11 Lymphatic and Immune Systems

• Thymus
  • The thymus gland, where T cells mature, is a bilobed organ found in the space between the sternum and the aorta of the heart (see Figure 11.4). Connective tissue holds the lobes closely together but also separates them and forms a capsule.
  • The loss of immune function with age is called immunosenescence. One major cause of age-related immune deficiencies is thymic involution.
    • The shrinking of the thymus gland begins at birth at a rate of about three percent tissue loss per year.  This shrinking continues until 35–45 years of age then the rate declines to about one percent loss per year for the rest of one’s life. At that pace, the total loss of thymic epithelial tissue and thymocytes would occur at about 120 years of age. So, in theory, 120 years could be the maximum life span.

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” (see Figure 11.6). 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.

Spleen

The spleen is a vascular organ that is somewhat fragile due to the absence of a capsule. It is about 12 cm long and is attached to the lateral border of the stomach. 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. (See Fig 11.6).

Lymphoid Nodules

The other lymphoid tissues, the lymphoid nodules, 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 are lymphoid nodules located along the inner surface of the pharynx and are important in developing immunity to oral pathogens (see Figure 11.7). 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. Tonsils have deep grooves called crypts, which accumulate all sorts of materials taken into the body through eating and breathing and actually “encourage” pathogens to penetrate deep into the tonsillar tissues where they are eliminated. A major function of tonsils is 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 children who have recurring throat infections since swollen palatine tonsils can interfere with breathing and/or swallowing.

Concept Check

Tonsils are named after their locations.

• Look at the figure above and determine which anatomical structure is closely associated with each set of tonsils and was therefore used to name the tonsils, for example, the lingual tonsils are named after the tongue (lingula).
• Can you tell which structures were used to name the palatine tonsils and the pharyngeal tonsils?

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Cells of the Innate Immune Response

Phagocytes: Macrophages and Neutrophils

A phagocyte is a cell that is able to surround and engulf a particle or cell, a process called phagocytosis. The phagocytes of the immune system engulf other particles or cells, either to clean an area of debris, old cells, or to kill pathogenic organisms such as bacteria. Macrophages, neutrophils, and dendritic cells are the major phagocytes of the immune system and are the body’s fast acting, front line immunological defense against organisms that have breached barrier defenses and have entered the body.

Macrophages 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 fibers within specific tissues such as lymph nodes. When pathogens breach the body’s barrier defenses, macrophages are the first line of defense.

A neutrophil is a phagocytic cell that is attracted via chemotaxis from the bloodstream to infected tissues. contains cytoplasmic granules, which in turn contain a variety of vasoactive mediators such as histamine. 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.

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

Cytokines and Chemokines

A cytokine is signaling 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.

Inflammatory Response

The hallmark of the innate immune response is inflammation. Stub a toe, cut a finger, or do any activity that causes tissue damage and inflammation will result, with its four characteristics: heat, redness, pain, and swelling (“loss of function” is sometimes mentioned as a fifth characteristic). It is important to note that inflammation does not have to be initiated by an infection, but can also be caused by tissue injuries. The release of damaged cellular contents into the site of injury is enough to stimulate the response, even in the absence of breaks in physical barriers that would allow pathogens to enter (by hitting your thumb with a hammer, for example). The inflammatory reaction brings in phagocytic cells to the damaged area to clear cellular debris and encourages the entry of clotting factors to set the stage for wound repair. Inflammation also facilitates the transport of antigen to lymph nodes by dendritic cells for the development of the adaptive immune response. (Fig. 11.8).

The above image summarizes the following events in the inflammatory response:

• • The released contents of injured cells stimulate the release of substances from mast cells including histamine, leukotrienes, and prostaglandins.

• • Histamine increases blood flow to the area by vasodilation, resulting in heat and redness. Histamine also increases the permeability of local capillaries, causing plasma to leak out and form interstitial fluid, resulting in swelling

• • Leukotrienes attract neutrophils from the blood by chemotaxis.
    When local infections are severe, neutrophils are attracted to the sites of infections in large numbers, and as they phagocytose the pathogens and subsequently die, their accumulated cellular remains are visible as pus at the infection site.

• • Prostaglandins cause vasodilation by relaxing vascular smooth muscle and are a major cause of the pain associated with inflammation. Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen relieve pain by inhibiting prostaglandin production.

Acute inflammation is a short-term innate immune response to an insult to the body. If the cause of the inflammation is not resolved, however, it can lead to chronic inflammation, which is associated with major tissue destruction and fibrosis.

Phase 3: Adaptive Immune Response

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Benefits of the Adaptive Immune Response

• Specificity
  • The ability to specifically recognize and mount a response against almost any pathogen.
  • Antigens, are recognized by receptors on the surface of B and T lymphocytes.

• Immunological Memory
  • The 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 re-exposure to the same pathogen, a secondary adaptive immune response is generated, which is stronger and faster that the primary response, often eliminating the pathogen before it can cause damage or even symptoms.
  • This secondary response is the basis of immunological memory, which gives us immunity.

