Chapter 17. The Immune System and Disease

Viruses were first discovered after the development of a porcelain filter, called the Chamberland-Pasteur filter, which could remove all bacteria visible under the microscope from any liquid sample. In 1886, Adolph Meyer demonstrated that a disease of tobacco plants, tobacco mosaic disease, could be transferred from a diseased plant to a healthy one through liquid plant extracts. In 1892, Dmitri Ivanowski showed that this disease could be transmitted in this way even after the Chamberland-Pasteur filter had removed all viable bacteria from the extract. Still, it was many years before it was proven that these “filterable” infectious agents were not simply very small bacteria but were a new type of tiny, disease-causing particle.

Virions, single virus particles, are very small, about 20–250 nanometers (1 nanometer = 1/1,000,000 mm). These individual virus particles are the infectious form of a virus outside the host cell. Unlike bacteria (which are about 100 times larger), we cannot see viruses with a light microscope, with the exception of some large virions of the poxvirus family (Figure 17.3).

Figure 17.3. 

The size of a virus is very small relative to the size of cells and organelles.

It was not until the development of the electron microscope in the 1940s that scientists got their first good view of the structure of the tobacco mosaic virus (Figure 17.2) and others. The surface structure of virions can be observed by both scanning and transmission electron microscopy, whereas the internal structures of the virus can only be observed in images from a transmission electron microscope (Figure 17.4).

Figure 17.4. 

The ebola virus is shown here as visualized through (a) a scanning electron micrograph and (b) a transmission electron micrograph. (credit a: modification of work by Cynthia Goldsmith, CDC; credit b: modification of work by Thomas W. Geisbert, Boston University School of Medicine; scale-bar data from Matt Russell)

The use of this technology has allowed for the discovery of many viruses of all types of living organisms. They were initially grouped by shared morphology, meaning their size, shape, and distinguishing structures. Later, groups of viruses were classified by the type of nucleic acid they contained, DNA or RNA, and whether their nucleic acid was single- or double-stranded. More recently, molecular analysis of viral replication cycles has further refined their classification.

A virion consists of a nucleic-acid core, an outer protein coating, and sometimes an outer envelope made of protein and phospholipid membranes derived from the host cell. The most visible difference between members of viral families is their morphology, which is quite diverse. An interesting feature of viral complexity is that the complexity of the host does not correlate to the complexity of the virion. Some of the most complex virion structures are observed in bacteriophages, viruses that infect the simplest living organisms, bacteria.

Viruses come in many shapes and sizes, but these are consistent and distinct for each viral family (Figure 17.5). All virions have a nucleic-acid genome covered by a protective layer of protein, called a capsid. The capsid is made of protein subunits called capsomeres. Some viral capsids are simple polyhedral “spheres,” whereas others are quite complex in structure. The outer structure surrounding the capsid of some viruses is called the viral envelope. All viruses use some sort of glycoprotein to attach to their host cells at molecules on the cell called viral receptors. The virus exploits these cell-surface molecules, which the cell uses for some other purpose, as a way to recognize and infect specific cell types. For example, the measles virus uses a cell-surface glycoprotein in humans that normally functions in immune reactions and possibly in the sperm-egg interaction at fertilization. Attachment is a requirement for viruses to later penetrate the cell membrane, inject the viral genome, and complete their replication inside the cell.

The T4 bacteriophage, which infects the E. coli bacterium, is among the most complex virion known; T4 has a protein tail structure that the virus uses to attach to the host cell and a head structure that houses its DNA.

Adenovirus, a nonenveloped animal virus that causes respiratory illnesses in humans, uses protein spikes protruding from its capsomeres to attach to the host cell. Nonenveloped viruses also include those that cause polio (poliovirus), plantar warts (papillomavirus), and hepatitis A (hepatitis A virus). Nonenveloped viruses tend to be more robust and more likely to survive under harsh conditions, such as the gut.

Enveloped virions like HIV (human immunodeficiency virus), the causative agent in AIDS (acquired immune deficiency syndrome), consist of nucleic acid (RNA in the case of HIV) and capsid proteins surrounded by a phospholipid bilayer envelope and its associated proteins (Figure 17.5). Chicken pox, influenza, and mumps are examples of diseases caused by viruses with envelopes. Because of the fragility of the envelope, nonenveloped viruses are more resistant to changes in temperature, pH, and some disinfectants than enveloped viruses.

Overall, the shape of the virion and the presence or absence of an envelope tells us little about what diseases the viruses may cause or what species they might infect, but is still a useful means to begin viral classification.

