Chapter 48-The Immune System in Animals

explain how activated lymphocytes endure

Activated lymphocytes endure. Some of the cloned cells descended from an activated lymphocyte persist long after the pathogen is eliminated. As a result, the cloned cells can respond quickly and effectively if the infection reoccurs.

Explain Figure 48.13

(a) An inactive B cell has a small amount of cytoplasm with few organelles. (b) An activated B cell, called a plasma cell, has extensive rough endoplasmic reticulum (ER) and many mitochondria—suggesting that a great deal of protein synthesis is taking place.

After vaccination what happens?

After vaccination, the body mounts a primary immune response that produces memory cells. If a second infection occurs later, these populations of memory cells respond quickly and eliminate the threat before illness develops. Vaccinations function like fire drills or earthquake preparedness exercises—they prepare the immune system for a specific threat.

What are the recombination events that lead to BCR diversity?

1. In the light-chain gene, one of 40 V40 V segments recombines with one of 5 J5 J segments. This step can produce 40×5=20040×5=200 different light chains. 2. In the heavy-chain gene, any one of 51 V51 V segments, 27 D27 D segments, and 6 J6 J segments can recombine. 3. The light-chain and heavy-chain gene rearrangements occur independently. When the polypeptides from each gene are assembled in the BCR, they form a specific antigen-binding site.

What are examples of exterior surfaces of being deterrents to infections?

-The armored bodies of insects are covered with a tough layer called cuticle, which includes a layer of wax (Ch. 40, Section 40.4). -Soft-bodied invertebrates like slugs, snails, and earthworms are covered with a protective layer of mucus (the adjective is "mucous"), a slimy mix of glycoproteins and water that traps pathogens and sloughs off. -Human skin, an epithelial tissue (Ch. 39, Section 39.2), has an outer layer of dead cells that are reinforced with tough fibers of the protein keratin (Ch. 7, Section 7.6).

Explain how lymphocytes require receptor epitope binding

2. Lymphocytes require receptor-epitope binding and cross-linking to become activated. When receptors on a lymphocyte bind to epitopes, the receptors are cross-linked and "throw a switch" to change the metabolic activities in the lymphocyte that ultimately pushes the cell from a resting to an activated state.

When a pattern-recognition receptor, such as a TLR, on the surface of a white blood cell binds to its antigen, it triggers a signal cascade within the cell that will orchestrate the most appropriate innate immune response (see Ch. 11, Section 11.3, for an introduction to signal transduction). What are some examples?

-When the Toll protein in wild-type fruit flies or TLR2 in humans binds to zymosan, a common molecule in fungi, a signal cascade activates the production and secretion of antimicrobial peptides, which destroy the fungal pathogens. -When human TLR4 is activated by LPS, a signal cascade leads to the production and secretion of cytokines ("cell-movers"). Cytokines are a class of diverse molecules that signal other immune system cells in various ways, such as increasing white blood cell production, attracting other immune cells to the site of infection, or stimulating other immune cells into action. -When TLR7 on a human white blood cell binds single-stranded viral RNA, the cell may produce and secrete a specific type of cytokine called an interferon. Interferons stimulate neighboring cells to produce proteins that interfere with viral replication, enabling those cells to resist viral infection.

Explain how antigens are recognized by receptors

1. Antigens are recognized by receptors on B cells and T cells. Each lymphocyte that matures in the bone marrow or thymus expresses a unique receptor on its surface that binds to a unique epitope in an antigen.

Explain Figure 48.15- Humoral Response Eliminates Extracellular Pathogens

1. Opsonization ("preparation for eating") Antibodies from plasma cells coat pathogens at the infection site. Pathogens that are coated with antibodies are readily destroyed by phagocytes. 2. Neutralization Coated pathogens are blocked from interacting with—and thus infecting—host cells. Their participation in the infection is neutralized. 3.Agglutination ("gluing together") In many cases, antibodies cause the clumping of antigens, including those on cells and viruses, via a process called agglutination. Each antibody has at least two binding sites (see Table 48.3), so a single antibody can bind epitopes on cells or viruses and cross-link them. Clumped cells and viruses cannot infect the cells of the body and are easy targets for phagocytes. 4.Co-stimulation of complement proteins Antibodies that are bound to pathogens also activate a lethal group of proteins called the complement system. Complement proteins circulate in the bloodstream and assemble at antigen-antibody complexes. When complement proteins are activated, they participate in activities that result in punching deadly holes in the plasma membranes of pathogens. Within a few days, this combination of killing mechanisms—armies of phagocytic cells and complement proteins that home in on antibody-tagged material—usually eliminates all of the extracellular pathogens.

The take-home message is that the adaptive immune response can recognize a seemingly limitless array of antigens. This observation, and subsequent research on antibody production, led to the identification of four key characteristics of adaptive immunity:

1.Specificity Antibodies and other components of the adaptive immune response bind only to specific sites on specific antigens. 2. Diversity The adaptive immune response can recognize and be activated by virtually any type of antigen. 3. Memory Adaptive immune responses are stronger and quicker when an individual is exposed to antigens encountered in previous infections. 4. Self-nonself recognition Molecules that are produced by the individual do not normally trigger a response, meaning that adaptive immunity can distinguish between self and nonself. Nonself molecules serve as antigens; self molecules do not.

What do BCRs consist of?

A BCR consists of two distinct polypeptides (Figure 48.5a). The smaller polypeptide is called the light chain. The larger polypeptide is roughly twice the size of the light chain and is called the heavy chain. Each BCR has two copies of the light chain and two copies of the heavy chain that are all held together by disulfide bonds (Ch. 3, Section 3.2). Each heavy chain includes a transmembrane domain that anchors the BCR in the plasma membrane of the B cell.

explain how activated lymphocytes are cloned

Activated lymphocytes are cloned. An activated lymphocyte divides, reenters the cell cycle, and thus makes many identical copies of itself. In this way, specific cells are selected and cloned in response to an infection.

