Introduction to the Immune System

As the vertebrate immune system evolved, the network of lymphatic vessels became convenient avenues for transporting the cells of the immune system. Cells of the immune system not only use lymphatic vessels to make their way from interstitial spaces back into circulation, but they also use organs of the lymphatic system as major staging areas for the development of critical immune responses. The functioning of these systems allows our bodies to initiate and coordinate an immune response to remove cellular debris, bacteria, toxins, fungi, parasites, and viruses that accumulate in our bodies.

Let’s start our discussion by examining the Big Ideas of Human Biology and exploring some ways these Big Ideas may be seen in the functioning of the Lymphatic System and in Immunity. These ideas have been identified as common throughout the body systems and will provide secure footing as we continue to build our understanding of these key functions.

1. The processes that occur in living organisms follow the laws of physics and chemistry. When molecules and atoms leave tissues and enter the lymph vessels as lymph fluid, the driving forces behind those movements are chemical processes, namely osmosis and diffusion. Movement of the lymph fluid relies on capillary action as wells as differential changes in the pressure on the fluid inside the lymph vessels. The immune function of the lymphatic system uses the partial charges and shapes of larger biomolecules like proteins to determine the fit of a cell surface receptor for a variety of molecules. In the immune and lymphatic system recognition of histocompatibility markers by cell surface receptors and recognition of foreign antigen by the immune cells relies on these underlying properties of molecules
2. The cellis the basic unit of life.
   A key piece of the lymphatic and immune systems is the bone marrow, which produces white blood cells that can protect the body by attacking pathogens that have entered the blood stream. The bone marrow contains stem cells which are not only capable of replication but remain multi-potent. The division of the stem cells and further differentiation of those daughter cells into functioning cells of the immune system allows the body to defend against foreign invaders as well as monitor cells which may have change and are growing in way which could disrupt homeostasis.
3. Life requiresinformation flowwithin and between cells and between the environment and the organism.
   The cornerstone of the immune system is its ability to distinguish self from non-self, in the molecular sense. Once the recognition has occurred, multiple waves of information within the cells and between cells take place, mobilizing immune cells and provoking changes in them in order to attack and destroy the invader. In addition, damaged tissues and cells release signaling molecules which activate not only other cells but also protein cascades which promote blood clotting, wound healing and activation of a several kinds of cells which may be involved in the immune response.
4. Living organisms must obtain matter and energy from the external world. Matter and energy are transformed and transferred in different ways to build the organism and to perform work.
   Energy ingested and digested can be stored as high energy molecules like ATP but can also be used to construct large biological molecules like those found in and on cell membranes, as well as RNA and DNA. Cell functioning requires proper transcription and translation of the DNA and well as accurate replication of the DNA when the cell divides–in other words, the DNA runs the machinery of the cell. In the lymphatic system that energy is used for the replication of cells to build and maintain the lymphatic vessels, the cells of the immune system which fight pathogens directly and the cellular manufacture of antibodies which are proteins and require energy for their manufacture. Additionally, some degree of fever is beneficial for the immune response as it enhances metabolism, and that way increases the activity of the cells.
5. Homeostasis (and “stability” in a more general sense) maintains the internal environment in a more or less constant state compatible with life.
