Chapter20 The Lymphatic and Immune System

Lymphatic Capillaries

Lymphatic capillaries, also called the terminal lymphatics, are vessels where interstitial fluid enters the lymphatic system to become lymph fluid. Located in almost every tissue in the body, these vessels are interlaced among the arterioles and venules of the circulatory system in the soft connective tissues of the body (Figure 20.2). Exceptions are the central nervous system, bone marrow, bones, teeth, and the cornea of the eye, which do not contain lymph vessels.

Lymphatic capillaries are formed by a one-cell-thick layer of endothelial cells and represent the open end of the system, allowing interstitial fluid to flow into them via overlapping cells (see Figure 20.2). When interstitial pressure is low, the endothelial flaps close to prevent “backflow.” As interstitial pressure increases, the spaces between the cells open up, allowing the fluid to enter. Entry of fluid into lymphatic capillaries is also enabled by the collagen filaments that anchor the capillaries to surrounding structures. As interstitial pressure increases, the filaments pull on the endothelial cell flaps, opening them up even further to allow easy entry of fluid.

In the small intestine, lymphatic capillaries called lacteals are critical for the transport of dietary lipids and lipid-soluble vitamins to the bloodstream. In the small intestine, dietary triglycerides combine with other lipids and proteins and enter the lacteals to form a milky fluid called chyle. The chyle then travels through the lymphatic system, eventually entering the bloodstream.

Larger Lymphatic Vessels, Trunks, and Ducts

The lymphatic capillaries empty into larger lymphatic vessels, which are similar to veins in terms of their three-tunic structure and the presence of valves. These one-way valves are located fairly close to one another, and each one causes a bulge in the lymphatic vessel, giving the vessels a beaded appearance (see Figure 20.2).

The superficial and deep lymphatics eventually merge to form larger lymphatic vessels known as lymphatic trunks. On the right side of the body, the right sides of the head, thorax, and right upper limb drain lymph fluid into the right subclavian vein via the right lymphatic duct (Figure 20.3). The remaining portions of the left side of the body drain into the larger thoracic duct, which drains into the left subclavian vein. The thoracic duct itself begins just beneath the diaphragm in the cisterna chyli, a sac-like chamber that receives lymph from the lower abdomen, pelvis, and lower limbs by way of the left and right lumbar trunks and the intestinal trunk.

The overall drainage system of the body is asymmetrical (see Figure 20.3). The right lymphatic duct receives lymph from only the upper right side of the body. The lymph from the rest of the body enters the bloodstream through the thoracicduct via all the remaining lymphatic trunks. In general, the lymphatic vessels of the subcutaneous tissues of the skin—that is, the superficial lymphatics—follow the same routes as veins, whereas the deep lymphatic vessels of the viscera generally follow the paths of arteries.

B Cells

B cells are immune cells that function primarily by producing antibodies. An antibody is any of the group of proteins that binds specifically to pathogen-associated molecules known as antigens. An antigen is a chemical structure on the surface of a pathogen that binds to T or B lymphocyte antigen receptors. Once activated by binding to an antigen, B cells differentiate into cells that secrete a soluble form of their surface antibodies. These activated B cells are known as plasma cells.

T Cells

The T cell, on the other hand, does not secrete antibodies but performs a variety of functions in the adaptive immune response. Different T cell types have the ability to either secrete soluble factors that communicate with other cells of the adaptive immune response or destroy cells infected with intracellular pathogens. The roles of T and B lymphocytes in the adaptive immune response will be discussed further in this chapter.

Plasma Cells

Another type of lymphocyte of importance is the plasma cell. A plasma cell is a B cell that has differentiated in response to antigen binding and has thereby gained the ability to secrete soluble antibodies. These cells differ in morphology from standard B and T cells in that they contain a large amount of cytoplasm packed with the protein-synthesizing machinery known as rough endoplasmic reticulum.

Natural Killer Cells

A fourth important lymphocyte is the natural killer cell, a participant in the innate immune response. A natural killer (NK) cell is a circulating blood cell that contains cytotoxic (cell-killing) granules in its extensive cytoplasm. It shares this mechanism with the cytotoxic T cells (Tc) of the adaptive immune response. NK cells are among the body’s first lines of defence against viruses and certain types of cancer.