Art Connection

 

Figure 17.5. 

Viruses can be complex in shape or relatively simple. This figure shows three relatively complex virions: the bacteriophage T4, with its DNA-containing head group and tail fibers that attach to host cells; adenovirus, which uses spikes from its capsid to bind to the host cells; and HIV, which uses glycoproteins embedded in its envelope to do so. Notice that HIV has proteins called matrix proteins, internal to the envelope, which help stabilize virion shape. HIV is a retrovirus, which means it reverse transcribes its RNA genome into DNA, which is then spliced into the host’s DNA. (credit “bacteriophage, adenovirus”: modification of work by NCBI, NIH; credit “HIV retrovirus”: modification of work by NIAID, NIH)

Which of the following statements about virus structure is true?

1. All viruses are encased in a viral membrane.
2. The capsomere is made up of small protein subunits called capsids.
3. DNA is the genetic material in all viruses.
4. Glycoproteins help the virus attach to the host cell.

Unlike all living organisms that use DNA as their genetic material, viruses may use either DNA or RNA as theirs. The virus core contains the genome or total genetic content of the virus. Viral genomes tend to be small compared to bacteria or eukaryotes, containing only those genes that code for proteins the virus cannot get from the host cell. This genetic material may be single-stranded or double-stranded. It may also be linear or circular. While most viruses contain a single segment of nucleic acid, others have genomes that consist of several segments.

DNA viruses have a DNA core. The viral DNA directs the host cell’s replication proteins to synthesize new copies of the viral genome and to transcribe and translate that genome into viral proteins. DNA viruses cause human diseases such as chickenpox, hepatitis B, and some venereal diseases like herpes and genital warts.

RNA viruses contain only RNA in their cores. To replicate their genomes in the host cell, the genomes of RNA viruses encode enzymes not found in host cells. RNA polymerase enzymes are not as stable as DNA polymerases and often make mistakes during transcription. For this reason, mutations, changes in the nucleotide sequence, in RNA viruses occur more frequently than in DNA viruses. This leads to more rapid evolution and change in RNA viruses. For example, the fact that influenza is an RNA virus is one reason a new flu vaccine is needed every year. Human diseases caused by RNA viruses include hepatitis C, measles, and rabies.

Viruses can be seen as obligate intracellular parasites. The virus must attach to a living cell, be taken inside, manufacture its proteins and copy its genome, and find a way to escape the cell so the virus can infect other cells and ultimately other individuals. Viruses can infect only certain species of hosts and only certain cells within that host. The molecular basis for this specificity is that a particular surface molecule, known as the viral receptor, must be found on the host cell surface for the virus to attach. Also, metabolic differences seen in different cell types based on differential gene expression are a likely factor in which cells a virus may use to replicate. The cell must be making the substances the virus needs, such as enzymes the virus genome itself does not have genes for, or the virus will not be able to replicate using that cell.

Steps of Virus Infections

A virus must “take over” a cell to replicate. The viral replication cycle can produce dramatic biochemical and structural changes in the host cell, which may cause cell damage. These changes, called cytopathic effects, can change cell functions or even destroy the cell. Some infected cells, such as those infected by the common cold virus (rhinovirus), die through lysis (bursting) or apoptosis (programmed cell death or “cell suicide”), releasing all the progeny virions at once. The symptoms of viral diseases result from the immune response to the virus, which attempts to control and eliminate the virus from the body, and from cell damage caused by the virus. Many animal viruses, such as HIV (human immunodeficiency virus), leave the infected cells of the immune system by a process known as budding, where virions leave the cell individually. During the budding process, the cell does not undergo lysis and is not immediately killed. However, the damage to the cells that HIV infects may make it impossible for the cells to function as mediators of immunity, even though the cells remain alive for a period of time. Most productive viral infections follow similar steps in the virus replication cycle: attachment, penetration, uncoating, replication, assembly, and release.

A virus attaches to a specific receptor site on the host-cell membrane through attachment proteins in the capsid or proteins embedded in its envelope. The attachment is specific, and typically a virus will only attach to cells of one or a few species and only certain cell types within those species with the appropriate receptors.

Concept in Action

View this video for a visual explanation of how influenza attacks the body.

Unlike animal viruses, the nucleic acid of bacteriophages is injected into the host cell naked, leaving the capsid outside the cell. Plant and animal viruses can enter their cells through endocytosis, in which the cell membrane surrounds and engulfs the entire virus. Some enveloped viruses enter the cell when the viral envelope fuses directly with the cell membrane. Once inside the cell, the viral capsid is degraded and the viral nucleic acid is released, which then becomes available for replication and transcription.