What do class I and class II MHC proteins do?

Along with the class II MHC proteins, class I MHC proteins also are involved in the cell-mediated response. Recall that class I MHC proteins display peptides processed from cytosolic proteins (Section 48.3). This means that if a cell were infected, peptides from the foreign proteins present inside the cell would be loaded onto some of the class I MHC proteins and presented to circulating cytotoxic T cells.

What is clonal expansion?

An activated T cell divides repeatedly to produce genetically identical daughter cells. This event, called clonal expansion, is a crucial step in the adaptive immune response. It leads to a large population of lymphocytes (in this case, T cells) capable of responding specifically to the antigen that has entered the body. During clonal expansion, in addition to replication, the daughter T cells differentiate to become effector cells, undergoing many morphological changes that prepare them for their specific functional roles in the immune response.

What message do Antigen presenting dendrite cells carry?

Antigen-presenting dendritic cells carry a message to naive T cells saying, "I've found something. Is it foreign?" If a TCR binds, then the antigen is recognized as being foreign, and additional interactions between the dendritic cell and the T cell begin an activation process. In most cases, full activation of CD8+ T cells also requires cytokines produced by activated CD4+ T cells.

How do Lymphocytes Recognize a Diverse Array of Antigens

By the 1960s, biologists understood that B cells can produce antibodies to many different antigens, that each kind of B cell can synthesize only one kind of antibody, and that each antibody is specific to a particular antigen. The next question was: How do B cells receive the message to start making antibodies? Researchers hypothesized that each B cell formed in the bone marrow has thousands of copies of a receptor on its surface that, like its antibody, recognizes only one message—the antigen.

How are openings in the body protected?

As Figure 48.1 shows, openings in the outer surface of animal bodies are protected by an array of specialized secretions and structures that discourage pathogen entry.

What happens as lymphocyte matures?

As a lymphocyte matures, the various gene regions are randomly mixed and matched to produce unique receptors. Figure 48.8 illustrates the steps involved in the production of a BCR light chain. A similar process occurs in the DNA encoding a BCR heavy chain.

What are memory cells? What is the primary immune response?

Besides producing the cells that implement the humoral and cell-mediated responses, activated B cells and T cells produce specialized daughter cells called memory cells. Memory cells do not participate in the initial adaptive immune response—the primary immune response. Instead, they provide surveillance after the original infection has been cleared. Memory cells remain in the spleen and lymph nodes for years or decades, ready to mount a rapid response should an infection with the same antigen reoccur. The production of memory lymphocytes is a hallmark of the vertebrate immune response.

What do outer surfaces ensure?

Besides providing a physical barrier, outer surfaces also ensure a restrictive chemical environment. For example, the oil secreted by your skin cells is converted to fatty acids by bacteria that live harmlessly on your body. The fatty acids lower the pH of the skin's surface to about 5, creating an acidic environment that prevents the growth of most pathogens. Unless the protective exterior surface is broken by an injury, the places in animal bodies that are most vulnerable to pathogen entry are the openings in the surface where the digestive tract, reproductive tract, gas-exchange surfaces, and sensory organs contact the environment.

What is immunoglobulin (Ig)?

Both the BCRs and the antibodies produced by B cells belong to the immunoglobulin (Ig) family of proteins. Immunoglobulins are crucial to the adaptive immune response.

What do cells that display antigens do?

Cells that display the antigens of intracellular pathogens are effectively waving a flag that says, "I'm infected. If you destroy me, you'll destroy the infection." Elimination of the intracellular pathogens involves several steps (Figure 48.16).

What are the three general types of vaccines against viruses?

Consider the three general types of vaccines against viruses: 1. Subunit vaccines consist of isolated viral proteins. Familiar examples include vaccines against hepatitis B and influenza. Inactivated viruses have been damaged by chemical treatments—often exposure to formaldehyde—or exposure to ultraviolet light. They do not cause infections but are antigenic. If you have been vaccinated for hepatitis A or polio, you may have received an 2. inactivated virus. Human papilloma virus (HPV) vaccines are based on virus-like particles that are formed by HPV surface proteins. They are not infectious, because they lack the virus's DNA. 3. Attenuated viruses are also called "live" virus vaccines because they consist of complete virus particles that infect cells. Researchers make these viruses harmless by culturing them on cells from species other than the normal host. In adapting to the atypical cells, the viruses lose the ability to replicate rapidly in their normal host cells and are eliminated by the immune response before causing disease. The smallpox and measles vaccines consist of attenuated viruses.

Explain Figure 48.11

Dendritic cells take in antigens, break them into fragments, and present the fragments in the grooves of MHC proteins. This figure shows the process for class II MHC proteins. Figure 48.11 shows how dendritic cells process extracellular protein antigens and load the peptide fragments onto class II MHC proteins. (A similar loading process takes place for class I MHC proteins in the ER, but with antigens derived directly from the cytosol.)

What happens after self-reactive lymphoctycles are inactivated or removed?

Even after self-reactive lymphocytes are inactivated or removed, the structural diversity that remains in the receptors of mature B and T cells is sufficient for recognizing virtually any foreign antigen. But this diversity alone is not enough to mount an effective immune response. The enormous repertoire of possible BCRs and TCRs means that only a few cells will possess any particular epitope-specific receptor. To engage the invading pathogen successfully, these few lymphocytes must proliferate. How does this selective proliferation take place?

What are antibodies?

