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PUBH 3100 Human Disease and Prevention

Week 2 – The Human Body – How It Works: The Immune System

(ON-SCREEN GRAPHIC ---Films for the Humanities & Sciences)

(ON-SCREEN GRAPHIC ---The Human Body – How It Works: The Immune System)

NARRATOR: The immune system is extremely important to your health and well-being. It protects you against disease-causing antigens like bacteria, viruses, and toxins. An antigen is anything your immune system recognizes as foreign, and reacts against. Your immune system protects you in a variety of ways. Let's begin by taking a look at your innate immunity and defenses.

(ON-SCREEN GRAPHIC ---Innate Immunity & Defenses)

Innate immunity is something you are born with. There are two kinds, nonspecific reactive responses, and passive barrier defenses. First, let's consider the passive barrier defenses. People don't often think of the skin as part of the immune system, but the skin is your first line of defense. When unbroken by cuts or sores, it's generally impermeable to bacteria and viruses. We all know there are entrances to the body through the eyes, nose, mouth, ears, and urogenital tracts.

A second passive defensive barrier in most of these areas are the mucous membranes. Mucous is a thick, sticky liquid produced by the mucous membranes that acts like fly paper to trap microscopic particles of dust and soot, as well as unwelcome microorganisms. Your eyes have their own defenses. Tears contain an enzyme that kills microorganisms by breaking down their cell walls. In the mouth, saliva plays a similar role.

But sometimes, an invading antigen makes it through these passive barriers. For example, when your skin is cut or punctured, then what happens? Your nonspecific reactive defenses come into play. They attack anything recognized as foreign, and try to remove it. Damaged cells release chemicals known as inflammatory mediators, which stimulate the body's inflammatory response. Capillaries dilate and become leaky, so fluid seeps into the tissues around the wounded site. With the fluid come white blood cells, and protein molecules called antibodies. Antibodies attach themselves to foreign materials, and serve as markers for the macrophage, a type of white blood cell. The macrophage binds to the antibody, then surrounds and engulfs the invader in a process

called phagocytosis. It then releases powerful chemicals that kill the foreign cell, and make it fall apart.

One of the most interesting and complex of the nonspecific reactive defenses is the complement system. In a classical complement pathway, an antibody molecule binds to the surface of a foreign cell, such as a bacterium. Then one of up to 60 different complement proteins binds to the antibody molecule. Once attached, the compliment molecule breaks apart. Some fragments are released into the bloodstream, and serve to draw additional complement proteins to the infection site. One piece remains attached to the antibody, where it too attracts other complement proteins. This cascade process continues as more and more compliment molecules are drawn to the site. Eventually, the compliment molecules form a ring on the cell's surface. In the center, they produce a hole in the cell membrane, or wall. Fluids rush into the hole causing the cell to lyse, or explode. In an alternate complement pathway, complement proteins bind directly to a foreign cell without the antibody as the intermediary, but the result is the same.

The different types of white cells and what they do is possibly the most complex aspect of the immune system. All white cells begin in the bone marrow as stem cells. Stem cells are capable of evolving into many types of cells, including white blood cells called leukocytes. As leukocytes mature, they evolve into two general classes of white blood cells, the phagocytic family, and the lymphoid family. Cells in the phagocytic family evolve into mononuclear leukocytes, and polymorphonuclear leukocytes. Mononuclear leukocytes become monocytes, which transform themselves at the site of an infection into the macrophage, or "cell eater" that we saw earlier. Polymorphonuclear leukocytes are more complex. They develop into three different types of white cells-- basophils, neutrophils, and eosiniphils. All contain little granules of powerful chemicals that are released when they encounter an intruder. These cells cause the redness and swelling seen at the site of an infection. Lymphoid cells become lymphocytes, which play a number of different roles in the immune response, including the production of antibodies.

