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The term immunity refers to all of the mechanisms used in the body to protect against foreign agents. The origin of this term is from the Latin immunitas (meaning “freedom from”) (4). Immunity results from a well-coordinated immune system that consists of complex cellular and chemical components that provide overlapping protection against infectious agents. This overlapping of immune system components is designed to ensure that these redundant systems are efficient in protecting the body against infection from pathogens (disease-causing agents) such as bacteria, viruses, and fungi. The redundancy of the immune system is achieved by the teamwork of two arms of the immune system referred to as the innate and acquired immune system (also called the adaptive or specific immune system). A short introduction to these two immune systems follows.
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Humans and other animals are born with an innate, non-specific immune system that is made up of a diverse collection of both cellular and protein elements. This system provides both physical barriers and internal defenses against foreign invaders (Fig. 6.1). Physical barriers are the first line of innate defense and are composed of barriers such as the skin and the mucus membranes (i.e., mucosa) that line our respiratory, digestive (gut), and genitourinary tracts. So, in order to cause trouble, bacteria and other foreign agents must cross these barriers. An invader that crosses the physical barrier of skin or mucosa is greeted by a second line of innate defense. This internal defense is composed of both specialized cells (e.g., phagocytes and natural killer cells) designed to destroy the invader, and a group of proteins called the complement system, which is located in the blood and tissues. The complement system is composed of more than 20 different proteins that work together to destroy foreign invaders; this system also signals other components of the immune system that the body has been attacked. Let’s discuss each of these components of innate immunity in more detail.
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Again, the first line of defense against invaders is the physical barrier of the skin and the mucosa. Although we tend to think about the skin as being the primary barrier against foreign agents, the area covered by the skin is only about 2 square meters (29). In contrast, the area covered by the mucosa (i.e., respiratory, digestive, and genitourinary tracts) measures about 400 square meters (an area about the size of two tennis courts) (29). The key point here is that there is a larger perimeter that must be defended to keep unwanted foreign agents from entering the body.
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Numerous types of immune cells exist to protect the body against infection, but a complete discussion of all these cells is beyond the scope of this chapter. Therefore, we will focus the discussion on a few types of cells that play a major role in the immune system. Specifically, we will direct our attention toward select members of the leukocyte family of immune cells that work together with another key immune cell, macrophages, to protect the body against infection. Leukocytes (also called white blood cells) are an important class of immune cells designed to recognize and remove foreign invaders (e.g., bacteria) in the body. Similarly, macrophages are another type of immune cell that is capable of engulfing bacteria and protecting against infection. Let’s begin with a discussion of how the body produces these key cellular players in immune function.
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Where do leukocytes come from? All blood cells (red and white) are made in the bone marrow, where they are produced from common “self-renewing” stem cells. These cells are self-renewing because when stem cells divide into two daughter cells, one of the daughter cells remains a stem cell (unspecialized cell), whereas the second daughter cell becomes a mature blood cell. This strategy of renewal ensures that there will always be stem cells available to produce mature blood cells.
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When stem cells divide, the maturing daughter cell must make a choice as to what type of blood cell it will become when it matures. These choices are not random but are highly regulated by complicated control systems. Figure 6.2 illustrates the process of stem cells forming a bipotential stem cell that then can form a variety of different leukocytes. Table 6.1 provides a brief description of the function of each of these leukocytes. Also, notice that macrophages are derived from a specific type of leukocyte called a monocyte (Fig. 6.2). In the next segments, we discuss the role that both leukocytes and monocytes play in innate immunity by protecting against both bacterial and viral infections.
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Immune cells that consume (i.e., engulf) bacteria are classified as phagocytes. Specifically, phagocytes are cells that engulf foreign agents in a process called phagocytosis. To remove unwanted bacteria, the body produces several different types of phagocytes that participate in the innate immune system. Two key phagocytes are macrophages and neutrophils. Together, these important phagocytes form an important line of defense against infection.
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As illustrated in Figure 6.2, macrophages are derived from monocytes. Macrophages are located in tissues throughout the body and are often called “professional” phagocytes because they make their living by destroying bacteria (29). When bacteria enter the body, macrophages recognize these invading cells and attach to the bacteria. This results in the bacteria being engulfed into a pouch (vesicle) that is moved inside the macrophage. When the bacterium is engulfed by the macrophage, the bacterium is killed by powerful chemicals and enzymes contained within the macrophage (4).
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Macrophages can also contribute to innate immunity in two other important ways. First, when macrophages are destroying bacteria, they give off chemicals to increase the amount of blood flow to the infected site. This increased blood flow brings additional leukocytes to the area to assist in the battle of removing the invading bacteria.