Experiments conducted in the early 1920s answered this question. Researchers synthesized organic compounds that do not exist in nature, injected the novel molecules into rabbits, and observed whether they activated the animals' adaptive immune response. To the scientists' amazement, the rabbits could recognize and respond to every novel antigen tested. Each rabbit produced proteins in its blood, called antibodies, that specifically bound to the particular antigen that was injected.

What is Hemmagglutinin?

Figure 48.7 illustrates the structure of a protein called hemagglutinin, which is found on the surface of the influenza virus (Ch. 33, Section 33.3). This protein is an antigen with several distinct epitopes. In hemagglutinin, as in many antigens, the epitopes recognized by BCRs and antibodies are different from those for TCRs because of how epitopes are presented: BCRs and antibodies bind to epitopes that are part of an intact antigen, while TCRs bind to epitopes that have been processed and presented by other cells. Each epitope is recognized by a particular BCR, antibody, or TCR. It is not unusual for an antigen to have between 10 and 100 epitopes.

What happens following activation and clonal expansion?

Following activation and clonal expansion, effector T cells leave the lymphatic system, enter the blood, and migrate to the site of infection.

How can glycoproteins affect the result of transfusions?

For example, if you have type A blood, it means that your red blood cells have the A glycoprotein. If your red blood cells are transfused into a person who lacks the A glycoprotein—meaning someone who has type B or type O blood—the recipient's immune system will recognize the A glycoprotein as an antigen and mount a response against it. For a transfusion to be successful, the recipient must be given blood that contains the same glycoproteins found on his or her own red blood cells or that lacks the A and B glycoproteins entirely (type O).

What are the light and heavy chains?

Further research showed that the light and heavy chains each consist of two regions: one whose amino acid sequence is virtually identical among different BCRs, and another whose sequence varies, forming a unique antigen-binding site. These regions are known as the constant (CC) region and variable (VV) region, respectively.

What happens to gaps in the body that are not covered with mucous layers?

Gaps in the body that are not covered with mucous layers are often protected by other types of secretions. For example, your ears are protected by waxy secretions, and your eyes are protected by tears that contain the enzyme lysozyme, which catalyzes the hydrolysis of the molecules that make up bacterial cell walls (Ch. 5, Section 5.2).

What is Gene Recombination response for?

Gene recombination is the molecular mechanism responsible for the specificity and diversity of the adaptive immune response. This process allows each lymphocyte to produce a unique BCR, antibody, or TCR—enabling it to recognize a unique epitope. The surface geometry of each variable region makes the interaction between an immunoglobin and its epitope extremely specific.

What is the Innate Immune Response?

If foreign invaders penetrate the body's protective barrier, the innate immune response is triggered—the body's first response to pathogens. The cells responsible for this response are a class of blood cells known as white blood cells, or leukocytes ("white-cells"), to distinguish them from the red blood cells that transport oxygen in vertebrates (Ch. 42, Section 42.4). The white blood cells involved in innate immunity provide an immediate, generic response that is directed against the general type of pathogen encountered. Don't let the term "generic" mislead you into thinking that the response is indiscriminant. Instead, innate immunity is considered generic because it is directed against broad groups of pathogens. For example, the innate immune response can distinguish between fungi and bacteria but cannot identify a specific strain within either group.

How Does the Immune system distinguish self from nonself?

If the immune system has the remarkable ability to generate specific, targeted responses against virtually any substance, what keeps it from reacting against an individual's own molecules? If a receptor responded to a self molecule—that is, a molecule belonging to the host—the receptor would trigger an immune response. Because this type of response is extremely rare compared to responses against foreign antigens, biologists hypothesized that there must be some mechanism for eliminating self-reactive B cells and T cells.

If a pathogen is able to replicate only inside host cells, then what happens?

If the pathogen is able to replicate only inside host cells, as is the case with viruses, this cell-mediated response limits the spread of the infection by preventing the production of new generations of pathogens.

The Second Response is Strong and Fast. Explain.

If the same antigen enters the body a second time, memory cells are able to recognize certain epitopes of the antigen and will trigger a second adaptive immune response, or secondary immune response. Figure 48.17 compares the rate of antibody production during the first and second exposures to a virus. The launching of a secondary immune response by means of memory cells is known as immunological memory.

How do Receptors and Antibodies bind to Epitopes?

Immunoglobulins (antibodies, BCRs, and TCRs) do not bind to entire antigens. Instead, they bind to a selected region of the antigen called an epitope. To understand the relationship between an antigen and an epitope, consider that every bacterium, virus, fungus, and protist is made up of a large number of different molecules. Many of these molecules serve as antigens because they would be recognized as being foreign to your cells. In other words, your cells do not synthesize such molecules. In turn, each antigen may have many different epitopes, where binding by lymphocyte receptors and antibodies takes place.

What is the adaptive immune response?

In addition to the innate immune response, vertebrates have evolved the ability to recognize specific antigens and to differentiate between different species and even different strains of pathogens. The response of white blood cells involved in this ability is customized to particular invaders, so this arm of the immune system is often referred to as the adaptive immune response.

What are helper T cells?

In contrast, the daughter cells of activated CD4+ T cells differentiate into effector cells called helper T cells (bottom left of Figure 48.12). The adjective "helper" is also appropriate: Helper T cells assist with the activation of other cells involved in the immune response. There are two types of helper T cells, designated TH1 and TH2, and they have distinct functions: TH1TH1 cells help activate cytotoxic T cells; TH2 cells help activate B cells. During the activation phase, the dendritic cell will often direct which type of helper T cell the CD4+ lymphocyte becomes. The outcome usually depends on which types of Toll-like receptors (TLRs) were activated in the dendritic cell at the site of infection.

What are major histocompatibility (MHC) proteins?