   The lymphatic system contributes to homeostasis in several ways. The lymph and lymph vessels drain away excess fluid and molecules which could contribute to edema and swelling disrupting tissue integrity. The immune response helps to neutralize pathogens which may not only disrupt homeostasis on a local tissue level but could result in a systemic disruption as well. Likewise, loss of control of lymphatic functions which would normally contribute to maintaining homeostasis can also lead themselves to a disruption of homeostasis. Inflammation should stop as soon as it is not necessary anymore, because the presence of those powerful molecules may cause damage to tissues. Many conditions are caused by an inflammatory process that goes on, such as rheumatoid arthritis or Crohn’s disease.
6. Understanding the functioning of the human body requires understanding the relationship betweenstructure and function(at each and every level of organization).
   Lymphatic vessels have larger openings than blood vessels allowing them to pick up and transport larger molecules back to blood circulation. B lymphocytes with a small cytoplasm become, upon the right stimulus, plasma cells with large amounts of rough endoplasmic reticulum churning out amazing amounts of antibodies. A set of small plasma proteins, called complement, self-assemble to form a deadly ring that opens a hole in the membranes of invading cells. Lymph nodes and and the spleen have much larger total cross-sectional areas than the vessels feeding into them. This structural arrangement decreases the velocity of flow through these structures, providing more time to detect and react with foreign pathogens.
7. Living organisms carry out functions at many different levels of organization simultaneously (at the same time).
   Generally speaking the molecules of the immune system, antibodies, complement, cell surface receptors, cell recognition molecules and pathogen recognition molecules stimulate a response within the appropriate cells of the immune system. The cellular immune responses may result in changes to the affected tissues such those found associated with the inflammatory response. The lymph fluids, lymph vessels and other specialized lymph structures continue to support the immune response while also providing a means for the tissues to remove excess fluids, cellular debris and dead and dying cells and pathogens.
8. All life exists within anecosystemmade up of the physiochemical and biological worlds.
   The body can be viewed as interacting with two ecosystems, 1) the external ecosystem of the world around us and 2) the internal ecosystem, which contains symbiotic bacteria and in which your cells and tissues must function. The lymphatic system serves at the interface of both those ecosystems. The immune function modulates the impact that other organisms living in the external ecosystem may have as pathogens. The lymphatic impact on the internal ecosystem involves not only immune function but includes the inflammatory response to tissue injury, the transport of large lipid molecules away from the digestive system and helping to maintain fluid and molecular balances for a healthy internal ecosystem.
9. Evolution provides a scientific explanation for the history of life on Earth and the mechanisms by which changes to life have occurred.
   The lymphatic and immune systems have become more complex during evolution. But even in the context of the immune response, we can observe examples of evolutionary changes. For one, many microbes mutate (change) in a short time, provoking the immune system to develop a new response each time (ever wondered why you need a new flu shot every year?) On the other hand, the antibodies produced during the immune response can also be switched to be complementary to new antigens, resulting in more effective antibodies. Humans live with organisms inside their internal environment as well as free-living organisms found in the external environment. Random mutation in genetic material is the source for change in an organism or species. Most mutations are either neutral or deleterious. A very small percentage of mutations result in a new trait or character which allows that organism to thrive in a changing environment. Organisms that have rapid reproductive cycles can change much more quickly as a species than organisms that have a long reproductive cycle. In bacteria, the reproductive cycle is often hours compared to humans which may be 20+ years. The lymphatic system can adapt to changes in pathogenic organisms by rearranging the genes used to make antibodies, activating a different clone of lymphocytes, or altering the expression of cell surface molecules on white blood cells.