The replication mechanism depends on the viral genome. DNA viruses usually use host cell proteins and enzymes to make additional DNA that is used to copy the genome or be transcribed to messenger RNA (mRNA), which is then used in protein synthesis. RNA viruses, such as the influenza virus, usually use the RNA core as a template for synthesis of viral genomic RNA and mRNA. The viral mRNA is translated into viral enzymes and capsid proteins to assemble new virions (Figure 17.6). Of course, there are exceptions to this pattern. If a host cell does not provide the enzymes necessary for viral replication, viral genes supply the information to direct synthesis of the missing proteins. Retroviruses, such as HIV, have an RNA genome that must be reverse transcribed to make DNA, which then is inserted into the host’s DNA. To convert RNA into DNA, retroviruses contain genes that encode the virus-specific enzyme reverse transcriptase that transcribes an RNA template to DNA. The fact that HIV produces some of its own enzymes, which are not found in the host, has allowed researchers to develop drugs that inhibit these enzymes. These drugs, including the reverse transcriptase inhibitor AZT, inhibit HIV replication by reducing the activity of the enzyme without affecting the host’s metabolism.

The last stage of viral replication is the release of the new virions into the host organism, where they are able to infect adjacent cells and repeat the replication cycle. Some viruses are released when the host cell dies and other viruses can leave infected cells by budding through the membrane without directly killing the cell.

Art Connection

 

Figure 17.6. 

In influenza virus infection, glycoproteins attach to a host epithelial cell. As a result, the virus is engulfed. RNA and proteins are made and assembled into new virions.

Influenza virus is packaged in a viral envelope, which fuses with the plasma membrane. This way, the virus can exit the host cell without killing it. What advantage does the virus gain by keeping the host cell alive?

Concept in Action

Click through this tutorial on viruses to identify structures, modes of transmission, replication, and more.

Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis (Figure 17.7). These diseases can be treated by antiviral drugs or by vaccines, but some viruses, such as HIV, are capable of avoiding the immune response and mutating so as to become resistant to antiviral drugs.

Figure 17.7. 

Viruses are the cause of dozens of ailments in humans, ranging from mild illnesses to serious diseases. (credit: modification of work by Mikael Häggström)

The body has significant physical barriers to potential pathogens. The skin contains the protein keratin, which resists physical entry into cells. Other body surfaces, particularly those associated with body openings, are protected by the mucous membranes. The sticky mucus provides a physical trap for pathogens, preventing their movement deeper into the body. The openings of the body, such as the nose and ears, are protected by hairs that catch pathogens, and the mucous membranes of the upper respiratory tract have cilia that constantly move pathogens trapped in the mucus coat up to the mouth.

The skin and mucous membranes also create a chemical environment that is hostile to many microorganisms. The surface of the skin is acidic, which prevents bacterial growth. Saliva, mucus, and the tears of the eye contain an enzyme that breaks down bacterial cell walls. The stomach secretions create a highly acidic environment, which kills many pathogens entering the digestive system.

Finally, the surface of the body and the lower digestive system have a community of microorganisms such as bacteria, archaea, and fungi that coexist without harming the body. There is evidence that these organisms are highly beneficial to their host, combating disease-causing organisms and outcompeting them for nutritional resources provided by the host body. Despite these defenses, pathogens may enter the body through skin abrasions or punctures, or by collecting on mucosal surfaces in large numbers that overcome the protections of mucus or cilia.

When pathogens enter the body, the innate immune system responds with a variety of internal defenses. These include the inflammatory response, phagocytosis, natural killer cells, and the complement system. White blood cells in the blood and lymph recognize pathogens as foreign to the body. A white blood cell is larger than a red blood cell, is nucleated, and is typically able to move using amoeboid locomotion. Because they can move on their own, white blood cells can leave the blood to go to infected tissues. For example, a monocyte is a type of white blood cell that circulates in the blood and lymph and develops into a macrophage after it moves into infected tissue. A macrophage is a large cell that engulfs foreign particles and pathogens. Mast cells are produced in the same way as white blood cells, but unlike circulating white blood cells, mast cells take up residence in connective tissues and especially mucosal tissues. They are responsible for releasing chemicals in response to physical injury. They also play a role in the allergic response, which will be discussed later in the chapter.