Bone Marrow

In the embryo, blood cells are made in the yolk sac. As development proceeds, this function is taken over by the spleen, lymph nodes, and liver. Later, the bone marrow takes over most hematopoietic functions, although the final stages of the differentiation of some cells may take place in other organs. The red bone marrow is a loose collection of cells where hematopoiesis occurs, and the yellow bone marrow is a site of energy storage, which consists largely of fat cells (Figure 20.5).

The B cell undergoes nearly all of its development in the red bone marrow, whereas the immature T cell, called a thymocyte, leaves the bone marrow and matures largely in the thymus gland.

Thymus

The thymus, also called the thymus gland, is a bilobed organ found in the space between the sternum and the aorta of the heart (Figure 20.6). Connective tissue holds the lobes closely together but also separates them and forms a capsule.

The connective tissue capsule further divides the thymus into lobules via extensions called trabeculae. The outer region of the organ is known as the cortex and contains large numbers of thymocytes with some epithelial cells, macrophages, and dendritic cells (two types of phagocytic cells that are derived from monocytes). The cortex is densely packed, so it stains more intensely than the rest of the thymus (see Figure 20.6). The medulla, where thymocytes migrate before leaving the thymus, contains a less dense collection of thymocytes, epithelial cells, and dendritic cells.

Lymph Nodes

Lymph nodes function to remove debris and pathogens from the lymph and are thus sometimes referred to as the “filters of the lymph” (Figure 20.7). Any bacteria that infect the interstitial fluid are taken up by the lymphatic capillaries and transported to a regional lymph node. Dendritic cells and macrophages within this organ internalize and kill many of the pathogens that pass through, thereby removing them from the body. The lymph node is also the site of adaptive immune responses mediated by T cells, B cells, and accessory cells of the adaptive immune system. Like the thymus, the bean-shaped lymph nodes are surrounded by a tough capsule of connective tissue and are separated into compartments by trabeculae, the extensions of the capsule. In addition to the structure provided by the capsule and trabeculae, the structural support of the lymph node is provided by a series of reticular fibres laid down by fibroblasts.

The major routes into the lymph node are via afferent lymphatic vessels (see Figure 20.7). Cells and lymph fluid that leave the lymph node may do so by another set of vessels known as the efferent lymphatic vessels. Lymph from afferent lymphatic vessels enters the lymph node via the subcapsular sinus, which is occupied by dendritic cells, macrophages, and reticular fibres. Within the cortex of the lymph node are lymphoid follicles, which consist of germinal centres of rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. As the lymph continues to flow through the node, it enters the medulla, which consists of medullary cords of B cells and plasma cells, and the medullary sinuses, where the lymph collects before leaving the node via the efferent lymphatic vessels.

Spleen

In addition to the lymph nodes, the spleen is a major secondary lymphoid organ (Figure 20.8). It is about 12 cm long and is attached to the lateral border of the stomach via the gastrosplenic ligament. The spleen is a fragile organ without a strong capsule and is dark red due to its extensive vascularization. The spleen is sometimes called the “filter of the blood” because of its extensive vascularization and the presence of macrophages and dendritic cells that remove microbes and other materials from the blood, including dying red blood cells. The spleen also functions as the location of immune responses to blood-borne pathogens.

The spleen is also divided by trabeculae of connective tissue, and within each splenic nodule is an area of red pulp, consisting of mostly red blood cells, and white pulp, which resembles the lymphoid follicles of the lymph nodes.

Upon entering the spleen, the splenic artery splits into several arterioles (surrounded by white pulp) and eventually into sinusoids. Blood from the capillaries subsequently collects in the venous sinuses and leaves via the splenic vein. The red pulp consists of reticular fibres with fixed macrophages attached, free macrophages, and all of the other cells typical of the blood, including some lymphocytes. The white pulp surrounds a central arteriole and consists of germinal centres of dividing B cells surrounded by T cells and accessory cells, including macrophages and dendritic cells. Thus, the red pulp primarily functions as a filtration system of the blood, using cells of the relatively nonspecific immune response, and white pulp is where adaptive T and B cell responses are mounted.

Lymphoid Nodules

The other lymphoid tissues, the lymphoid nodules, have a simpler architecture than the spleen and lymph nodes in that they consist of a dense cluster of lymphocytes without a surrounding fibrous capsule. These nodules are located in the respiratory and digestive tracts, areas routinely exposed to environmental pathogens.