Our body is in constant exchange with the environment through breathing, eating, and other activities. Therefore, it is important to screen the body and its components regularly to identify foreign invaders that might enter during these activities (or in any other manner). Further, it is important to rapidly and effectively remove these invaders before they can cause significant harm. Our body has specialized transport systems to carry out these functions. The cardiovascular and lymphatic systems work together to transport excess fluids (blood and lymph fluid, respectively) away from body tissues. The cardiovascular and lymphatic systems also participate in the function of immunity, helping defend the body’s cells from foreign organisms that may enter the body tissues or fluids.

Structure and Function of the Immune System

The human immune system is a complex, multilayered system for defending against external and internal threats to the integrity of the body. The environment consists of numerous pathogens, which are agents that cause disease in their hosts. A host is an organism that is invaded and often harmed by a pathogen. Pathogens include bacteria, protists, fungi, and other infectious organisms. We are constantly exposed to pathogens in food and water, on surfaces, and in the air. Mammalian immune systems evolved for protection from such pathogens; they are composed of an extremely diverse array of specialized cells and soluble molecules that coordinate a rapid and flexible defense system capable of providing protection from a majority of these disease agents.

The Organization of Immune Function

Components of the immune system constantly search the body for signs of pathogens. When pathogens are found, immune factors are mobilized to the site of an infection. The immune factors identify the nature of the pathogen, strengthen the corresponding cells and molecules to combat it efficiently, and then halt the immune response after the infection is cleared to avoid unnecessary host cell damage. The immune system can remember pathogens to which it has been exposed to create a more efficient response upon re-exposure. This memory can last several decades. Features of the immune system, such as pathogen identification, specific response, amplification, retreat, and remembrance are essential for survival against pathogens. The immune response can be classified as either innate or adaptive, although both arms of the immune system interact. The innate immune response is present at birth and is always active. It attempts to defend against all pathogens rather than focusing on specific ones. Conversely, the adaptive (or acquired) immune response stores information about past infections and mounts pathogen-specific defenses.

The immune system is a collection of barriers, cells, and soluble proteins that interact and communicate with each other in extraordinarily complex ways. The modern model of immune function is organized into three phases based on the timing of their effects. The three phases are the following:

• Barrier defenses such as the skin and mucous membranes act instantaneously to prevent pathogenic invasion into the body tissues
• The rapid but nonspecific innate immune response, which consists of a variety of specialized cells and soluble factors
• The slower but more specific and effective adaptive immune response, which involves many cell types and soluble factors, but is primarily controlled by white blood cells (leukocytes) known as lymphocytes, which help control immune responses.

The cells of the blood, including all those involved in the immune response, arise in the bone marrow via various differentiation pathways from hematopoietic stem cells. In contrast with embryonic stem cells, hematopoietic(heme = blood, poieo = create) stem cells are present throughout adulthood and allow for the continuous differentiation of blood cells to replace those lost to age or function. These cells can be divided into three classes based on function:

1. Phagocytic cells ingest pathogens to destroy them
2. Lymphocytes specifically coordinate the activities of adaptive immunity
3. Cells contain cytoplasmic granules that help mediate immune responses against parasites and intracellular pathogens such as viruses.

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 throughout 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. Using a process called extravasation (extra = out, vas = vessel), cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial (inter = between, stitium = place) space.

Innate Immunity

Innate immunity is not caused by an infection or vaccination and depends initially on physical and chemical barriers that work on all pathogens, sometimes called the first line of defense. The second line of defense of the innate system includes chemical signals that produce inflammation and fever responses. These molecules also mobilize protective cells and other chemical defenses. The adaptive immune system mounts a highly specific response to substances and organisms that do not belong in the body. The adaptive system takes longer to respond and has a memory system that allows it to respond with greater intensity should the body re-encounter a pathogen even years later.

External and Chemical Barriers

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 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 lysozyme, 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 (flora) 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 out-competing 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 protection of mucus or cilia.

The table below summarizes the body’s barrier defenses.

Internal Defenses

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 by reorganizing its cytoskeleton. 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.

The table below summarizes the role of various white blood cells in innate immunity.

When a pathogen is recognized as foreign, chemicals called cytokines are released. Acytokineis 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.

Interferons are one class of early-acting cytokines that are released by infected cells as a warning to nearby uninfected cells. Aninterferonis 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. Inflammation is a response to physical trauma, such as a cut or a blow, chemical irritation, and infection by pathogens (viruses, bacteria, or fungi) and is characterized by redness, swelling, heat, and pain. 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, the 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. Macrophages follow neutrophils and take over the phagocytosis function. They are involved in the repair of an inflamed site, cleaning up cell debris and pathogens.

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.

Natural Killer Cells

A lymphocyte is a white blood cell that contains a large nucleus. 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 class1 (MHC 1) molecules on the surface of infected cells. MHC class 1 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 1 protein on their cell surfaces.

The NK cell can detect abnormal cell surface molecules produced by virally infected and tumor cells. The NK cell then induces programmed cell death, or apoptosis. Phagocytic cells follow and digest the cellular debris left behind. NK cells are constantly patrolling the body and are an effective mechanism for controlling potential infections and preventing cancer progression.