When a pathogen is recognized as foreign, chemicals called cytokines are released. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to produce a variety of immune responses. Approximately 40 types of cytokines exist in humans. In addition to being released from white blood cells after pathogen recognition, cytokines are also released by the infected cells and bind to nearby uninfected cells, inducing those cells to release cytokines. This positive feedback loop results in a burst of cytokine production.

One class of early-acting cytokines is the interferons, which are released by infected cells as a warning to nearby uninfected cells. An interferon is a small protein that signals a viral infection to other cells. The interferons stimulate uninfected cells to produce compounds that interfere with viral replication. Interferons also activate macrophages and other cells.

The Inflammatory Response and Phagocytosis

The first cytokines to be produced encourage inflammation, a localized redness, swelling, heat, and pain. Inflammation is a response to physical trauma, such as a cut or a blow, chemical irritation, and infection by pathogens (viruses, bacteria, or fungi). The chemical signals that trigger an inflammatory response enter the extracellular fluid and cause capillaries to dilate (expand) and capillary walls to become more permeable, or leaky. The serum and other compounds leaking from capillaries cause swelling of the area, which in turn causes pain. Various kinds of white blood cells are attracted to the area of inflammation. The types of white blood cells that arrive at an inflamed site depend on the nature of the injury or infecting pathogen. For example, a neutrophil is an early arriving white blood cell that engulfs and digests pathogens. Neutrophils are the most abundant white blood cells of the immune system (Figure 17.9). Macrophages follow neutrophils and take over the phagocytosis function and are involved in the resolution of an inflamed site, cleaning up cell debris and pathogens.

Figure 17.9. 

White blood cells (leukocytes) release chemicals to stimulate the inflammatory response following a cut in the skin.

Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, muscle pain, and nausea. Cytokines also increase the core body temperature, causing a fever. The elevated temperatures of a fever inhibit the growth of pathogens and speed up cellular repair processes. For these reasons, suppression of fevers should be limited to those that are dangerously high.

Concept in Action

Check out this 23-second, stop-motion video showing a neutrophil that searches and engulfs fungus spores during an elapsed time of 79 minutes.

Natural Killer Cells

A lymphocyte is a white blood cell that contains a large nucleus (Figure 17.10). Most lymphocytes are associated with the adaptive immune response, but infected cells are identified and destroyed by natural killer cells, the only lymphocytes of the innate immune system. A natural killer (NK) cell is a lymphocyte that can kill cells infected with viruses (or cancerous cells). NK cells identify intracellular infections, especially from viruses, by the altered expression of major histocompatibility class (MHC) I molecules on the surface of infected cells. MHC class I molecules are proteins on the surfaces of all nucleated cells that provide a sample of the cell’s internal environment at any given time. Unhealthy cells, whether infected or cancerous, display an altered MHC class I complement on their cell surfaces.

Figure 17.10. 

Lymphocytes, such as NK cells, are characterized by their large nuclei that actively absorb Wright stain and therefore appear dark colored under a microscope. (credit: scale-bar data from Matt Russell)

After the NK cell detects an infected or tumor cell, it induces programmed cell death, or apoptosis. Phagocytic cells then come along and digest the cell debris left behind. NK cells are constantly patrolling the body and are an effective mechanism for controlling potential infections and preventing cancer progression. The various types of immune cells are shown in Figure 17.11.

Figure 17.11. 

Cells involved in the innate immune response include mast cells, natural killer cells, and white blood cells, such as monocytes, macrophages and neutrophils.

Lymphocytes, which are white blood cells, are formed with other blood cells in the red bone marrow found in many flat bones, such as the shoulder or pelvic bones. The two types of lymphocytes of the adaptive immune response are B and T cells (Figure 17.12). Whether an immature lymphocyte becomes a B cell or T cell depends on where in the body it matures. The B cells remain in the bone marrow to mature (hence the name “B” for “bone marrow”), while T cells migrate to the thymus, where they mature (hence the name “T” for “thymus”).

Maturation of a B or T cell involves becoming immunocompetent, meaning that it can recognize, by binding, a specific molecule or antigen (discussed below). During the maturation process, B and T cells that bind too strongly to the body’s own cells are eliminated in order to minimize an immune response against the body’s own tissues. Those cells that react weakly to the body’s own cells, but have highly specific receptors on their cell surfaces that allow them to recognize a foreign molecule, or antigen, remain. This process occurs during fetal development and continues throughout life. The specificity of this receptor is determined by the genetics of the individual and is present before a foreign molecule is introduced to the body or encountered. Thus, it is genetics and not experience that initially provides a vast array of cells, each capable of binding to a different specific foreign molecule. Once they are immunocompetent, the T and B cells will migrate to the spleen and lymph nodes where they will remain until they are called on during an infection. B cells are involved in the humoral immune response, which targets pathogens loose in blood and lymph, and T cells are involved in the cell-mediated immune response, which targets infected cells.