Tonsils (specifically named the palatine, pharyngeal, and lingual tonsils) are lymphoid nodules located along the inner surface of the pharynx and are important in developing immunity to oral pathogens (Figure 20.9). The tonsil located at the back of the throat, the pharyngeal tonsil, is sometimes referred to as the adenoid when swollen. Such swelling is an indication of an active immune response to infection. Histologically, tonsils do not contain a complete capsule, and the epithelial layer invaginates deeply into the interior of the tonsil to form tonsillar crypts. These structures, which accumulate all sorts of materials taken into the body through eating and breathing, actually “encourage” pathogens to penetrate deep into the tonsillar tissues, where they are acted upon by numerous lymphoid follicles and eliminated. This seems to be the major function of tonsils—to help children’s bodies recognize, destroy, and develop immunity to common environmental pathogens so that they will be protected in their later lives. Tonsils are often removed in those children who have recurring throat infections, especially those involving the palatine tonsils on either side of the throat, whose swelling may interfere with their breathing and/or swallowing.

Mucosa-associated lymphoid tissue (MALT) consists of an aggregate of lymphoid follicles directly associated with the mucous membrane epithelia. MALT makes up dome-shaped structures found underlying the mucosa of the gastrointestinal tract, breast tissue, lungs, and eyes. Peyer’s patches, a type of MALT in the small intestine, are especially important for immune responses against ingested substances (Figure 20.10). Peyer’s patches contain specialized endothelial cells called M (or microfold) cells that sample material from the intestinal lumen and transport it to nearby follicles so that adaptive immune responses to potential pathogens can be mounted. A similar process occurs involving MALT in the mucosa and submucosa of the appendix. A blockage of the lumen triggers these cells to elicit an inflammatory response that can lead to appendicitis.

Bronchus-associated lymphoid tissue (BALT) consists of lymphoid follicular structures with an overlying epithelial layer found along the bifurcations of the bronchi and between bronchi and arteries. They also have the typically less-organized structure of other lymphoid nodules. These tissues, in addition to the tonsils, are effective against inhaled pathogens.

Phagocytes: Macrophages and Neutrophils

Many of the cells of the immune system have a phagocytic ability, at least at some point during their life cycles. Phagocytosis is an important and effective mechanism of destroying pathogens during innate immune responses. The phagocyte takes the organism inside itself as a phagosome, which subsequently fuses with a lysosome and its digestive enzymes, effectively killing many pathogens. On the other hand, some bacteria, including Mycobacterium tuberculosis, the cause of tuberculosis, may be resistant to these enzymes and are therefore much more difficult to clear from the body. Macrophages, neutrophils, and dendritic cells are the major phagocytes of the immune system.

A macrophage is an irregularly shaped phagocyte that is amoeboid in nature and is the most versatile of the phagocytes in the body. Macrophages move through tissues and squeeze through capillary walls using pseudopodia. They not only participate in innate immune responses but have also evolved to cooperate with lymphocytes as part of the adaptive immune response. Macrophages exist in many tissues of the body, either freely roaming through connective tissues or fixed to reticular fibres within specific tissues such as lymph nodes. When pathogens breach the body’s barrier defences, macrophages are the first line of defence (Table 20.3). They are called different names, depending on the tissue: Kupffer cells in the liver, histiocytes in connective tissue, and alveolar macrophages in the lungs.

A neutrophil is a phagocytic cell that is attracted via chemotaxis from the bloodstream to infected tissues. These spherical cells are granulocytes. A granulocyte contains cytoplasmic granules, which in turn contain a variety of vasoactive mediators such as histamine. In contrast, macrophages are agranulocytes. An agranulocyte has few or no cytoplasmic granules. Whereas macrophages act like sentries, always on guard against infection, neutrophils can be thought of as military reinforcements that are called into a battle to hasten the destruction of the enemy. Although usually thought of as the primary pathogen-killing cell of the inflammatory process of the innate immune response, new research has suggested that neutrophils play a role in the adaptive immune response as well, just as macrophages do.

A monocyte is a circulating precursor cell that differentiates into either a macrophage or a dendritic cell, which can be rapidly attracted to areas of infection by signal molecules of inflammation.