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Further, during the battle with bacteria, macrophages also produce proteins called cytokines. Cytokines are cell signals that regulate the immune system by facilitating communication between cells within the immune system (4). For example, some cytokines alert immune cells that the battle is on and cause these cells to exit the blood to help fight the rapidly multiplying bacteria (29). In this case, cytokines serve as a chemoattractant. Chemoattractants are chemicals that recruit other immune system “soldiers” to the battle site to assist in protecting the body from infection. Other cytokines promote fever, stimulate production of other components of the immune response, and promote inflammation (8).
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Macrophages are not the only phagocytes involved in innate immunity. Indeed, neutrophils may be the most important phagocyte in innate immunity (29). Neutrophils are leukocytes that also participate as phagocytes during a bacterial invasion. Neutrophils have been called professional killers that are “on call” in the blood (29). After neutrophils have been summoned to the infected area, these important phagocytes exit the blood and become activated to begin destroying the foreign invaders. Similar to macrophages, neutrophils also produce cytokines that can alert other immune cells. Further, activated neutrophils also release chemicals that promote increased blood flow to the infected area.
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In addition to the professional phagocytes (i.e., macrophages and neutrophils), another key cellular component of the innate immune system is the natural killer cell. These cells are produced in the bone marrow from stem cells (Fig. 6.2) and are “on call” to fight an infection. Most natural killer cells are found in the blood, liver, or spleen and when called to fight an infection, these cells exit the blood and move to the battle ground to take part in the fight. When they reach the battle site (i.e., location of the bacteria), natural killer cells play two key roles in defending us against infections. First, natural killer cells can destroy virus-infected cells, bacteria, parasites, fungi, and cancer cells. Second, natural killer cells also give off cytokines that help with immune defense. So, natural killer cells are an important part of the innate immune system because they are versatile “killers” of foreign agents, including bacteria, viruses, cancer cells, and other unwanted invaders of the body.
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To summarize, phagocytes (macrophages and neutrophils) and natural killer cells are important cellular components of the innate immune system and form the second line of defense against infection. Collectively, these cells remove dangerous invading agents and protect the body against infection whenever the physical barriers of defense are compromised (e.g., skin wound). When these cellular components of the innate immune system are activated following an infection, a physiologic response known as inflammation occurs. The hallmark signs of inflammation are redness, swelling, heat, and pain. More details about inflammation can be found in A Closer Look 6.1.
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A CLOSER LOOK 6.1 Inflammation Is a Normal Part of the Immune Response
The word inflammation comes from the Latin word inflammare, which means “to set on fire.” Inflammation is a normal part of the biological response to harmful stimuli, such as bacteria entering the body. In short, the goal of inflammation is to restore homeostasis by helping the injured tissue return to its normal state. Inflammation can be classified as either acute or chronic. A brief explanation of the differences between acute and chronic inflammation follows.
Acute Inflammation The following example illustrates an acute inflammatory response. At some time in your life, you have probably experienced a small cut on your finger or hand. In this case, the break in your skin allows bacteria to enter through the wound and results in an acute (i.e., brief) and localized inflammatory response. The clinical signs of localized inflammation are redness, swelling, heat, and pain. This occurs because of a cascade of events triggered by the innate immune system. The redness, swelling, and heat around the injured tissue result from the increased blood flow to the damaged area. This increased blood flow is triggered by the release of chemicals from phagocytes that are summoned to the infected area. Indeed, both macrophages and neutrophils release chemicals (e.g., bradykinin) that promote vasodilation (i.e., widening of the diameter of blood vessels). This vasodilation increases blood flow and fluid collection (i.e., edema) around the injured tissue. The pain associated with this type of local inflammatory response comes from chemicals (e.g., kinins) that stimulate pain receptors in the inflamed area.
Chronic Inflammation Typically, a small cut on your finger results in acute inflammation that is resolved within a few days when the immune system removes the invading bacteria, a scab forms, and the tissue returns to normal. However, chronic (i.e., unending) systemic inflammation occurs in situations of persistent infection (e.g., tuberculosis) or constant activation of the immune response as seen in diseases such as cancer, heart failure, rheumatoid arthritis, or chronic obstructive lung disease. Interestingly, both obesity and aging are also associated with chronic inflammation (1, 2). Regardless of the cause, chronic inflammation is associated with increased circulating cytokines and the so-called “acute-phase proteins” such as c-reactive protein. This is significant because chronically elevated blood levels of both cytokines and c-reactive proteins are thought to contribute to the risk of many diseases, including heart disease (1).
