The Immune Response

By Anthony A. Goodman, M.D., Montana State University

The immune response in a human’s immune system is remarkably complex, efficient, and profoundly fascinating. Investigate how this system works to protect you.

There are many critical characteristics of the immune system, starting with the fact that your immune system is specific in trying to recognize a stranger. Call it stranger danger, other, or non-self, but these are all terms used in referring to what the immune system responds to. It’s anything that is not the person or the unit.

The immune system has a very long-term memory for a recurring event. This means that over time—during your lifetime—your immune system stays poised and up-regulated so that when it sees the same attacker again, the response will be much faster the second time or the third time around. The immune system also has a characteristic called being inducible. This means that we can get the immune system to wake up and activate it with inoculation on purpose. Primarily this is done by vaccination—giving it something to respond to—or it can have natural exposure. Either of these will induce the immune system to go upon work.

Immune Tolerance

The immune system will 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 will be tolerant of it. This is called immune tolerance; it only happens one time in our lives. After birth, everything else is seen as foreign or stranger.

Your immune system kicks in after the external barriers, such as skin, are breached and after the inflammatory response has been activated and begins to subside; that’s when it’s building up. It’s working all the time. It’s sitting there, on the lookout. It’s alert. While you’re sleeping, your immune system is wide awake. It’s even there when you’re in a coma. It never stops looking for “stranger danger.”

This is a transcript from the video series The Human Body: How We Fail, How We Heal. Watch it now, on The Great Courses.

There are several responses to this “stranger danger,” including the humoral response and the cell-mediated response. The name “humoral response” comes from the antiquated medical concept of the evil humors that cause disease. Humoral, in this case, simply means “circulating in the blood.”

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Humoral Response

The immune system has two kinds of cells: the T lymphocyte and the B lymphocyte. Looking at a lymphocyte under a microscope, it’s impossible to tell if 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, which is how they derive their name. 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. It starts large at birth and shrivels up and atrophies over time. 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. 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 the self. They tend to be very geometric, literally, which is critical. If the geometry of the antigen is changed at all, the immune system needs to produce a whole new antibody. It’s the analogy of the lock and key to make it fit.

Thus, the first response is humoral. Once these cells are called out into the system they enter the circulation, and 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 is activated by a series of chemicals.

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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. Perhaps 1 to 2 percent of them will become memory cells. Those cells become dormant and hide out somewhere in the lymphatic system, maybe in the spleen, or in the bone marrow. If ever the invader is seen again, these memory cells will be released immediately because of the memory. If at some point later—a few weeks or a lifetime later in some cases—you experience a second exposure, your memory cells are already there. They don’t have to go through the process of activation, and there is 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 or the antibody response.

Immunoglobulins

In the humoral-mediated response, the actual molecules are called immunoglobulins. They are globulins because they are large, complex protein molecules in the immune system. They are complex glycoprotein, sugar, and protein, and they’re produced by the plasma cell.

They’re all designated with an Ig name. The first, most important of these is IgG. It represents most of the circulating antibodies in the body at roughly 80 percent. It is a neutralizing antibody for bacterial toxins and viruses. It’s also important because it crosses the placental membrane to allow the mother to give these immunities to the fetus for protection for about six months of the fetus’s life, giving the fetus’s immune system time to catch up and build up some of its own antibodies.

Next is IgA, which is synthesized on the surface of the lining of your intestine, what they call GALT—gut-associated lymphoid tissue. It is secreted and part of that physical barrier. It’s molecular but works on the surface to act before things get in.

IgD is a monomer, 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.

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, there is IgM, which is the first antibody synthesized by babies, and the first one to appear in the bloodstream. It’s very critical that IgM occurs early because it’s confined to the bloodstream 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 by phagocytes and taken away.

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What Do Antibodies Do?

Antibodies generally cause neutralization of toxins, for example. They also neutralize and kill viruses, and promote phagocytosis. They help the phagocytes get to work and they up-regulate the entire inflammatory response. Then, some of the organisms are prevented from even attaching or entering cells. Like viruses, they may not be killed but they can’t enter a cell, meaning they can’t replicate. They have indirect actions, which include binding to the antigen by one end of a molecule, while the other informs the host that the molecule is there. This is called the presenting function.

The phagocyte eats up the antigen and breaks it into pieces and 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 a complicated molecular dance before triggering the killing potential of the T cells. Imagine that 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.

There are also additional uses for the antibodies. We can make artificial antibodies called monoclonal antibodies because they’re derived from one cell in the laboratory and provide very specific information. We use them to find only the specific substance that has that antigen. They’ll only attach to the right antigen that you want them to. 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. By loading up monoclonal antibodies with a chemical or radiation, 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.

All of these attributes are part of the humoral immune response. It’s probably the one you’re most familiar with, via our antibodies and the various vaccinations we’ve had.

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Cell-Mediated Response

What isn’t discussed much in the real world is the cell-mediated response, which comes 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 B cells are, but require antigen presentation by the phagocyte that made the 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 HIV. 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. After this connection, it 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.

Other cells work in this system 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 antibodies with them. 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 invades a cell and changes a lot of things. Some of the viruses we know a lot of information about, while some we know very little. The killer T cell, however, will do something very similar to this.

A killer T cell recognizes a situation that’s not antigen mediated and physically acts by touching the surface of the other cell. This is 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 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. Because of these mechanisms, killer T cells are very, very important. There is also the possibility of killer T cells looking at some of our own cells that became abnormal—non-antigenically abnormal, but functionally abnormal—and they can kill those cells as well.

Our bodies 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.

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Common Questions about the Immune Response

This article was updated on May 7, 2020

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