Figure 17.12. 

This scanning electron micrograph shows a T lymphocyte. T and B cells are indistinguishable by light microscopy but can be differentiated experimentally by probing their surface receptors. (credit: modification of work by NCI; scale-bar data from Matt Russell)

As mentioned, an antigen is a molecule that stimulates a response in the immune system. Not every molecule is antigenic. B cells participate in a chemical response to antigens present in the body by producing specific antibodies that circulate throughout the body and bind with the antigen whenever it is encountered. This is known as the humoral immune response. As discussed, during maturation of B cells, a set of highly specific B cells are produced that have many antigen receptor molecules in their membrane (Figure 17.13).

Figure 17.13. 

B cell receptors are embedded in the membranes of B cells and bind a variety of antigens through their variable regions.

Each B cell has only one kind of antigen receptor, which makes every B cell different. Once the B cells mature in the bone marrow, they migrate to lymph nodes or other lymphatic organs. When a B cell encounters the antigen that binds to its receptor, the antigen molecule is brought into the cell by endocytosis and reappears on the surface of the cell bound to an MHC class II molecule. When this process is complete, the B cell is sensitized. In most cases, the sensitized B cell must then encounter a specific kind of T cell, called a helper T cell, before it is activated. The helper T cell must already have been activated through an encounter with the antigen (discussed below).

The helper T cell binds to the antigen-MHC class II complex and is induced to release cytokines that induce the B cell to divide rapidly, which makes thousands of identical (clonal) cells. These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point, until another later encounter with the antigen, caused by a reinfection by the same bacteria or virus, results in them dividing into a new population of plasma cells. The plasma cells, on the other hand, produce and secrete large quantities, up to 100 million molecules per hour, of antibody molecules. An antibody, also known as an immunoglobulin (Ig), is a protein that is produced by plasma cells after stimulation by an antigen. Antibodies are the agents of humoral immunity. Antibodies occur in the blood, in gastric and mucus secretions, and in breast milk. Antibodies in these bodily fluids can bind pathogens and mark them for destruction by phagocytes before they can infect cells.

These antibodies circulate in the blood stream and lymphatic system and bind with the antigen whenever it is encountered. The binding can fight infection in several ways. Antibodies can bind to viruses or bacteria and interfere with the chemical interactions required for them to infect or bind to other cells. The antibodies may create bridges between different particles containing antigenic sites clumping them all together and preventing their proper functioning. The antigen-antibody complex stimulates the complement system described previously, destroying the cell bearing the antigen. Phagocytic cells, such as those already described, are attracted by the antigen-antibody complexes, and phagocytosis is enhanced when the complexes are present. Finally, antibodies stimulate inflammation, and their presence in mucus and on the skin prevents pathogen attack.

Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the pathogen that enhance their infectivity (such as receptors that “dock” pathogens on host cells) (Figure 17.14). Antibody neutralization can prevent pathogens from entering and infecting host cells. The neutralized antibody-coated pathogens can then be filtered by the spleen and eliminated in urine or feces.

Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or neutrophils, in a process called opsonization. In a process called complement fixation, some antibodies provide a place for complement proteins to bind. The combination of antibodies and complement promotes rapid clearing of pathogens.

The production of antibodies by plasma cells in response to an antigen is called active immunity and describes the host’s active response of the immune system to an infection or to a vaccination. There is also a passive immune response where antibodies come from an outside source, instead of the individual’s own plasma cells, and are introduced into the host. For example, antibodies circulating in a pregnant woman’s body move across the placenta into the developing fetus. The child benefits from the presence of these antibodies for up to several months after birth. In addition, a passive immune response is possible by injecting antibodies into an individual in the form of an antivenom to a snake-bite toxin or antibodies in blood serum to help fight a hepatitis infection. This gives immediate protection since the body does not need the time required to mount its own response.

Figure 17.14. 

Antibodies may inhibit infection by (a) preventing the antigen from binding its target, (b) tagging a pathogen for destruction by macrophages or neutrophils, or (c) activating the complement cascade.