(ON-SCREEN GRAPHIC ---Timothy Shaw, PhD – Professor of Human Anatomy Bethel University)

TIMOTHY SHAW, PhD: There are two types of lymphocytes, B-lymphocytes and T lymphocytes. These two cell types work independently, but they also work together to provide protection to the body against foreign agents that may be introduced into the body, such as bacteria, viruses, fungi, toxins, and certain chemicals.

NARRATOR: B-lymphocytes remain and mature in the bone marrow, while T cells get their name from the fact that they leave the bone marrow to mature in the thymus gland. In addition to your white blood cells, there are several major organs that are a part of your immune response. The first is your lymphatic system. This system of vessels and lymph nodes is similar to your circulatory system. But rather than blood, a fluid

called lymph flows through it. The lymphatic system bathes cells in lymph and flushes out bacteria that are then carried to the lymph nodes to be destroyed. Lymph nodes are scattered throughout the body, but especially through the neck and trunk. The nodes attract and retain phagocytic and other white cells, and are often the sites where infecting bacteria are attacked and destroyed.

Another important mass of lymphoid tissue is the appendix. While we still don't completely understand its function, it's probably involved in protecting the lower digestive tract and body cavity from infectious agents that enter the body through food and water. One additional group of lymphoid tissues are the Peyer's patches found in the intestines, which may serve a role similar to the appendix. Closely related to Peyer's patches are the skin-associated lymphoid tissue, or SALT, and the mucosal-associated lymphoid tissue, or MALT, found in patches near the mucous membranes.

There are several organs that are critical to the proper functioning of your immune system. First, is the bone marrow. Marrow of the vertebrae, ribs, sternum, pelvis, and the long bones of the arms and legs, are the most important sites of blood cell production, and the location for the specialization of B cells. The thymus gland is a small lymphoid organ, located just in front of the heart. The thymus gland is critical in the development of T lymphocytes, or T cells. The spleen is a fist-sized organ located on the left posterior side of the abdomen, just above the kidney. It's an intricate meshwork of tiny blood vessels and white blood cells that filters your blood to remove foreign organisms. Now let's take a look at what happens to bacteria and other invaders if they make it past your nonspecific defenses.

(ON-SCREEN GRAPHIC ---The Humoral Immune Response)

In contrast to the passive defenses that are designed to attack anything foreign that enters the body, the humoral immune response is tailored to destroy one specific entity. The two key components of this response are your B cells and the protein molecules they generate, called antibodies, or immunoglobulins. The body has five basic types. Immunoglobulin G, IgG for short, is the most common type in the blood, and is shaped like the letter Y. Immunoglobulin M is the kind our bodies make when we are first exposed to a new foreign agent. Immunoglobulin A is the most common type of antibody. It is usually found in areas with lots of membranes, such as the nose, throat, and digestive system, but can also be found in the blood. Immunoglobulin E, the least common antibody, plays an important role in allergies. The last antibody is immunoglobulin D. IgD is found on the surface of B and T cells, and serves as the antigen receptor site that triggers B cell activation, and humoral immune response. Immunoglobulins are made up of proteins. This immunoglobulin G molecule has two large proteins, and two small ones. Each arm of the Y is an antigen-binding site. On the base are binding sites for phagocytes and complement.

OK, now let's see how immunoglobulins work in the humoral immune response. Let's assume a bacterium that your body hasn't seen before makes it past your nonspecific barrier defenses and into the deeper tissues or bloodstream. Macrophages recognize the bacterial cell as foreign, bind to it, engulf it, and break it down into little pieces. The macrophage then displays pieces of the bacterium on special sites on its surface called antigen-presenting sites. The macrophage also sends out special chemical messengers called interleukins to attract helper T cells to the site. Once they arrive, the helper T cells bind tightly to the antigen-presenting site on the macrophage, and begin sending out their own interleukin messages to attract B cells. B cells, with the appropriate antibodies on their surface, recognize and bind to the macrophage T cell complex.