It is also important to appreciate that chronic systemic inflammation is not “all or none,” but can exist in differing levels that are often described as “high grade” or “low grade” inflammation. A severe “high grade” level of inflammation might occur in patients suffering from certain types of cancers or rheumatoid arthritis. In contrast, even in the absence of diagnosed diseases, low grade inflammation can exist in both older and obese individuals (2). The health significance of “low grade” systemic inflammation is a hot topic in medicine because low grade inflammation has been linked to increased risks of cancer, Alzheimer disease, diabetes, and heart disease (1, 2). However, whether chronic inflammation actually causes all of these diseases or merely accompanies them is currently unknown.
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The complement system plays an important role in innate immunity and consists of numerous proteins that circulate in the blood in inactive forms. Like phagocytes and natural killer cells, the complement system is another component of the innate defense against infection. The more than 20 proteins that make up the complement system are produced primarily by the liver and are present in high concentrations in the blood and tissues (29). When the body is exposed to a foreign agent (e.g., bacterium), the complement system is activated to attack the invader. These activated complement proteins recognize the surface of the bacterium as a foreign agent and attach to the surface of the foreign cell. This triggers a rapid series of events resulting in the binding of more and more complement proteins on the surface of the bacteria. The addition of multiple complement proteins to the surface of the bacterium forms a “hole” (i.e., channel) in the surface of the bacterium. And once a bacterium has a hole in its membrane, the bacterium dies.
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In addition to forming membrane attack complexes, the complement system performs two other jobs in innate immunity. The second function is to “tag” the cell surface of invading bacteria so that other cellular components (e.g., phagocytes) of the innate immune system can recognize and kill the invader. The third and final role of complement proteins is to serve as chemoattractants. As mentioned earlier, a chemoattractant recruits other immune players to the battle site to assist in protecting the body from infection.
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To summarize, the complement system performs three important jobs when the body is invaded by foreign agents. First, this system can destroy invaders by punching a hole in the surface of the invading bacterium. Second, it can enhance the function of other cells (e.g., phagocytes) within the immune system by tagging the invading agent for destruction. Third, it can alert other cells in the immune system that the body is being attacked. Importantly, all these functions of the complement system can respond rapidly to protect the body during invasion.
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Acquired Immune System
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Over 95 percent of all animals get along fine with only the innate immune system to protect them (29). However, for humans and other vertebrates, Mother Nature developed another layer of protection against disease, the acquired immune system. This system of immunity adapts to protect us against almost any type of invader. The primary purpose of the acquired immune system is to protect us against viruses because the innate immune system cannot eliminate many viruses (29). The first evidence that the acquired immune system existed was provided by Dr. Edward Jenner in the 1790s (see A Look Back—Important People in Science).
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A LOOK BACK—IMPORTANT PEOPLE IN SCIENCE Edward Jenner Was the Pioneer of the Smallpox Vaccine
Edward Jenner (1749–1823) was an English physician who played a major role in developing the smallpox vaccine. Because of this accomplishment, he is sometimes referred to as the “father of immunology.” Here is the story behind Jenner’s discovery of the smallpox vaccine.
After discovering that the immune system was adaptive, Jenner began vaccinating the English against smallpox in 1796. During the life of Jenner, smallpox was a huge health problem, and approximately 30 percent of the people infected with smallpox died. In fact, hundreds of thousands of people died from the disease, and many others were horribly disfigured (29). Two observations led Edward Jenner to develop a vaccination procedure against smallpox. First, Jenner observed that milkmaids often contracted a disease called cowpox, which caused them to develop lesions that were similar to the sores associated with smallpox. Second, Jenner observed that the milkmaids that contracted cowpox almost never got smallpox, which, as it turns out, is a close relative of the cowpox virus (29). Based upon these observations, Jenner reasoned that exposure to a small amount of cowpox virus can promote immunity against smallpox.
To test this hypothesis, Jenner decided to perform a bold experiment. He collected pus from the sores of milkmaids infected with cowpox. He then injected this fluid into the arm of a young boy named James Phipps. This inoculation produced a fever, but no great illness resulted. A few weeks following this treatment, Jenner then injected Phipps with pus collected from sores of a patient infected with smallpox. This daring experiment was a huge success because, remarkably, the young boy did not contract smallpox. However, Phipps was still able to contract other childhood diseases (e.g., measles). This illustrates one of the hallmarks of the adaptive immune system. That is, the acquired immune system adapts to defend against specific invaders.
Obviously, Jenner’s experiments on this boy would not be performed today because of ethical concerns. Nonetheless, we can be thankful that Jenner’s experiments were a success because it paved the way for future vaccines that have saved the lives of countless numbers of people around the world.