Unlike B cells, T lymphocytes are unable to recognize pathogens without assistance. Instead, dendritic cells and macrophages first engulf and digest pathogens into hundreds or thousands of antigens. Then, an antigen-presenting cell (APC) detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will engulf and break it down through phagocytosis. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. A dendritic cell is an immune cell that mops up antigenic materials in its surroundings and presents them on its surface. Dendritic cells are located in the skin, the linings of the nose, lungs, stomach, and intestines. These positions are ideal locations to encounter invading pathogens. Once they are activated by pathogens and mature to become APCs they migrate to the spleen or a lymph node. Macrophages also function as APCs. After phagocytosis by a macrophage, the phagocytic vesicle fuses with an intracellular lysosome. Within the resulting phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class II molecules and are transported to the cell surface for antigen presentation (Figure 17.15). Helper T cells cannot properly respond to an antigen unless it is processed and embedded in an MHC class II molecule. The APCs express MHC class II on their surfaces, and when combined with a foreign antigen, these complexes signal an invader.

Figure 17.15. 

An antigen-presenting cell (APC), such as a macrophage, engulfs a foreign antigen, partially digests it in a lysosome, and then embeds it in an MHC class II molecule for presentation at the cell surface. Lymphocytes of the adaptive immune response must interact with antigen-embedded MHC class II molecules to mature into functional immune cells.

Concept in Action

View this animation from Rockefeller University to see how dendritic cells act as sentinels in the body’s immune system.

T cells have many functions. Some respond to APCs of the innate immune system and indirectly induce immune responses by releasing cytokines. Others stimulate B cells to start the humoral response as described previously. Another type of T cell detects APC signals and directly kills the infected cells, while some are involved in suppressing inappropriate immune reactions to harmless or “self” antigens.

There are two main types of T cells: helper T lymphocytes (T_H) and the cytotoxic T lymphocytes (T_C). The T_H lymphocytes function indirectly to tell other immune cells about potential pathogens. T_H lymphocytes recognize specific antigens presented by the MHC class II complexes of APCs. There are two populations of T_H cells: T_H1 and T_H2. T_H1 cells secrete cytokines to enhance the activities of macrophages and other T cells. T_H2 cells stimulate naïve B cells to secrete antibodies. Whether a T_H1 or a T_H2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

Cytotoxic T cells (T_C) are the key component of the cell-mediated part of the adaptive immune system and attack and destroy infected cells. T_C cells are particularly important in protecting against viral infections; this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. Once activated, the T_C creates a large clone of cells with one specific set of cell-surface receptors, as in the case with proliferation of activated B cells. As with B cells, the clone includes active T_C cells and inactive memory T_C cells. The resulting active T_C cells then identify infected host cells. Because of the time required to generate a population of clonal T and B cells, there is a delay in the adaptive immune response compared to the innate immune response.

T_C cells attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. T_C cells also support NK lymphocytes to destroy early cancers. Cytokines secreted by the T_H1 response that stimulates macrophages also stimulate T_C cells and enhance their ability to identify and destroy infected cells and tumors. A summary of how the humoral and cell-mediated immune responses are activated appears in Figure 17.16.

B plasma cells and T_C cells are collectively called effector cells because they are involved in “effecting” (bringing about) the immune response of killing pathogens and infected host cells.

Figure 17.16. 

A helper T cell becomes activated by binding to an antigen presented by an APC via the MHCII receptor, causing it to release cytokines. Depending on the cytokines released, this activates either the humoral or the cell-mediated immune response.

The adaptive immune system has a memory component that allows for a rapid and large response upon reinvasion of the same pathogen. During the adaptive immune response to a pathogen that has not been encountered before, known as the primary immune response, plasma cells secreting antibodies and differentiated T cells increase, then plateau over time. As B and T cells mature into effector cells, a subset of the naïve populations differentiates into B and T memory cells with the same antigen specificities (Figure 17.17). A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into an effector cell during the primary immune response, but that can immediately become an effector cell on reexposure to the same pathogen. As the infection is cleared and pathogenic stimuli subside, the effectors are no longer needed and they undergo apoptosis. In contrast, the memory cells persist in the circulation.

Art Connection

 

Figure 17.17. 

After initially binding an antigen to the B cell receptor, a B cell internalizes the antigen and presents it on MHC class II. A helper T cell recognizes the MHC class II- antigen complex and activates the B cell. As a result, memory B cells and plasma cells are made.

