins and viruses, and it’s important because it crosses the placental membrane. So, the mother can give these to the fetus for protection for about six months of the fetus’s life, and that way the fetus’s immune system has time to catch up and do some building up of its own antibodies.
Then there’s IgA, which is synthesized in the surface of the lining of your intestine, what they call GALT—gut associated lymphoid tissue. It is secreted so it’s really part of that physical barrier. It’s molecular, but it’s on the surface. It’s trying to act before things get in.
There is a monomer called IgD, which is a surface antibody on the B lymphocytes. Together with another one called IgM, they interact and they can cause suppression. It may be an immunoregulatory molecule—very little is known about this molecule.
The IgE is interesting; it has the smallest number of molecules, but it is the responder for allergies and parasites. It tends to be in very low numbers unless you’re allergic to a substance or you have another invasion that it responds to.
Finally, we have IgM, which is the first antibody synthesized by babies, the first one to appear in the blood stream. It’s very critical that IgM occurs so early because it’s confined to the blood stream for infection against blood-borne bacteria or pathogens, which are very, very threatening to babies; babies do better with viruses. For example, babies who get polio are never as sick or usually not as sick as adults who get polio. But, with bacteria, babies get very sick and IgM antibodies are critical for their defense. IgM causes agglutination—things stick together so they can be eaten up by phagocytes and taken away.
What Do Antibodies Do?
Antibodies generally cause neutralization of toxins, for example. They also neutralize and kill the viruses. They promote phagocytosis. They help the phagocytes get to it and they up-regulate the entire inflammatory response. Then, some of the organisms are actually prevented from even attaching or entering cells. Like viruses, they may not be killed but they can’t get into a cell, so they can’t replicate. They have indirect actions, which includes the binding to the antigen by one end of a molecule, while the other informs the host that the molecule is there. It’s rather dramatic; it’s like when your mother taught you to present somebody to someone else whom they don’t know. This is called the presenting function. The phagocyte eats up the antigen and breaks it into pieces and literally holds up the antigenic factors to a T cell. The T cell attaches, locks in on one of the antigens, which in turn stimulates the giant phagocyte to produce Interleukin-1, which locks onto another receptor in this very complicated molecular dance and then triggers the killing potential of the T cells. So, the presenting system says, “How do you do? I’m a phagocyte and here’s a germ.” It up-regulates the whole system, and all the T cells go to work.
We also have uses for the antibodies. We can make artificial antibodies; they’re called monoclonal antibodies because they’re derived from one cell in the laboratory and they can give you very specific information by using them to find only the specific substance that has that antigen. They’ll only attach exactly on the right antigen that you want them to. So, we could find, for example, evidence of disease in a person who may have been infected before the symptoms or other tests show them. Monoclonal antibodies can be used in early diagnosis of unknown diseases. We can also load up monoclonal antibodies with a chemical or radiation and we can make it go to a cell we want to kill, if we know the antigenic specificity of that cell—this is very, very useful.
So all of this is the humoral immune response. It’s probably the one you’re most familiar with. Most of us know about our antibodies and the various vaccinations we’ve had.
What we don’t talk so much about in the real world is the cell-mediated response, which is through the lymphocytes. They have designators like CD8 and CD4 which refer to surface antigens on them and surface antigen receptors. The T lymphocytes come out through the thymus, where they mature, and they are programmed internally to recognize a specific cell-bound antigen. They have to have, in most cases, previous recognition. They are not activated by the circulating antigens the way the B cells are, but require antigen presentation by the phagocyte that made that presentation to the T cells. There are cytotoxic T cells that get activated with the help, again, of the CD4 cells. There are T helper cells, which by the way are the ones that are compromised by the HIV virus. These cytotoxic cells are very effective in killing foreign invaders, usually of a cellular kind. They attach to a cell they have recognized because the cell was infected by a virus. The virus has altered the surface receptors and attracted the activated T cell, which then after this connection releases something called a perforin, because it perforates, and this can enter the virus-infected cell, destroy it, and prevent the virus from using the mechanism in the nucleus to replicate itself. This is different from preventing the virus from attaching to the cell.
We have other cells called natural killer cells. They don’t have any surface antigen receptors. They don’t know what’s going on out there. They require no prior recognition at all. These are cells that don’t bind with antibodies. They are innately programmed to recognize, for example, virus-infected cells, tumor cells, and occasionally, unfortunately, even some of the host cells. They’re another first line defense. They’ll kick in before the rest of the cell-mediated response kicks in. They recognize non-antigen, chemical changes in the virus-infected cell. So, it’s not an antigen-mediated response. The virus gets in there and changes a lot of things in the cell. Some of these we know a lot about; some of these we know nothing about. But the killer T cell will do something very similar to this.
A killer T cell recognizes something that’s not antigen mediated, and physically gets on there and touches the surface of the other cell. It’s called the “kiss of death.” They release perforins, which penetrate and make holes in the cell, and then they release lysins—that group of chemicals that just dissolves the cellular structure. If it does it in a tumor cell, that would be terrific; it would kill the tumor cell. If it does it in a cell that is infected by something else but that needs the cellular product—such as a parasite or lower forms of organisms—again, it’ll prevent further replication. So, these killer T cells are very, very important. They also have the possibility of looking at some of our own cells that became abnormal, our body cells—non-antigenically abnormal, but functionally abnormal, and they can kill those cells as well.
So, we have both the cell-mediated and the humoral-mediated response working hand-in-hand and attacking invaders with the linkage of the helper T cell to up-regulate both sides of this response. Unquestionably, it’s one of the most important surveillance factors that protect us from unseen invasion. However, this system is capable of over-responding and causing far more damage than it actually prevents, which is something we must always keep in mind.
From the lecture series The Human Body: How We Fail, How We Heal
Taught by: Professor Anthony A. Goodman, M.D., Montana State University