Natural Killer Cells

NK cells are a type of lymphocyte that have the ability to induce apoptosis—that is, programmed cell death—in cells infected with intracellular pathogens such as obligate intracellular bacteria and viruses. NK cells recognize these cells by mechanisms that are still not well understood but that presumably involve their surface receptors. NK cells can induce apoptosis, in which a cascade of events inside the cell causes its own death by either of two mechanisms:

1. 1. NK cells are able to respond to chemical signals and express the fas ligand. The fas ligand is a surface molecule that binds to the fas molecule on the surface of the infected cell, sending it apoptotic signals, thus killing the cell and the pathogen within it; or
2. 2. The granules of the NK cells release perforins and granzymes. A perforin is a protein that forms pores in the membranes of infected cells. A granzyme is a protein-digesting enzyme that enters the cell via the perforin pores and triggers apoptosis intracellularly.

Both mechanisms are especially effective against virally infected cells. If apoptosis is induced before the virus has the ability to synthesize and assemble all its components, no infectious virus will be released from the cell, thus preventing further infection.

Cytokines and Chemokines

A cytokine is a signalling molecule that allows cells to communicate with each other over short distances. Cytokines are secreted into the intercellular space, and the action of the cytokine induces the receiving cell to change its physiology. A chemokine is a soluble chemical mediator similar to cytokines except that its function is to attract cells (chemotaxis) from longer distances.

Early Induced Proteins

Early induced proteins are those that are not constitutively present in the body but are made as they are needed early during the innate immune response. Interferons are an example of early induced proteins. Cells infected with viruses secrete interferons that travel to adjacent cells and induce them to make antiviral proteins. Thus, even though the initial cell is sacrificed, the surrounding cells are protected. Other early induced proteins specific for bacterial cell wall components are mannose-binding protein and C-reactive protein, made in the liver, which bind specifically to polysaccharide components of the bacterial cell wall. Phagocytes such as macrophages have receptors for these proteins, and they are thus able to recognize them as they are bound to the bacteria. This brings the phagocyte and bacterium into close proximity and enhances the phagocytosis of the bacterium by the process known as opsonization. Opsonization is the tagging of a pathogen for phagocytosis by the binding of an antibody or an antimicrobial protein.

Complement System

The complement system is a series of proteins constitutively found in the blood plasma. As such, these proteins are not considered part of the early induced immune response, even though they share features with some of the antibacterial proteins of this class. Made in the liver, they have a variety of functions in the innate immune response, using what is known as the “alternate pathway” of complement activation. Additionally, the complement system functions in the adaptive immune response as well in what is called the classical pathway. The complement system consists of several proteins that enzymatically alter and fragment later proteins in a series, which is why it is termed cascade. Once activated, the series of reactions is irreversible and releases fragments that have the following actions:

• • Bind to the cell membrane of the pathogen that activates it, labelling it for phagocytosis (opsonization)
• • Diffuse away from the pathogen and act as chemotactic agents to attract phagocytic cells to the site of inflammation
• • Form damaging pores in the plasma membrane of the pathogen.

Primary Disease and Immunological Memory

The immune system’s first exposure to a pathogen is called a primary adaptive response. Symptoms of a first infection, called primary disease, are always relatively severe because it takes time for an initial adaptive immune response to a pathogen to become effective.

Upon reexposure to the same pathogen, a secondary adaptive immune response is generated, which is stronger and faster than the primary response. The secondary adaptive response often eliminates a pathogen before it can cause significant tissue damage or any symptoms. Without symptoms, there is no disease, and the individual is not even aware of the infection. This secondary response is the basis of immunological memory, which protects us from getting diseases repeatedly from the same pathogen. By this mechanism, an individual’s exposure to pathogens early in life spares the person from these diseases later in life.

Self-Recognition

A third important feature of the adaptive immune response is its ability to distinguish between self-antigens, those that are normally present in the body, and foreign antigens, those that might be on a potential pathogen. As T and B cells mature, there are mechanisms in place that prevent them from recognizing self-antigens, preventing a damaging immune response against the body. These mechanisms are not 100 percent effective, however, and their breakdown leads to autoimmune diseases, which will be discussed later in this chapter.