Recall that the receptors on T cells can bind only to epitopes that have been processed and presented on the surface of other cells. The surface proteins responsible for presenting these epitopes are called major histocompatibility (MHC) proteins. MHC proteins have a groove that binds to small epitope-containing antigen fragments that are typically 8 to 20 amino acids in length (see Figure 48.10).

Explain Figure 48.8

In the mature B cell depicted here, the final light-chain gene consists of the V12,V12, J3,J3, and CC segments joined together; the final heavy-chain gene might consist of the V48,V48, D22,D22, J1,J1, and CC segments joined together (not shown).

Explain Figure 48.10

In this class II MHC protein, an epitope-containing fragment processed from the hemagglutinin antigen (see Figure 48.7) fits into the epitope-binding groove like a hot dog in a bun. Two alpha helices (Ch. 3, Section 3.2) flank the epitope-binding groove. Class I MHC proteins have a similar binding groove.

Innate Immunity vs Adaptive Immunity

Innate immunity is so named because it is inherent in all animals and is ready to go from the moment of birth. In contrast, adaptive immunity occurs in only 1 percent of animals—the vertebrates—and in humans, it is not fully developed until 6 months after birth. Clearly, innate immunity on its own has succeeded in protecting a spectacular abundance and diversity of animals, both invertebrates and vertebrates. It is the first line of defense and includes exterior anatomical structures that protect animals from invading pathogens as well as systems for interior detection and responses.

Explain how the activation of B cells is a controlled process

It's important to note that activation of relevant B cells and T cells is a tightly controlled process. The mechanism is reminiscent of the precautions that nations with powerful missiles take to avoid accidental launches. For the most dangerous weapons, the signal to launch is checked and cross-checked, using a series of codes and signals. In the immune system, the checking and cross-checking occur through protein-protein interactions on the surfaces of cells, and the release and receipt of cytokines and other signaling molecules.

Do humans produce several proteins of each class?

It's important to note that humans have multiple genes encoding class I and class II MHC proteins. As a result, humans can produce several distinct proteins of each class that vary in the type of peptide that is presented. In addition, the MHC genes are among the most polymorphic of any genes known—meaning that many different alleles (Ch. 14, Section 14.2) exist in the population. Because so many distinct alleles exist, a wide array of peptides can be bound and presented—allowing dendritic cells to activate a response to many different pathogens. Also keep in mind that MHC class I proteins occur on all types of nucleated cells, not just cells of the immune system.

Where are lymphocytes found?

Large numbers of lymphocytes, as well as other white blood cells, are associated with the skin and with epithelial tissues that secrete mucus—primarily in the digestive and respiratory tracts. Collectively, the immune system cells found in these mucus-secreting tissues are called mucosa-associated lymphoid tissue (MALT). White blood cells in the skin and MALT are important because they surveil points of pathogen entry.

What is the inflammatory response in humans?

The appearance of your scraped elbow is a direct result of the innate immune response acting to promote tissue healing and repair, and to defend against infection. Figure 48.3 focuses on what happens if a wound becomes infected, and summarizes the major steps in an inflammatory ("in-flames") response—a multistep, innate immune response to trauma or infection observed in an array of animals. Note that this overview simplifies the situation—many other cell types and cell-cell signals are involved in responding to pathogens at a site of infection.

Explain Figure 48.13a and 48.13b

Like T cells, B cells undergo clonal expansion: They are replicated and undergo significant morphological changes when they are activated. As Figure 48.13a shows, inactive B cells have a large nucleus, little cytoplasm with few mitochondria, and a ruffled plasma membrane. Upon full activation, B cells produce a massive amount of rough ER and a large number of mitochondria (Figure 48.13b).

Explain Each part of Figure 48

Lymphocyte origin: All lymphocytes originate in bone marrow. The bone marrow is the major blood-forming organ in the human body, responsible for the production of red blood cells and white blood cells. It consists of soft lymphoid tissue that fills the internal cavities in bones. Lymphocyte maturation B: cells mature in the bone marrow in humans and many other animals. T cells mature in the thymus, which is located just behind the sternum (breastbone) in humans. Lymphocyte activation: Lymphocytes have receptors that allow them to recognize antigens and become activated in the spleen and lymph nodes. The spleen, an organ located near the stomach in the abdominal cavity, is also involved in destroying old red blood cells. Lymph nodes are small, oval organs that are located all around the body. Lymph nodes filter the lymph passing through them. Recall that lymph is a mixture of fluid and lymphocytes (Ch. 42, Section 42.5). The liquid portion of lymph originates in fluid that is forced out of capillaries by blood pressure. Lymphocyte transport: Lymphocytes circulate through the lymphatic system, which consists of the blood, bone marrow, lymph nodes, and other organs, such as the spleen, that are involved in the production, maturation, and activation of lymphocytes. Lymph is transported throughout the body via lymphatic vessels, which are thin-walled branching tubules.

What are the two types of MHC proteins?

MHC proteins come in two types, called class I and class II MHC proteins. Dendritic cells present peptides to naive T cells via both classes of MHC proteins, but the origins of the peptides differ for the two classes: The antigens that are processed and loaded onto class I MHC proteins are derived from the cell's interior, while those loaded onto class II MHC proteins are obtained from outside the cell. Class I MHC loading takes place inside the endoplasmic reticulum (ER); class II MHC proteins are loaded inside endosomes.

What are macrophages?

Macrophages kill foreign cells and, at the same time, process and present antigens to activate the adaptive immune response via class II MHC proteins. Macrophages display the processed peptides on their surfaces at the site of infection. If the class II MHC-peptide complex is recognized by a TH1 helper T cell, two things happen. First, the phagocytic activity of the macrophages is enhanced. Second, the TH1 cells secrete cytokines that recruit additional phagocytic cells to the site and activate cytotoxic T cells—increasing the inflammatory response.

Many of the proteins synthesized in a cell's rough ER are inserted into...