Complement

An array of approximately 20 types of proteins, called the complement system, is also activated by infection and by the activity of the cells of the adaptive immune system. It functions to destroy extracellular pathogens. Liver cells and macrophages synthesize inactive forms of complement proteins continuously. These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. The complement system is so named because it is complementary to the innate and adaptive immune system. Complement proteins bind to the surfaces of microorganisms and are particularly attracted to pathogens that are already tagged by the adaptive immune system. This “tagging” involves the attachment of specific proteins called antibodies (discussed in detail later) to the pathogen. When they attach, the antibodies change shape providing a binding site for one of the complement proteins. After the first few complement proteins bind, a cascade of binding in a specific sequence of proteins follows in which the pathogen rapidly becomes coated in complement proteins.

Complement proteins perform several functions, one of which is to serve as a marker to indicate the presence of a pathogen to phagocytic cells and enhance engulfment. Certain complement proteins can combine to open pores in microbial cell membranes and cause lysis of the cells.

Summary
The innate immune system consists first of physical and chemical barriers to infection including the skin and mucous membranes and their secretions, ciliated surfaces, and body hairs. The second line of defense is an internal defense system designed to counter pathogenic threats that bypass the physical and chemical barriers of the body. Using a combination of cellular and molecular responses, the innate immune system identifies the nature of a pathogen and responds with inflammation, phagocytosis, cytokine release, destruction by NK cells, or the complement system.

Adaptive Immunity

The adaptive, or acquired, immune response takes days or even weeks to become established—much longer than the innate response; however, adaptive immunity is more specific to an invading pathogen. Adaptive immunity is immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. An antigen is a molecule that stimulates a response in the immune system. This part of the immune system is activated when the innate immune response is insufficient to control infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is controlled by activated T cells, and the humoral or antibody-mediated immune response, which is controlled by activated B cells and antibodies. Activated T and B cells whose surface binding sites are specific to the molecules on the pathogen greatly increase in numbers and attack the invading pathogen. Their attack can kill pathogens directly, or they can secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to give the host long-term protection from reinfection with the same type of pathogen; on re-exposure, this host memory will facilitate a rapid and powerful response.

B and T Cells
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. Whether an immature lymphocyte becomes a B cell or a 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. 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. Antigens that are present inside body cells are called endogenous or self-antigens. Foreign or exogenous antigens may be viral proteins produced after a virus infects the cell, toxins produced from intracellular bacteria, or abnormal proteins synthesized by a cancerous cell. When a peptide fragment comes from a self-protein, T cells ignore it.

The process of B and T cells becoming immunocompetent occurs during fetal development and continues throughout life. The specificity of the receptors 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 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.

Humoral (or Antibody)-Mediated Immune Response

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 the maturation of B cells, a set of highly specific B cells are produced that have many antigen receptor molecules in their membrane.

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 in turn direct the B cell to divide rapidly, which makes thousands of identical (clonal) cells via mitosis. This process is called clonal expansion. These daughter cells become either plasma cells or memory B cells. The memory B cells remain inactive at this point. If the same antigen is encountered in the future because of reinfection by the bacteria or virus, the memory B cell rapidly divides into a new population of plasma cells. During the initial infection, the plasma cells 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 bloodstream and lymphatic system and bind with the antigen whenever it is encountered. The binding can fight infection in five ways. First, antibodies can bind to viruses or bacteria and interfere with the chemical interactions required for them to infect or bind to other cells. Second, the antibodies may create bridges between different particles containing antigenic sites clumping them all together and preventing their proper functioning. Third, the antigen-antibody complex stimulates the complement system described previously, destroying the cell bearing the antigen. Fourth, 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 attacks.

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). 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 the 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 passive immunity, 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 anti-venom 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. Because the individual did not generate the antibodies, passive immunity is short-lived.

Cell-Mediated Immunity

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 pathogens activate them 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. 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.

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 cytotoxic T lymphocytes (T_C). The T_H lymphocytes function indirectly to tell other immune cells about potential pathogens.