Antigen Processing and Presentation

The mechanism that T cells use to recognize antigens is complex. T cells do not recognize free-floating or cell-bound antigens as they appear on the surface of the pathogen. They only recognize antigens on the surface of specialized cells called antigen-presenting cells. Antigens are internalized by these cells. Antigen processing is a mechanism that enzymatically cleaves the antigen into smaller pieces. The antigen fragments are then brought to the cell’s surface and associated with a specialized type of antigen-presenting protein known as a major histocompatibility complex (MHC) molecule. The MHC proteins are encoded by a cluster of genes that encode these antigen-presenting molecules. The association of the antigen fragments with an MHC molecule on the surface of a cell is known as antigen presentation and results in the recognition of antigen by a T cell. This association of antigen and MHC occurs inside the cell, and it is the complex of the two that is brought to the surface. The peptide-binding cleft is a small indentation at the end of the MHC molecule that is farthest away from the cell membrane; it is here that the processed fragment of antigen sits. MHC molecules (which are specifically named class I MHC and class II MHC molecules) are capable of presenting a variety of antigens, depending on the amino acid sequence, in their peptide-binding clefts. It is the combination of the MHC molecule and the fragment of the original peptide or carbohydrate that is actually physically recognized by the T cell receptor (Figure 20.14).

Professional Antigen-Presenting Cells

Many cell types express class I molecules for the presentation of intracellular antigens. These MHC molecules may then stimulate a cytotoxic T cell immune response, eventually destroying the cell and the pathogen within. This is especially important when it comes to the most common class of intracellular pathogens, the virus. Viruses infect nearly every tissue of the body, so all these tissues must necessarily be able to express class I MHC or no T cell response can be made.

On the other hand, class II MHC molecules are expressed only on the cells of the immune system, specifically cells that affect other arms of the immune response. Thus, these cells are called “professional” antigen-presenting cells to distinguish them from those that bear class I MHC. The three types of professional antigen presenters are macrophages, dendritic cells, and B cells (Table 20.4).

Macrophages stimulate T cells to release cytokines that enhance phagocytosis. Dendritic cells also kill pathogens by phagocytosis (see Figure 20.14), but their major function is to bring antigens to regional draining lymph nodes. The lymph nodes are the locations in which most T cell responses against pathogens of the interstitial tissues are mounted. Macrophages are found in the skin and in the lining of mucosal surfaces, such as the nasopharynx, stomach, lungs, and intestines. B cells may also present antigens to T cells, which are necessary for certain types of antibody responses, to be covered later in this chapter.

Helper T Cells and Their Cytokines

Helper T cells (Th), bearing the CD4 molecule, function by secreting cytokines that act to enhance other immune responses. There are two classes of Th cells, and they act on different components of the immune response. These cells are distinguished not by their surface molecules but by the characteristic set of cytokines they secrete (Table 20.5).

Th1 cells are a type of helper T cell that secretes cytokines that regulate the immunological activity and development of a variety of cells, including macrophages and other types of T cells.

Th2 cells, on the other hand, are cytokine-secreting cells that act on B cells to drive their differentiation into plasma cells that make antibodies. In fact, T cell help is required for antibody responses to most protein antigens, and these are called T cell–dependent antigens.

Cytotoxic T cells

Cytotoxic T cells (Tc) are T cells that kill target cells by inducing apoptosis using the same mechanism as NK cells. They either express fas ligand, which binds to the fas molecule on the target cell, or act by using perforins and granzymes contained in their cytoplasmic granules. As was discussed earlier with NK cells, killing a virally infected cell before the virus can complete its replication cycle results in the production of no infectious particles. As more Tc cells are developed during an immune response, they overwhelm the ability of the virus to cause disease. In addition, each Tc cell can kill more than one target cell, making them especially effective. Tc cells are so important in the antiviral immune response that some speculate that this was the main reason the adaptive immune response evolved in the first place.

Regulatory T Cells

Regulatory T cells (Treg), or suppressor T cells, are the most recently discovered of the types listed here, so less is understood about them. In addition to CD4, they bear the molecules CD25 and FOXP3. Exactly how they function is still under investigation, but it is known that they suppress other T cell immune responses. This is an important feature of the immune response, because if clonal expansion during immune responses were allowed to continue uncontrolled, these responses could lead to autoimmune diseases and other medical issues.

Not only do T cells directly destroy pathogens, but they regulate nearly all other types of the adaptive immune response as well, as evidenced by the functions of the T cell types, their surface markers, the cells they work on, and the types of pathogens they work against (see Table 20.5).