The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

If the pathogen is never encountered again during the individual’s lifetime, B and T memory cells will circulate for a few years or even several decades and will gradually die off, having never functioned as effector cells. However, if the host is re-exposed to the same pathogen type, circulating memory cells will immediately differentiate into plasma cells and T_C cells without input from APCs or T_H cells. This is known as the secondary immune response. One reason why the adaptive immune response is delayed is because it takes time for naïve B and T cells with the appropriate antigen specificities to be identified, activated, and proliferate. On reinfection, this step is skipped, and the result is a more rapid production of immune defenses. Memory B cells that differentiate into plasma cells output tens to hundreds-fold greater antibody amounts than were secreted during the primary response (Figure 17.18). This rapid and dramatic antibody response may stop the infection before it can even become established, and the individual may not realize they had been exposed.

Figure 17.18. 

In the primary response to infection, antibodies are secreted first from plasma cells. Upon re-exposure to the same pathogen, memory cells differentiate into antibody-secreting plasma cells that output a greater amount of antibody for a longer period of time.

Vaccination is based on the knowledge that exposure to noninfectious antigens, derived from known pathogens, generates a mild primary immune response. The immune response to vaccination may not be perceived by the host as illness but still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to a secondary exposure. Because each reinfection generates more memory cells and increased resistance to the pathogen, some vaccine courses involve one or more booster vaccinations to mimic repeat exposures.

Lymph is the watery fluid that bathes tissues and organs and contains protective white blood cells but does not contain erythrocytes. Lymph moves about the body through the lymphatic system, which is made up of vessels, lymph ducts, lymph glands, and organs, such as tonsils, adenoids, thymus, and spleen.

Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which include monocytes (the precursor of macrophages) and lymphocytes. Most cells in the blood are red blood cells. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).

Recall that cells of the immune system originate from stem cells in the bone marrow. B cell maturation occurs in the bone marrow, whereas progenitor cells migrate from the bone marrow and develop and mature into naïve T cells in the organ called the thymus.

On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body house large populations of T and B cells, dendritic cells, and macrophages (Figure 17.19). Lymph gathers antigens as it drains from tissues. These antigens then are filtered through lymph nodes before the lymph is returned to circulation. APCs in the lymph nodes capture and process antigens and inform nearby lymphocytes about potential pathogens.

Figure 17.19. 

(a) Lymphatic vessels carry a clear fluid called lymph throughout the body. The liquid passes through (b) lymph nodes that filter the lymph that enters the node through afferent vessels and leaves through efferent vessels; lymph nodes are filled with lymphocytes that purge infecting cells. (credit a: modification of work by NIH; credit b: modification of work by NCI, NIH)

The spleen houses B and T cells, macrophages, dendritic cells, and NK cells (Figure 17.20). The spleen is the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, and the spleen filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.

Figure 17.20. 

The spleen functions to immunologically filter the blood and allow for communication between cells corresponding to the innate and adaptive immune responses. (credit: modification of work by NCI, NIH)

The innate and adaptive immune responses compose the systemic immune system (affecting the whole body), which is distinct from the mucosal immune system. Mucosa associated lymphoid tissue (MALT) is a crucial component of a functional immune system because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. The mucosal tissue includes the mouth, pharynx, and esophagus, and the gastrointestinal, respiratory, and urogenital tracts.

Mucosal immunity is formed by MALT, which functions independently of the systemic immune system, and which has its own innate and adaptive components. MALT is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. The systemic and mucosal immune systems use many of the same cell types. Foreign particles that make their way to MALT are taken up by absorptive epithelial cells and delivered to APCs located directly below the mucosal tissue. APCs of the mucosal immune system are primarily dendritic cells, with B cells and macrophages having minor roles. Processed antigens displayed on APCs are detected by T cells in the MALT and at the tonsils, adenoids, appendix, or the mesenteric lymph nodes of the intestine. Activated T cells then migrate through the lymphatic system and into the circulatory system to mucosal sites of infection.

The immune system has to be regulated to prevent wasteful, unnecessary responses to harmless substances, and more importantly, so that it does not attack “self.” The acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance known not to cause disease, or self-antigens, is described as immune tolerance. The primary mechanism for developing immune tolerance to self-antigens occurs during the selection for weakly self-binding cells during T and B lymphocyte maturation. There are populations of T cells that suppress the immune response to self-antigens and that suppress the immune response after the infection has cleared to minimize host cell damage induced by inflammation and cell lysis. Immune tolerance is especially well developed in the mucosa of the upper digestive system because of the tremendous number of foreign substances (such as food proteins) that APCs of the oral cavity, pharynx, and gastrointestinal mucosa encounter. Immune tolerance is brought about by specialized APCs in the liver, lymph nodes, small intestine, and lung that present harmless antigens to a diverse population of regulatory T (T_reg) cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. The combined result of T_reg cells is to prevent immunologic activation and inflammation in undesired tissue compartments and to allow the immune system to focus on pathogens instead.