Many of the proteins synthesized in a cell's rough ER are inserted into the plasma membrane or secreted from the cell (Ch. 7, Section 7.5). The increased amount of rough ER in activated B cells is required for manufacturing and secreting antibodies.

What is the thymus?

Not long after this observation was published, three groups of scientists independently conducted a related experiment in mice. To explore the function of the thymus—an organ located in the upper part of the chest of vertebrates—these scientists removed the organ from newborn mice. Mice lacking a thymus developed pronounced defects in their immune systems. For example, when they received skin grafts from unrelated mice, their immune systems did not recognize the skin as foreign. In contrast, mice with an intact thymus quickly mounted an immune response that killed the foreign skin cells.

Table 48.2: Key Cells and Signaling Molecules of Innate Immunity

Note that Chemokines are a subset of cytokines

Once effector B and T cells have been activated, what happens?

Once effector B cells and T cells have been activated, the adaptive immune response is in full swing. Cytotoxic and helper T cells move into the site of infection, and plasma B cells begin releasing antibodies specific to the invading pathogen to circulate in the blood and lymph. The immune system has recognized the invaders and initiated its response.

What happens once the signal of invasion is received by TLRs?

Once the general signal of an invasion is received by TLRs, the first response is sent out, followed by a cascade of further actions that result in a fully engaged immune response. For example, consider what would happen if you were to trip on the sidewalk while running across campus and scrape your elbow. You would rapidly observe redness, swelling, and pain in the affected area. What is responsible for these changes?

What is TCR comprised of?

Other data showed that a TCR is composed of two protein chains: an alpha (α) chain and a beta (β) chain (Figure 48.5b). TCRs belong to the immunoglobulin family of proteins: their overall shape is similar to the shape of one of the two "arms" of an antibody or BCR, and the VV and CC regions of TCRs are arranged like those in BCRs.

Explain T-Cell Activation

Recall that as the innate immune response battles invaders at the site of an infection, dendritic cells gobble up antigens and debris via endocytosis (see Section 48.1). Dendritic cells collect information from the battle scene and then report to the lymph nodes, where they present antigens to T cells. Antigen presentation is a key event that links the innate and adaptive arms of the immune system. To understand how the activation system works, let's explore how antigens are taken up, processed, and presented to naive T cells—inactive T cells that have not yet encountered antigen—by dendritic cells. (Section 48.4 examines other types of immune cells that are involved in presenting antigens to activated T cells.)

How do regulatory T-cells limit the intensity of normal responses?

Researchers have also identified another type of T cell that can regulate immune responses. Regulatory T cells limit the intensity of normal responses by suppressing certain parts of the immune system, and they may help inhibit any self-reactive cells that slip through the self-education system. Defective or insufficient numbers of regulatory T cells may be partly responsible for the development of immune disorder diseases (see Section 48.5).

To review the adaptive immune response, including how B cells and T cells are activated, expanded, and differentiated into the various effector cells, study Table

Review table

Explain an adaptive immune response to MHC Proteins?

Similar problems arise in tissue and organ transplants, except that the molecules directing rejection are the class I MHC proteins. There is an adaptive immune response against the foreign MHC proteins, and the innate immune response is activated based on the absence of "self MHC" signals. If transplanted cells do not display the same class I MHC proteins as host cells, components of innate immunity kill them.

What are the steps for inflammatory response in humans?

Step 1: A break in the skin allows pathogens to enter the body. Step 2: If capillaries and other small blood vessels are broken, blood components called platelets immediately release proteins that participate in the reactions that lead to the formation of clots and lessen bleeding. Other clotting proteins in the blood form cross-linked structures that help wall off the wound and reduce blood loss. Step 3: Wounded tissues and white blood cells called macrophages secrete chemokines, which are a class of small cytokines that recruit other cells to the site of injury and infection. The localized production of chemokines is important because it forms a gradient that marks a path to the wound site. Step 4: Other white blood cells, called mast cells, release chemical messengers such as histamine that induce blood vessels slightly farther from the wound to dilate and become more permeable. Step 5; The combination of dilated blood vessels and a chemokine gradient is like a 911 call reporting a building on fire. White blood cells called neutrophils move out of dilated blood vessels and migrate to the site of the infection. Neutrophils destroy invading cells by engulfing them, a process called phagocytosis (see the micrograph at the start of the chapter, and Ch. 7, Section 7.5). Cells that perform phagocytosis are collectively referred to as phagocytes. Once inside neutrophils, the invading cells are killed by a complex array of antimicrobial compounds, including lysozyme. Step 6Other white blood cells arrive at the wound, where they mature into macrophages. Besides secreting chemokines, these new macrophages produce additional cytokines that have an array of effects: stimulating bone marrow to make and release additional white blood cells, inducing fever—an elevated body temperature that aids in healing—and activating cells involved in tissue repair and wound healing. Macrophages also act as phagocytes, helping to clear invading cells from the area.

Explain the Steps in Figure 48.16

Step 1: As cytotoxic T cells migrate into the area, those that recognize the class I MHC-peptide complex are stimulated to respond to the signal. Step 2: After cytotoxic T cells recognize an infected target, they form a tight attachment that directs the secretion of molecules from the T cell to the target cell's surface. Adjacent cells are not exposed. Some of the molecules are proteins that assemble into pores in the target cell's plasma membrane. These pores allow other proteins from the T cell to pass directly into the cytoplasm of the target cell. Step 3: Once in the cytoplasm, the T cell proteins activate a signaling cascade that causes the target cell to self-destruct via apoptosis (Ch. 21, Section 21.4). The result of apoptosis is the death and fragmentation of a cell into smaller vesicles, called apoptotic bodies, which are ingested by phagocytes like macrophages. Once the cytotoxic T cell has delivered this signal, often referred to as the "kiss of death," the T cell releases the dying cell and binds to another infected cell. Over time, all the infected cells are eliminated.