Cytotoxic T cells (T_C) are the key component of the cell-mediated part of the adaptive immune system and attack and directly destroy infected cells. T_Ccells 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 clonal expansion of activated B cells. As with B cells, the clone includes active T_C cells and inactive memory T_Ccells. The resulting active T_Ccells 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_Ccells 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_H response that stimulates macrophages also stimulate T_Ccells 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 below.

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.

The table below summarizes the major cells that carry out the adaptive immune response.

Immunological Memory

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. 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 re-exposure 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 circulation.

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 that 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. 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.

Vaccination is based on the knowledge that exposure to noninfectious antigens derived from known pathogens generates a mild primary immune response. The host may not perceive the immune response to vaccination as an illness, but it still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to 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.

Summary

The adaptive immune response is a slower-acting, longer-lasting, and more specific response than the innate response. However, the adaptive response requires information from the innate immune system to function. APCs display antigens on MHC molecules to naïve T cells. T cells with cell-surface receptors that bind a specific antigen will bind to that APC. In response, the T cells differentiate and proliferate, becoming T_H cells or T_C cells. T_H cells stimulate B cells that have engulfed and presented pathogen-derived antigens. B cells differentiate into plasma cells that secrete antibodies, whereas T_C cells destroy infected or cancerous cells. Memory cells are produced by activated and proliferating B and T cells and persist after primary exposure to a pathogen. If re-exposure occurs, memory cells differentiate into effector cells without input from the innate immune system.

Homeostasis and Homeostatic Imbalances

The proper functioning of body cells depends on precise regulation of the composition of the interstitial fluid surrounding them. The composition of interstitial fluid changes as substances move back and forth between it and blood and lymph. In addition, some disruptions come from the external environment. Fortunately, the body has mechanisms to try to inhibit foreign substances from entering the internal environment of the body, and if they do get in, immune responses help to remove or neutralize the invader before the disruption leads to disease. Unfortunately, some factors or situations affecting the lymphatic system and immune responses could disrupt homeostasis.

Inflammatory Response and Clinical Disruptions of Homeostasis

Lymph Nodes
Lymph nodes play key roles in the body’s immune function. Lymph nodes filter harmful bacteria and other pathogens from the lymph, preventing them from reaching the blood and circulating throughout the body.

Sometimes, however, the lymph nodes and appendix become overwhelmed by these tasks, resulting in homeostatic imbalance. Lymph nodes can become swollen and tender as the pathogen they are designed to fight infect them and result in inflammation. This is a common symptom of many illnesses and is often (incorrectly) referred to as having “swollen glands.” Swollen lymph nodes often occur behind the ears, on the neck, near the jaw or chin, and in the armpits. Colds, the flu, tonsillitis, ear infections, and mononucleosis are common causes of this swelling. Although pain and tenderness associated with swollen lymph nodes typically diminish within a few days of onset, the swelling can last for several weeks after the onset of infection. After the infection has been eradicated from the body, the lymph nodes return to their normal size.

Appendix
The lymph tissue of the appendix helps control microbes in the colon from moving into the small intestine. Both of these structures activate the immune system to mount an attack against these pathogens.

Acute inflammation of the appendix, termed appendicitis, can be preceded by a number of possible causes. It is characterized by pain, high fever, and increased white blood count. The infection results in edema and ischemia and my progress to gangrene and perforation within 24 hours. Removal of the appendix may be recommended.

Ruptured SpleenCan Create Homeostatic Imbalances
Homeostatic imbalances can also afflict the spleen, another lymph organ. Although the ribs protect the spleen from trauma, direct blows to the left upper abdominal area or even severe infection can result in rupture. When this happens, the spleen spills blood into the peritoneal cavity. As a result, it has been customary for such injuries to result in splenectomy or total removal of the spleen to prevent excessive blood loss or further infection. In recent years, however, it has been found that the spleen has a significant capacity for self-repair. As a result, splenectomies have become less common, as doctors elect to leave part or all of damaged spleens in patients in the hopes the tissue will repair itself. In severe cases, when the spleen has completely ruptured and/or there is a high risk of infection, the spleen is still removed. The liver and bone marrow take over many of the spleen’s functions, although immune responses may be less robust in individuals without spleens.