Once the B cell is in place, the helper T cell releases another chemical message, activating the B cell to reproduce itself. Through this replication process, many new B cells are created and programmed to make antibodies that will bind to the presented antigen. This is called B cell amplification. These antibodies then seek out and bind directly to the invading bacteria cells, and destroy them. Some B cells created in the amplification process become memory cells. They can be activated to function just like the original B cells if the body becomes exposed to the same bacterium in the future. The memory B cells will allow the body to respond much more quickly, to eliminate the threat before it can cause enough damage to result in disease symptoms.

(ON-SCREEN GRAPHIC ---Cell-Mediated Immunity)

The last component of your specific immune response is a process called cell-mediated immunity. It involves your T cells, and what's called the major histocompatibility complex, or MHC. How do your white cells distinguish harmful foreign cells from your body's own healthy ones? Each of your cells has identifying protein molecules on its surface that show it is a part of you. These molecules are called the major histocompatibility complex. The MHC serves much the same function as uniforms do for a football team. Each player has a color-coded jersey that allows other team members to recognize him as part of their team. There are two types of MHC, MHC-1 and MHC-2. MHC-1 molecules are present on the surface of all mammalian cells. If a cell becomes infected with a virus or bacterium, it will present some of the antigens of that organism on its surface at the MHC-1 site. MHC-2 is only found on the surface of phagocytic cells, those involved in the removal of foreign materials.

Your T cells are the key component of cell-mediated immunity. They arise in the bone marrow and differentiate into three types: Helper T cells, which we've already seen in the humoral immune response, cytotoxic, or killer T cells, and suppressor T cells. Helper T cells regulate the nature and extent of all your immune responses. For example, when a harmful antigen is present, you saw how they send out chemical messages to attract

and stimulate the production of B cells. And when an infection is under control, they stop the immune response. They also attract and stimulate killer T cells.

If something interferes with your helper T cells, your immune system is seriously compromised. In fact, that's what happens to people who are infected with HIV, the human immunodeficiency virus, the virus that causes AIDS. When a person is infected with HIV, the virus can immediately begin reproducing inside helper T cells, destroying them. When the level of helper T cells is sufficiently low, the body is unable to mount an effective defense against invading antigens. As a result, the HIV or AIDS patient is susceptible to many different infectious diseases and cancers.

TIMOTHY SHAW, PhD: HIV infects T cells by binding to receptors on the T cell's surface, and entering the cell. The virus then, once it's inside the cell, actually integrates into the DNA of the T cell, and becomes part of the human chromosome. At this point, it becomes very difficult for the immune system to recognize it, and to destroy it.

NARRATOR: The second type of T cell is the cytotoxic, or killer T cell. These cells, like their B cell counterparts, bind to the MHC-1 on the surface of our own cells, when those cells are presenting a foreign antigen. Once found, the killer T cell can destroy those infected cells by releasing perforins, a kind of protein that punch holes in the cell wall. This allows fluid to rush in causing the cell to swell and burst. This process is called the cell-mediated immune response. A third type of T cell, the suppressor T cell, is involved in mitigating excessive responses by our immune system, for example, in allergic reactions to things like pollen.

(ON-SCREEN GRAPHIC ---The Importance of Vaccines)

There are four different ways you can acquire immunity to a particular disease-- passive artificial immunity, passive natural immunity, active natural immunity, and active artificial immunity. In passive artificial immunity, you receive a serum made from the blood of persons that have already had the target disease, and have developed antibodies against it. The immunity produced will last as long as the serum antibodies. Babies receive passive natural immunity from their mothers while they are still in the womb.

The mother's antibodies pass through the placenta into the baby's blood. Active natural immunity occurs the first time you are exposed to an infectious organism. You'll probably get sick, but your body will provide protection against future illness caused by this same organism. Through vaccination it's possible to get the protection of an activated humoral immune response without suffering from the disease. This is called active artificial immunity.

TIMOTHY SHAW, PhD: In many of these vaccinations, either a dead form of the organism, or a form of the organism that cannot cause disease, is injected into a person, and they develop an immune response to the organism that results in immunity. So, once they have immunity to this particular organism, if they're ever exposed to it in the future, the immune system can respond quickly so the disease never develops in the body.