Explain Steps 1-5

Step 1: Dendritic cells ingest antigens at a site of infection by endocytosis. Step 2: In one common pathway, the antigen is moved from the endocytic vesicle to an endosome, where an enzyme complex catalyzes the hydrolysis of antigen proteins into small peptide fragments (Ch. 7, Section 7.5). Step 3: Some of the peptides are bound to the grooves of class II MHC proteins, which were made in the rough ER and transported to the endosome. Step 4: The MHC-peptide complexes are exported from the endosomes into vesicles for transport to the cell surface. Step 5:The vesicles fuse with the plasma membrane, resulting in MHC-peptide complexes being displayed on the cell surface.

What are Barriers to Entry?

The most effective way for animals to avoid getting an infection is to prevent pathogens from entering their bodies in the first place. In humans and many other animals, the most important deterrent to infection is the exterior surface.

The activation process that leads to these changes involves several steps and stimulation by TH2 helper T cells (Figure 48.14):

Step 1: The BCRs on B cells interact directly with antigens that are floating free in lymph or blood. This interaction results in the first part of B-cell activation. The bound antigen is internalized and digested into fragments, which are then loaded onto class II MHC proteins. As a result, a B cell that encounters its antigen displays peptide epitopes of the antigen cradled in class II MHC proteins on its own surface. Step 2: When a TH2TH2 helper T cell with a complementary receptor arrives, it binds to the MHC-peptide complex on the antigen-presenting B cell. This binding triggers activation signals that stimulate the helper T cell. Step 3: The TH2TH2 helper T cell responds by releasing cytokines that trigger the second part of B-cell activation. Step 4: The now fully activated B cell replicates, and some of the daughter cells differentiate into effector B cells called plasma cells. (Other activated B cells become memory cells, see Section 48.4). Plasma cells produce and secrete large numbers of antibodies. Recall that antibodies are identical to B-cell receptors, except that they lack a transmembrane domain and are secreted instead of being inserted into the plasma membrane (see Figure 48.6).

How are Naive T Cells Activated by Antigen Presenting Dendritic Cells?

T cells are classified as CD4+ or CD8+, based on whether they have proteins called CD4 or CD8 on their plasma membranes. CD4+CD4+ T cells and CD8+ T cells have distinct functions in the adaptive immune response. Figure 48.12 illustrates what happens when either type of naive (inactive) T cell recognizes an MHC-peptide complex on a dendritic cell. CD4+ T cells interact with class II MHC-bound epitopes on dendritic cells; CD8+ T cells interact with class I MHC-bound epitopes.

What are the five classes of immunoglobulins?

Table 48.3 shows the five classes of immunoglobulins that act as antibodies: IgG, IgE, IgD, IgA, and IgM. Each class is distinguished by unique amino acid sequences in the heavy chains, and each has a distinct function in the immune response. Besides acting as antibodies, IgD and monomeric forms of IgM also serve as BCRs.

How Are Intracellular Pathogens Eliminated?

The Cell-Mediated Response Recall that the innate immune response includes dendritic cells and macrophages, both of which can ingest some of the invaders at the site of infection (Section 48.1). Antigen-presenting dendritic cells then activate naive T cells in the lymph nodes, which differentiate into helper T cells, including cytotoxic T cells (see Figure 48.12).

Explain how B cells produce antibodies?

The antibodies produced by a B cell are identical in structure to its BCR, except that they lack the transmembrane domains. Instead of being inserted into the plasma membrane, antibodies are secreted from the cell and circulate via blood and lymph throughout the body (Figure 48.6).

Where are lymphocytes found?

The colored structures in Figure 48.4 mark the major sites in the human body that play key roles in the life of lymphocytes.

What is the clonal selection theory?

The diversity of the adaptive response is useful only if it can be directed against an infection. In the 1950s, Frank Bernet and colleagues developed the clonal selection theory to explain how only the most useful lymphocytes are activated during an infection. Their theory proposed four key points about the adaptive immune response (illustrated in Figure 48.9 using a B cell model):

Explain Figure 48.7

The envelope of the influenza virus (left) includes the protein hemagglutinin. As shown in the two space-filling models (right), each hemagglutinin monomer has several epitopes (indicated by different colors) for BCRs and antibodies, which are distinct from those for TCRs.

Gene of light chains have how many different variables?

The flurry of studies inspired by Tonegawa's result showed that the gene for light chains has dozens of different variable (V) segments, several different joining (JJ) segments, and a single constant (C) segment. The heavy-chain gene includes diversity (D) segments along with a set of V and J segments similar to those in the light-chain gene. The genes that encode the α and β chains of the TCR have a similar arrangement of distinct segments, each with multiple versions.

How are extracellular pathogens exlimanted?

The humoral response Recall that once a B cell recognizes an invader and is activated by TH2TH2 helper T cells, the activated B cell replicates and differentiates into plasma cells (see Figure 48.14). Antibodies from the plasma cells then begin attaching to extracellular bacteria, fungi, viruses, and other foreign material. These bound antibodies interfere with the infection in four ways (Figure 48.15):

For how long does the inflammatory response continue?

The inflammatory response continues until all foreign material is eliminated and the wound is repaired. But what happens when the innate immune response fails to contain and eliminate invading pathogens? Most invertebrates would be overcome by the infection and die, but vertebrates are protected by additional defenses. White blood cells known as dendritic ("tree-like") cells capture antigens and debris from the site of infection by endocytosis (Ch. 7, Section 7.5), in particular by macropinocytosis ("large-cell-drinking")—uptake of liquids and small particles into a vesicle—phagocytosis, and receptor-mediated endocytosis. They present this information to cells that confer adaptive immunity, acting as messengers between the innate immune response and the adaptive immune response (see Section 48.3). Without this transfer of information, the adaptive immune response would not be activated to respond to the infection.