As stated above, lymphocytes are the primary cells of adaptive immune responses. These cells were introduced in the previous chapter and are summarized in the following table:

Active Versus Passive Immunity

Immunity to pathogens, and the ability to control pathogen growth so that damage to the tissues of the body is limited, can be acquired by:

1. The active development of an immune response in the infected individual.
   or
2. The passive transfer of immune components from an immune individual to a non-immune one.

The downside to this passive immunity is the lack of the development of immunological memory. Once the antibodies are transferred, they are effective for only a limited time before they degrade.

Evasion of the Immune System by Pathogens

The immune system and pathogens are in a slow, evolutionary race to see who stays on top. Early childhood is a time when the body develops much of its immunological memory that protects it from diseases in adulthood. Pathogens have shown the ability, however, to evade the body’s immune responses, as described below.

• • Protective adaptations: It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example is in Mycobactrium tuberculosis, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis.

• • Multiple strains: Bacteria sometimes evade immune responses because they exist in multiple strains, each having different surface antigens and requiring individual adaptive immune responses. One example is a small group of strains of S. aureus, called methicillin-resistant Staphylococcus aureus (MRSA), which has become resistant to multiple antibiotics..

• • Antigen mutation: Because viruses’ surface molecules mutate continuously, viruses like influenza change enough each year that the flu vaccine for one year may not protect against the flu common to the next. New vaccine formulations must be derived for each flu season.

• • Genetic recombination: An example is the influenza virus, which contains gene segments that can recombine when two different viruses infect the same cell. Recombination between human and pig influenza viruses led to the 2010 H1N1 swine flu outbreak.

• • Immunosuppression: Pathogens, especially viruses, can produce immunosuppressive molecules that impair immune function.

Tissue Transplantation

Immunosuppressive drugs such as cyclosporine A have made transplants more successful, but tissue matching is still key. Family members, since they share a similar genetic background, are much more likely to share MHC molecules than unrelated individuals do.

One disease of transplantation occurs with bone marrow transplants, which are used to treat various diseases, including SCID and leukemia. Because the bone marrow cells being transplanted contain lymphocytes capable of mounting an immune response, and because the recipient’s immune response has been destroyed before receiving the transplant, the donor cells may attack the recipient tissues, causing graft-versus-host disease. Symptoms of this disease, which usually include a rash and damage to the liver and mucosa, are variable, and attempts have been made to moderate the disease by first removing mature T cells from the donor bone marrow before transplanting it.

Immune Responses Against Cancer

It is clear that with some cancers, like Kaposi’s sarcoma (see Figure 11.11), for example, that a healthy immune system does a good job at controlling them. This disease, which is caused by the human herpes virus, is almost never observed in individuals with strong immune systems. Other examples of cancers caused by viruses include liver cancer caused by the hepatitis B virus and cervical cancer caused by the human papilloma virus. As these last two viruses have vaccines available for them, getting vaccinated can help prevent these two types of cancer by stimulating the immune response.

On the other hand, as cancer cells are often able to divide and mutate rapidly, they may escape the immune response, just as certain pathogens such as HIV do.

There are three stages in the immune response to many cancers:

1. 1. Elimination occurs when the immune response first develops toward tumor-specific antigens specific to the cancer and actively kills most cancer cells.
   2. Equilibrium is the period that follows, during which the remaining cancer cells are held in check.
   3. Escape of the immune response, and resulting disease, occurs because many cancers mutate and no longer express any specific antigens for the immune system to respond to.

This fact has led to extensive research in trying to develop ways to enhance the early immune response to completely eliminate the early cancer and thus prevent a later escape. One method that has shown some success is the use of cancer vaccines. These differ from other vaccines in that they are directed against the cells of one’s own body. Treated cancer cells are injected into cancer patients to enhance their anti-cancer immune response and thereby prolong survival. The immune system has the capability to detect these cancer cells and proliferate faster than the cancer cells do, thus overwhelming the cancer in a similar way as they do for viruses. Cancer vaccines are being developed for malignant melanoma and renal (kidney) cell carcinoma.

Immune Responses and Stress

Underactive Immune System: Immunodeficiencies

Suppressed immunity can result from inherited genetic defects or by acquiring viruses (Betts, et al., 2021).

Inherited Immunodeficiencies/SCID

Hypersensitivities

The worst cases of the immune system over-reacting are autoimmune diseases in which the immune systems begin to attack cells of the patient’s own body, causing chronic inflammation and significant damage. The trigger for these diseases is often unknown, although environmental and genetic factors are likely involved. Treatments are usually based on resolving the symptoms using immunosuppressive and anti-inflammatory drugs. Figure 11.12 below provides two examples of autoimmune diseases: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (Betts, et al., 2021).

Overall, there are more than 80 different autoimmune diseases, which are a significant health problem in the elderly. Table 14.5 below lists several of the most common autoimmune diseases, the antigens that are targeted (autoantigen or “self” antigen), and the resulting tissue damage (Betts, et al., 2021).

Lymphoma

Lymphoma was briefly discussed in the previous chapter.