NARRATOR: Some viruses keep mutating and changing their structure, making it difficult to develop effective vaccines against them.

TIMOTHY SHAW, PhD: When we are infected with a virus, it has the capability to change its composition. HIV is a virus that in particular does this quite rapidly, and quite consistently. And that has been a major limiting factor in the development of an effective vaccine for the treatment of AIDS.

(ON-SCREEN GRAPHIC ---Allergies & Autoimmune Diseases)

NARRATOR: Sometimes B cells produce too many antibodies that are directed toward healthy cells of our own bodies. This is what happens in autoimmune diseases such as allergies, juvenile diabetes, and rheumatoid arthritis. For example, in people with allergies, the first time pollen enters the body; it stimulates B cells to make immunoglobulin E antibodies specific to it. These antibodies attach themselves to mast cells, a special type of white cell that contains granules of histamine. In subsequent exposures to the same pollen, the immunoglobulin G antibodies bind the pollen and stimulate the mast cells to release their histamine, resulting in an inflammatory reaction; the result, your nose drips, you cough and sneeze, and your eyes water. Some allergies to certain foods or toxins, such as bee venom, are life threatening. In an anaphylactic reaction, your throat can swell shut, cutting off their oxygen supply. Luckily, there are medications that relieve allergy symptoms by blocking the inflammatory response and treatments to desensitize the immune response.

Kyle Reno is a healthy active teen, with one exception. He has juvenile diabetes, also called Type-1 diabetes. People like Kyle have a genetic defect that causes their immune system to attack and kill the cells in the pancreas that produce insulin.

TIMOTHY SHAW, PhD: In type one diabetes, the B-lymphocytes produce an antibody that attacks the cells in the pancreas responsible for insulin production. As a consequence, individuals with this disease have a reduced amount of insulin produced. This causes the blood sugar, or glucose, to increase to very high levels, which can be very damaging to various tissues of the body.

NARRATOR: Rheumatoid arthritis is another disease caused by an overactive immune response. In this disease, antibodies and macrophages mistakenly attack the healthy cells in your joints and connective tissue, causing inflammation, swelling, and pain. Autoimmune responses are also involved in negative reactions to blood transfusions, and in the rejection of organ transplants. If blood and organs are not carefully matched to the person receiving them, the results can be deadly.

Our understanding of immunology has changed dramatically over the last thirty years. What was once poorly understood has become one of the fastest growing, and most significant areas of science. Some scientists are working on new vaccines to immunize people against HIV and other deadly diseases. Others are working on developing antibodies to target certain disease entities. One of the most promising lines of research is with stem cells, like those in the bone marrow.

TIMOTHY SHAW, PhD: Most tissues contain stem cells. Stem cells are unique in that they can develop in many different directions. For example, a given bone marrow stem cell could develop into a red blood cell, or it could develop into a T cell, or a B cell, or a monocyte, or a macrophage. Because stem cells can develop into many different cell types, there's a lot of promise in using them for treating various deficiencies of cell types.

NARRATOR: With all that we have learned, there is still much more to be discovered. Perhaps you will be one of the scientists to find the answers to the remaining mysteries of our body's most fascinating system, the human immune system.

(ON-SCREEN GRAPHIC ---

Based on the Book Series The Human Body – How It Works

The Immune System Chelsea House Publishers

Executive Producer – Craig Claudin Producer/Director – Christine Dean

Script Development – Christine Dean Script Consultant – Timothy Shaw, PhD – Professor of Human Anatomy Bethel University

Narrator – Erin Mathe Videographers – Tim Lewis and Matt Bjur

Editor – Matt Bjur Animator – Chris Parrish-Taylor

Graphics – Matt Bjur Illustrations – Britta Bjur

Thanks to the staff and students of Thomas Jefferson High School Bloomington, MN for

their assistance in producing this program series.

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