Four-Chain Models of Antibody Structures

All antibody molecules have two identical heavy chains and two identical light chains. (Some antibodies contain multiple units of this four-chain structure.) The Fc region of the antibody is formed by the two heavy chains coming together, usually linked by disulfide bonds (Figure 20.16).

The Fc portion of the antibody is important in that many effector cells of the immune system have Fc receptors. Cells having these receptors can then bind to antibody-coated pathogens, greatly increasing the specificity of the effector cells. At the other end of the molecule are two identical antigen-binding sites.

Five Classes of Antibodies and Their Functions

In general, antibodies have two basic functions. They can act as the B cell antigen receptor, or they can be secreted, circulate, and bind to a pathogen, often labelling it for identification by other forms of the immune response. Of the five antibody classes, notice that only two can function as the antigen receptor for naive B cells: IgM and IgD (Table 20.6). Mature B cells that leave the bone marrow express both IgM and IgD, but both antibodies have the same antigen specificity. Only IgM is secreted, however, and no other nonreceptor function for IgD has been discovered.

IgM consists of five four-chain structures (20 total chains with 10 identical antigen-binding sites) and is thus the largest of the antibody molecules. IgM is usually the first antibody made during a primary response. Its 10 antigen-binding sites and large shape allow it to bind well to many bacterial surfaces. It is excellent at binding complement proteins and activating the complement cascade, consistent with its role in promoting chemotaxis, opsonization, and cell lysis. Thus, it is a very effective antibody against bacteria at early stages of a primary antibody response. As the primary response proceeds, the antibody produced in a B cell can change to IgG, IgA, or IgE by the process known as class switching. Class switching is the change of one antibody class to another. While the class of antibody changes, the specificity and the antigen-binding sites do not. Thus, the antibodies made are still specific to the pathogen that stimulated the initial IgM response.

IgG is a major antibody of late primary responses and the main antibody of secondary responses in the blood. This is because class switching occurs during primary responses. IgG is a monomeric antibody that clears pathogens from the blood and can activate complement proteins (although not as well as IgM), taking advantage of its antibacterial activities. Furthermore, this class of antibody is the one that crosses the placenta to protect the developing fetus from disease and exits the blood to the interstitial fluid to fight extracellular pathogens.

IgA exists in two forms, a four-chain monomer in the blood and an eight-chain structure, or dimer, in exocrine gland secretions of the mucous membranes, including mucus, saliva, and tears. Thus, dimeric IgA is the only antibody to leave the interior of the body to protect body surfaces. IgA is also of importance to newborns, because this antibody is present in the mother’s breast milk (colostrum), which serves to protect the infant from disease.

IgE is usually associated with allergies and anaphylaxis. It is present in the lowest concentration in the blood, because its Fc region binds strongly to an IgE-specific Fc receptor on the surfaces of mast cells. IgE makes mast cell degranulation very specific, such that if a person is allergic to peanuts, there will be peanut-specific IgE bound to their mast cells. In this person, eating peanuts will cause the mast cells to degranulate, sometimes causing severe allergic reactions, including anaphylaxis, a severe, systemic allergic response that can cause death.

Clonal Selection of B Cells

Clonal selection and expansion work in much the same way in B cells as in T cells. Only B cells with appropriate antigen specificity are selected for and expanded (Figure 20.17).

Eventually, the plasma cells secrete antibodies with antigenic specificity identical to those that were on the surfaces of the selected B cells. Notice in the figure that both plasma cells and memory B cells are generated simultaneously.

Primary Versus Secondary B Cell Responses

Primary and secondary responses as they relate to T cells were discussed in section 20.3 The Adaptive Immune Response: T Lymphocytes and Their Functional Types. This section will look at these responses with B cells and antibody production. Because antibodies are easily obtained from blood samples, they are easy to follow and graph (Figure 20.18). As you will see from the figure, the primary response to an antigen (representing a pathogen) is delayed by several days. This is the time it takes for the B cell clones to expand and differentiate into plasma cells. The level of antibody produced is low, but it is sufficient for immune protection. The second time a person encounters the same antigen, there is no time delay, and the amount of antibody made is much higher. Thus, the secondary antibody response overwhelms the pathogens quickly, and in most situations, no symptoms are felt. When a different antigen is used, another primary response is made with its low antibody levels and time delay.