Why does the immune system reject foreign tissues and organs?

The innate and adaptive immune responses have devastating effects on invading pathogens. Unfortunately, they are equally deadly in their responses to tissues or organs that are introduced into a patient to heal a wound or cure a disease. Consider the problems that can arise with blood transfusions. You might recall that certain individuals have red blood cells with membrane glycoproteins called A and B (Ch. 14, Section 14.5). These molecules act as antigens if they are introduced into a person whose own blood cells lack those glycoproteins.

What are humoral (immune) response and cell mediated (immune) response?

The many different mechanisms used by adaptive immunity to dispose of foreign invaders are broadly grouped into two responses: 1. The humoral (immune) response is promoted by TH2TH2 cells and involves the production of antibodies and other proteins secreted into the blood and lymph by activated B cells. (The Latin root humor means "fluid.") 2.The cell-mediated (immune) response is promoted by TH1TH1 cells and involves the activation of phagocytic cells and cytotoxic T cells (activated CD8+CD8+ cells), among others. This response primarily takes place via cell-cell contact.

How does mucus protect the surface of soft-bodied invertebrates?

The mucus that protects the surface of soft-bodied invertebrates is equally important in protecting the surface openings in vertebrates. For example, many of the pathogens that you breathe in or ingest while eating or drinking stick to the mucus that lines your airways and digestive tract. Pathogens that are stuck in mucus cannot come in contact with the plasma membranes of epithelial cells. Many of these pathogens are swept out of the respiratory tract by the beating of moveable cellular structures called cilia (Ch. 7, Section 7.6). They are then either coughed out or swallowed and killed in the acidic environment of the stomach.

How do BCR, antibody, and TCR proteins recognize specific epitopes?

The presence of unique amino acid sequences in the VV regions of every BCR, antibody, and TCR (see Figure 48.5) explains why each of these proteins binds to a unique epitope. Your body can respond to an almost limitless number of antigens because the number of different BCRs, antibodies, and TCRs is virtually limitless. How does all this variation come to be?

How does vaccination lead to immunological memory?

The production and effectiveness of memory cells explain phenomena that have been observed throughout recorded history. For example, in the middle ages, Chinese and Turkish practitioners protected people from the smallpox virus (Ch. 33, Section 33.4) by intentionally exposing them to the dried crusts of smallpox pustules taken from infected individuals. This procedure is an example of immunization—the conferring of immunity to a particular disease.

Explain Figure 48.17

The two curves summarize results that are commonly observed when biologists inject the same antigen into a mouse at two different times and measure the concentration of antibodies to that antigen in the blood. The change in antibody concentration (plotted on a logarithmic scale) over time indicates the strength and speed of the response to the antigen.

What are B cells? What are T cells?

The results of these experiments and follow-up experiments showed that lymphocytes from the bursa of Fabricius and the thymus have different functions. The bursa-dependent lymphocytes, or B cells, produce antibodies. The thymus-dependent lymphocytes, or T cells, are involved in graft rejection along with other immune functions, including recognizing and killing host cells that are infected with a virus. Later work showed that in humans and other species that have no bursa of Fabricius, B cells mature in bone marrow. T-cells mature in the thymus.

Is the secondary immune response faster and more efficient than the primary response?

The secondary immune response is faster and more efficient than the primary response. It is faster because the presence of memory T and B cells increases the number of lymphocytes that already have the correct antigen-specific receptors, thus decreasing the lag time for activating the adaptive immune response. It is more efficient because some of the memory B cells pass through another round of somatic hypermutation, the same process that occurred at the start of the primary immune response (see Section 48.3). Memory B cells with receptors that bind best to the antigen's epitopes live and produce daughter cells.

What happens when the immune system activates inappropriate responses?

The vertebrate immune system is a marvel of adaptation. A healthy immune system can defeat the vast majority of infections without medical intervention and with little impact on the body. The immune system is a formidable threat to pathogens, but if its response is dysfunctional, it can also be a liability to an animal's health and even survival.

What are lymphocytes?

The white blood cells that carry out the major features of the adaptive immune response are called lymphocytes. In contrast to the diversity of white blood cells involved in the innate immune response, lymphocytes are primarily divided into two distinct cell types that differ in their role in the adaptive immune response and their site of maturation.

If B and T cells have anti-receptors, what is likely to happen?

To test this hypothesis, researchers injected B cells and T cells possessing anti-self receptors into mice and found that the injected lymphocytes were eliminated. Follow-up work showed that if B cells and T cells maturing in the bone marrow and thymus have anti-self receptors, the cells are likely to be destroyed or permanently inactivated before they leave these organs. The conclusion? Some form of "self-education" occurs during the maturation of lymphocytes.

What are pattern-recognition receptors?

This breakthrough was key to understanding how the innate immune response could defend against a particular type of pathogen. Toll-like receptors (TLRs) are a subset of a larger group of proteins called pattern-recognition receptors, which serve as sentinels that detect the presence of molecules associated with pathogens and relay an alert signal to the cell. TLRs have also been observed in fungi and plants, suggesting that they arose in a common ancestor of all eukaryotes. Eleven TLRs (TLR1-TLR11) have been identified in humans, each one responding to one or more antigens. What all the antigens have in common is that they are ubiquitous within the broad group in which they have been identified (e.g., all of the vast number of Gram-negative bacteria produce LPS), yet they do not occur in the host animal. Thus, these antigens serve as reliable signals of attack for the innate immune system. A mere 11 TLRs in humans is enough to detect virtually any type of invasion.