Graft Versus Host Disease and Transplant Rejection
A bone marrow transplant is a procedure in which damaged or destroyed bone marrow (the soft, flexible tissue inside bones) is replaced with healthy bone marrow stem cells from a donor. Bone marrow is important because it is where blood cells—including lymphocytes—are produced. When bone marrow stem cells become damaged as a result of certain types of cancer, chemotherapy, aplastic anemia, or other diseases, a bone marrow transplant or stem cell transplant is needed so that the body can continue to produce blood cells.

Graft versus host disease (GVHD) occurs when a patient receives a stem cell or bone marrow transplant from someone who is not closely histocompatible. The transplanted material attacks the recipient’s body. As mentioned previously, bone marrow contains stem cells that produce white blood cells and other immune system cells. No two people, except identical twins, have the same tissue type. Therefore, each individual expresses unique proteins on their cells that are a unique subset of major histocompatibility complex (MHC) proteins. These unique proteins help signal to the T and B cells that the cells are yours and should not be attacked and destroyed. When a person receives a bone marrow transplant, they are receiving someone else’s immune cells. These cells may not recognize the host cells as their own. As a result, the new immune cells can attack the host cells, resulting in fever, weight loss, pain, rashes, and of primary concern, the patient becomes more vulnerable to infection. Immunosuppressant medication is typically given to patients in order to reduce the chances of GVHD developing. If GVHD does occur, it is treated with high doses of corticosteroids. GVHD occurs in about 30–40% of patients who receive donations from relatives and 60–80% of patients for whom the donor is not a relative.

Transplant rejection is a process in which the recipient’s immune system attacks a transplanted organ or tissue. For example, a person receiving a new kidney will require immunosuppressant drugs to prevent their immune cells from attacking and destroying the new, foreign kidney. Transplant rejection can be lessened by determining the MHC similarities between the donor tissue and the transplant recipient and trying to match them as closely as possible. Rejection is a cellular immune response via cytotoxic T cells inducing lysis of transplanted cells as well as an antibody-mediated response via activated B cells secreting antibodies. The actions of the adaptive immune responses are joined by components of innate immune responses via phagocytes and soluble immune proteins.

Imbalances of Immune Function

Autoimmune Disorders
Finally, a homeostatic imbalance can occur if the immune system fails to distinguish self from non-self, resulting in an attack on cells and organs by auto-antibodies and self-reactive T cells. The autoimmune disease appears to be caused by the failure of the tolerance processes to protect the host from the action of self-reactive lymphocytes. In an organ-specific autoimmune disease, the immune response is directed to an epitope unique to a single organ or gland. Hashimoto’s thyroiditis, insulin-dependent diabetes mellitus (pancreas), myasthenia gravis (acetylcholine receptors on muscles) and Crohn’s disease (GI) are examples of organ-specific autoimmune diseases. Autoimmune diseases can also be directed toward a broad range of epitopes and involve a number of organs and tissues. Systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis are examples of systemic autoimmune diseases. A variety of mechanisms have been proposed for the induction of autoimmunity, and evidence exists for each of these mechanisms. Indeed there may be different pathways leading to autoimmune reactions. Current treatments include immunosuppressive drugs, thymectomy, and plasmapheresis for diseases involving immune complexes. Also, blockers of some cytokines show success in several autoimmune diseases.

Systemic Lupus Erythematosus (SLE), or lupus, is an autoimmune disease that results from an improper immune cell balance. It is a chronic inflammatory immune disorder that results from an increase in a subset of helper T cells and an improper activation of B cells and macrophages. This results in the activation of B cells that produce antibodies targeting the nucleic acids in the cells of several organs in the body. Depending on the B cells that are activated, many different locations can be affected including the brain, digestive tract, heart, lungs, skin, or kidneys. Arthritis in the joints is a common symptom in patients with SLE.