Immunodeficiency is a failure, insufficiency, or delay in the response of the immune system, which may be acquired or inherited. Immunodeficiency can allow pathogens or tumor cells to gain a foothold and replicate or proliferate to high enough levels so that the immune system becomes overwhelmed. Immunodeficiency can be acquired as a result of infection with certain pathogens that attack the cells of the immune system itself (such as HIV), chemical exposure (including certain medical treatments such as chemotherapy), malnutrition, or extreme stress. For instance, radiation exposure can destroy populations of lymphocytes and elevate an individual’s susceptibility to infections and cancer. Rarely, primary immunodeficiencies that are present from birth may also occur. For example, severe combined immunodeficiency disease (SCID) is a condition in which children are born without functioning B or T cells.

A maladaptive immune response toward harmless foreign substances or self-antigens that occur after tissue sensitization is termed a hypersensitivity. Types of hypersensitivities include immediate, delayed, and autoimmune. A large proportion of the human population is affected by one or more types of hypersensitivity.

Allergies

The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a usually harmless antigen is called an allergy. In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. On initial exposure to a potential allergen, an allergic individual synthesizes antibodies through the typical process of APCs presenting processed antigen to T_H cells that stimulate B cells to produce the antibodies. The antibody molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. On subsequent exposure to the same allergen, antibody molecules on mast cells bind the antigen and stimulate the mast cell to release histamine and other inflammatory chemicals; these chemical mediators then recruit eosinophils (a type of white blood cell), which also appear to be adapted to responding to parasitic worms (Figure 17.22). Eosinophils release factors that enhance the inflammatory response and the secretions of mast cells. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway constriction with severe respiratory distress, and plummeting blood pressure caused by dilating blood vessels and fluid loss from the circulatory system. This extreme reaction, typically in response to an allergen introduced to the circulatory system, is known as anaphylactic shock. Antihistamines are an insufficient counter to anaphylactic shock and if not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.

Figure 17.22. 

On first exposure to an allergen, an antibody is synthesized by plasma cells in response to a harmless antigen. The antibodies bind to mast cells, and on secondary exposure, the mast cells release histamines and other modulators that cause the symptoms of allergy. (credit: modification of work by NIH)

Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction. This type of hypersensitivity involves the T_H1 cytokine-mediated inflammatory response and may cause local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis, the organism that causes tuberculosis.

Concept in Action

Try your hand at diagnosing an allergic reaction by selecting one of the interactive case studies at the World Allergy Organization website.

Autoimmunity

Autoimmunity is a type of hypersensitivity to self-antigens that affects approximately five percent of the population. Most types of autoimmunity involve the humoral immune response. An antibody that inappropriately marks self-components as foreign is termed an autoantibody. In patients with myasthenia gravis, an autoimmune disease, muscle-cell receptors that induce contraction in response to acetylcholine are targeted by antibodies. The result is muscle weakness that may include marked difficultly with fine or gross motor functions. In systemic lupus erythematosus, a diffuse autoantibody response to the individual’s own DNA and proteins results in various systemic diseases (Figure 17.23). Systemic lupus erythematosus may affect the heart, joints, lungs, skin, kidneys, central nervous system, or other tissues, causing tissue damage through antibody binding, complement recruitment, lysis, and inflammation.

Figure 17.23. 

Systemic lupus erythematosus is characterized by autoimmunity to the individual’s own DNA and/or proteins, which leads to varied dysfunction of the organs. (credit: modification of work by Mikael Häggström)

Autoimmunity can develop with time and its causes may be rooted in molecular mimicry, a situation in which one molecule is similar enough in shape to another molecule that it binds the same immune receptors. Antibodies and T-cell receptors may bind self-antigens that are structurally similar to pathogen antigens. As an example, infection with Streptococcus pyogenes (the bacterium that causes strep throat) may generate antibodies or T cells that react with heart muscle, which has a similar structure to the surface of S. pyogenes. These antibodies can damage heart muscle with autoimmune attacks, leading to rheumatic fever. Insulin-dependent (Type 1) diabetes mellitus arises from a destructive inflammatory T_H1 response against insulin-producing cells of the pancreas. Patients with this autoimmunity must be treated with regular insulin injections.