Explain how the immune system rejects foreign cells

To prevent strong immune reactions against transplanted organs or tissues, physicians seek donors who have MHC proteins that are extremely similar to those of the recipient, as is often the case for siblings. Even with close relatives, however, molecular differences will exist between the donor and recipient. Thus, physicians must also treat the recipient with drugs that suppress the immune response. Thanks to steady improvements in drug development and in systems for matching MHC types between donors and recipients, the success rate for tissue and organ transplants has improved dramatically in recent years. As the transfusion and transplant examples show, the immune system rejects foreign cells because they either contain nonself molecules or lack self molecules. To your immune system, a mismatched blood transfusion or an organ transplant is indistinguishable from a massive influx of bacteria, viruses, or other foreign invaders.

What do B-Cell Receptors do?

To test the hypothesis that B cells have antigen-specific receptors on their surfaces, researchers injected experimental animals with radioactively labeled antigens. This strategy was similar to that of experiments with labeled estradiol that allowed biologists to isolate the estradiol receptor (Ch. 46, Section 46.2). As it turned out, the labeled antigens bound to a protein on the surface of only those B cells that produced antibodies to the antigen. Chemical analysis revealed that these surface proteins, now called B-cell receptors (BCRs), had the same overall structure as the antibodies that the B cells produced and secreted into the blood.

Explain how vaccination is effective against certain pathogens

To test this hypothesis, Jenner exposed a boy to fluid from a cowpox pustule. Later he exposed the same child to fluid from a smallpox pustule. As predicted, the boy did not contract smallpox. Jenner's technique was named vaccination, from the Latin root vacca, which means "cow" (Figure 48.18). Vaccination is the introduction of a vaccine, a preparation containing antigens from a weakened or altered pathogen. The vaccine mimics an infection, priming the body's immune system to effectively fight off later encounters with the unaltered pathogen. The data in Figure 48.17 explain why vaccination is an effective defense against certain pathogens—it speeds up the body's response to an infection. The antigens used in a vaccine are usually components of a pathogen's exterior because antibodies can readily attach to them.

What are Pattern-Recognition Receptors?

Transduces Signal: When a pattern-recognition receptor, such as a TLR, on the surface of a white blood cell binds to its antigen, it triggers a signal cascade within the cell that will orchestrate the most appropriate innate immune response (see Ch. 11, Section 11.3, for an introduction to signal transduction).

Do gene segments always join precisely?

What's more, gene segments do not always join precisely during recombination. Some variation occurs as to where the VV and DD and the DD and JJ segments join. As a result, an estimated 10^10 to 10^14 different BCRs can form in a single individual. TCR production is just as diverse.

What is somatic hypermutation?

When B cells are fully activated, they migrate to specialized areas in the lymph nodes and spleen called germinal centers. There, the DNA sequences that code for immunoglobulins (BCRs and antibodies) undergo rapid mutations that modify the variable regions. This process, called somatic hypermutation, is responsible for fine-tuning the adaptive immune response. Somatic hypermutation can generate BCRs that bind to the antigen more tightly than BCRs formed during B-cell maturation in the bone marrow. B cells with receptors that bind best to the free antigen live and produce daughter cells; those that bind to the antigen less effectively die. It's important to note that unlike germline mutation, somatic hypermutation affects only individual B cells, and the mutations are not transmitted to offspring.

What are cytotoxic T cells?

When activated CD8+ T cells undergo clonal expansion, the daughter cells develop into effector cells called cytotoxic ("cell-poison") T cells, also known as cytotoxic T lymphocytes (CTLs) or killer T cells (bottom right of Figure 48.12). The adjectives "cytotoxic" and "killer" are appropriate: Cytotoxic T cells kill cells that are infected with an intracellular pathogen.

How do pathogens gain entry?

When preventive measures fail, as they sometimes do, pathogens gain entry to animal tissues. Flu viruses, for example, have an enzyme on their surface that disrupts the mucous lining of the respiratory tract. When the outer surface of the virus contacts a host cell beneath the mucous layer, the virus can enter the cell and begin an infection. Wounds provide another important mode of entry. When the skin is broken, bacteria and other pathogens gain direct access to the tissues inside. To viruses, bacteria, and fungi, your body is an ecological paradise, brimming with resources. Given that a single bacterium could give rise to a population of 100 trillion in a day, something must be done, and fast, when the outer defenses of the body are penetrated. What happens then?

What is the activity of a lymphocyte?

lymphocytes are normally in a resting, or inactive, state. over the course of a day, an inactive lymphocyte may hang out in the skin or mucosa-associated lymphoid tissue (malt), enter the lymphatic vessels, migrate through a lymph node, cross over into the blood, pass through the spleen, return to the blood, and so on.

What are T-Receptor Cells?

t took much longer for researchers to isolate and characterize the T-cell receptor (TCR). The technique used to identify BCRs was not useful for the receptors on T cells, suggesting that TCRs cannot bind antigens on their own. It turns out that T cells require other cells to (1) process the antigens and (2) present them to the TCRs. This means that for a TCR to recognize an antigen, the foreign molecule must first undergo a complex process called antigen presentation. This is a fundamentally important distinction. B cells bind to antigens directly; T cells bind only to antigens that are displayed by other cells of the immune system or cells infected by a pathogen.

if an inactive lymphocyte does not encounter the epitope that it is programmed to respond to, what happens?

the cell eventually dies. as it turns out, this is the fate of most of the lymphocytes that originate from the bone marrow. during an infection, however, some of these inactive lymphocytes will go on to mount a massive attack that is targeted against the specific invader.

In combination with the [...] blood cells involved in [...] immunity, the cells of the adaptive immune response are almost always successful in eliminating threats from bacteria, fungi, viruses, and other parasites.

white, innate