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The acquired immune system is composed of highly specialized cells and processes that prevent or eliminate invading pathogens. This adaptive immune response provides us with the ability to recognize and remember specific pathogens (i.e., to generate immunity) and to mount stronger attacks each time a repeating pathogen is encountered. Therefore, this system is sometimes called the adaptive immune system because it prepares itself for future pathogen challenges.
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The major cells involved in the acquired immune system are B-cells (also called B-lymphocytes) and T-cells (also called T-lymphocytes). Both B- and T-cells are members of the leukocyte family of blood cells that have their origin from stem cells located within bone marrow (Fig. 6.2). A brief overview of how B- and T-cells function in acquired immunity follows.
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These cells are produced in the bone marrow and play a key role in specific immunity and combat both bacterial and viral infections by secreting antibodies into the blood. B-cells function as antibody factories and can produce more than 100 million different types of antibodies that are required to protect us against a wide variety of invading antigens. Antibodies (also called immunoglobulins) are proteins manufactured by B-cells to help fight against foreign substances called antigens. Antigens are any substance that stimulates the immune system to produce antibodies. For example, bacteria, viruses, or fungi are all antigens. Further, antigens that promote an allergic response are commonly called allergens. Common allergens include pollen, animal dander, dust, and the contents of certain foods. When the body is confronted by these antigens, B-cells respond by producing antibodies to protect against this invasion.
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Although the body can produce more than 100 million different antibodies, there are five general classes of antibodies, and each has a different function. The five classes of antibodies are IgG, IgA, IgM, IgD, and IgE. The abbreviation Ig stands for immunoglobulin (i.e., antibody). A detailed discussion of the specific function of each of these classes of antibodies exceeds the goals of this chapter. However, an example of how two classes of antibodies function is useful in understanding the role of antibodies in protecting against disease.
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When B-cells are activated by an invading antigen, IgM is one of the first classes of antibodies produced. Producing this antibody early during an infection is a good strategy because IgM antibodies can protect against invaders in two important ways. First, IgM antibodies can activate the complement cascade to assist in removing the unwanted invader. In fact, the term complement was coined by immunologists when they discovered that antibodies were much more effective in dealing with invaders if they are complemented by other proteins—the complement system (29). Second, IgM antibodies are good at neutralizing viruses by binding to them and preventing the virus from infecting cells. Hence, because of these combined properties, the IgM is the perfect “first” antibody to protect against viral or bacterial invasions (29).
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IgG antibodies are another important class of antibodies. These antibodies circulate in the blood and other body fluids and defend against invading bacteria and viruses (33). The binding of IgG antibodies to bacterial or viral antigens activates other immune cells (e.g., macrophages, neutrophils, and natural killer cells) that destroy these invaders and protect us against disease.
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T-cells are a family of immune cells produced in the bone marrow. T-cells and B-cells differ in several ways. First, while B-cells mature in the bone marrow, T-cells mature in a specialized immune organ called the thymus; this is why they are called T-cells. Further, T-cells do not produce antibodies but specialize in recognizing protein antigens in the body. There are three main types of T-cells: (1) killer T-cells (also called cytotoxic T-cells); (2) helper T-cells; and (3) regulatory T-cells. Killer T-cells are a potent weapon against viruses because they can recognize and kill virus-infected cells (6). Helper T-cells secrete cytokines that have a dramatic effect on other immune system cells. In this way, helper T-cells serve as the quarterback of the immune system by directing the action of other immune cells. Finally, as the name implies, the regulatory T-cells are involved in regulation of immune function. Specifically, these cells play a role in inhibiting responses to both self-antigens (i.e., preventing the immune system from attacking normal body cells) and foreign antigens. In this way, regulatory T-cells help to regulate self-tolerance and prevent autoimmune diseases (4).
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IN SUMMARY
The human immune system is a complex and redundant system designed to protect us against invading pathogens.
A healthy immune system requires the teamwork of two layers of immune protection: (1) innate immune system and (2) acquired immune system.
The innate system protects against foreign invaders and is composed of three major components: (1) physical barriers such as the skin and the mucous membranes that line our respiratory, digestive, and genitourinary tracts; (2) specialized cells (e.g., phagocytes and natural killer cells) designed to destroy invaders; and (3) a group of proteins called the complement system, which are located throughout the body to protect against invaders.
The acquired immune system adapts to protect against almost any type of invading pathogen. The primary purpose of the acquired immune system is to provide protection against viruses that the innate immune system cannot provide. B- and T-cells are the major cells involved in the acquired immune system. B-cells produce antibodies, whereas T-cells specialize in recognizing and removing antigens in the body.