SLE is more prevalent in women than in men. Symptoms can arise between the ages of 10 to 50 and range in severity. Depending on the affected organ, symptoms can include chest pain, headache, migraine, fever, fatigue, vomiting, arrhythmias, malaise, hair loss, mouth sores, and the characteristic butterfly skin rash. This rash occurs in about 50% of all cases. The cause (etiology) of SLE is still unknown and an active area of research. There is no cure for SLE, but in most patients, the disease can be managed, and the outcome (prognosis) for patients has been improving over the years.

Acquired Immunodeficiency Syndrome (AIDS)is caused by the retrovirus, the human immunodeficiency virus (HIV). HIV infects T cells. These T_H cells are also called CD₄⁺ cells because of the presence of the CD₄ protein on their surface. Once inside the cell, HIV hijacks the host transcriptional machinery to replicate the virus nucleic acids. After the nucleic acids have been replicated, the synthesis of virus proteins can occur. These newly synthesized viruses exit the cell and infect another T cell. In the process, HIV destroys the CD₄⁺ cells in the body. Once this population of immune cells is removed, the immune system of an infected person can no longer function properly.

Lymphoma
There are many types of cancer that affect either T or B cells. These are collectively called lymphomas. More than 30 types of lymphomas have been detected. Some are aggressive and fast-growing lymphomas, while others are less aggressive and slow growing. Lymphomas can arise at any age and occur within the germinal centers of lymph organs and nodes.

Allergy
An allergy or hypersensitivity reaction is an immune reaction to agents that are not normally harmful. These could be substances like strawberries, pollen, cat dander, or cockroach casings. Immediate hypersensitivities are allergic reactions that require prior exposure to the antigen. In this first exposure helper T cells produce IL-4, which drives the plasma cells to produce antibodies. Antibodies bind to receptors present on mast cells. Once enough antibodies are present on mast cells, exposure to the same antigen induces mast cells to respond with an inflammatory response that releases histamine, a chemical that increases the dilation of the lymph and blood vessels. In addition, histamine produces watery eyes, an itchy nose, and a cough. Delayed hypersensitivities take hours to days to develop and are caused by T cells. The most common types result from contact of a substance with the skin or mucous membranes. For example, poison ivy, soaps, and drugs can cause a delayed hypersensitivity reaction. The substance is absorbed by the epithelial cells, which are then destroyed by T cells. The inflammation and tissue destruction cause intense itching.

Immune Integration of Systems

All of the systems of the human body functioning together comprise the total human organism, the highest level of organization. All body systems influence and interact with one another. They work together to maintain health and provide protection from disease. Fluid balance allows for healthy circulation of substances throughout the body, optimal distances for the diffusion of ions and molecules, and proper ion concentration for excitable tissues. In addition, the lymphatic system helps protect the whole organism from the external invasion of foreign substances into the body that may cause disease and also removes damaged or worn-out body cells as a normal component of tissue repair and maintenance.

The following table highlights some of the lymphatic system’s interactions with several other body systems.

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“Learn By Doing” and “Did I Get This?” Feedback

Learn By Doing 17.6

In the diagram, where do pluripotent WBC stem cells come from?

• A: Incorrect. This is the thymus which is important for T cell maturation.
• B: Correct. The bone marrow contains pluripotent stem cells.
• C: Incorrect. This is the spleen; it functions to store mature white blood cells and serves as a reservoir for blood and red blood cells.
• D: Incorrect. Gut-associated lymphoid tissue (GALT) is diffuse active tissue.
• None of these choices: There is a correct answer.

In the diagram, where do T cells mature?

• A: Correct. T cells lines must spend some time in the thymus as part of the body’s MHC recognition system, which helps discern self from non-self.
• B: Incorrect. The bone marrow contains pluripotent stem cells, which are not yet capable of immune function.
• C: Incorrect. The white pulp of the spleen contains mature lymphocytes
• D: Incorrect. GALT is diffuse lymph tissue containing mature cells.
• None of these choices: There is a correct answer.

Where are T cell receptors that are self-directed deleted?

• thymus Correct. T cells lines must spend some time in the thymus as part of the body’s MHC recognition system, which helps discern self from non-self.
• lymph node
• lymph capillary
• bone marrow