15.5: Immune Responses

Once macrophages, Langerhans cells, T cells, and B cells have developed, the immune system is ready to initiate immune responses. The system begins to monitor substances in the body in an attempt to detect foreign materials.

Immune responses and other immune system activities are regulated by signaling substances from the nervous system and endocrine system, and from the immune system cells themselves. Some regulating substances act at great distances from their sites of production, and others affect cells close to their sources. Like hormones, these signaling substances contact many cell types, yet they affect only certain cells and organs. Usually, the affected cells respond because they contain receptor molecules to which the signaling molecules bind.

Different cells exposed to the same amount of a signal respond to different degrees because they have fewer or more receptors or because their receptors bind weakly or strongly to the signal molecules. The strength of each target's response can be changed by modifying the number or binding strength of its receptors. The effectiveness of a signal can be influenced by conditions in the target cells. Finally, as with hormones, signal effectiveness can be influenced by rates of formation and elimination. Therefore, determining secretion rates or measuring concentrations of signaling substances provides only a small portion of the information needed to evaluate immune system performance. In this section, only a few of the signaling substances will be mentioned and only some of their main effects will be described.

Processing and Presentation

The macrophages perform this surveillance by phagocytizing microbes, viruses, and unusual molecules (Figure 15.3).

Figure 15.3 Processing and presentation of antigens. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

(1) Macrophages (M) ingest antigen.

(2) Macrophages digest antigen and present antigen fragments.

(3) T cells (T) with antigen-specific receptors for the antigen join to the presenting macrophage, using HLA receptors and antigen-specific receptors. IL-1 from macrophages stimulates the joined T cells.

(4) T cells reproduce and form specialized T cells (hT, cT, dT, sT).

(5) Specialized T cells reproduce.

As a macrophage or Langerhans cell digests and destroys these items, it transports fragments of each one through its cell membrane. Then the cell presents the fragments, together with its own HLA protein, to neighboring T cells. If a fragment and the HLA protein bind to a T cell, the fragment and the item from which it came (microbe, virus, or molecule) are considered antigens. Both the macrophage and the T cell are activated to initiate an immune response against these antigens.

T-Cell Participation

T-Cell Specialization The activated macrophage secretes interleukin-1 (IL-1), which stimulates the T cell to produce more identical T cells. The new T cells specialize into any combination of four different types, depending on the source of the antigen fragment and the type of HLA used: helper T cells (hT cells), cytotoxic T cells (cT cells), delayed-hypersensitivity T cells (dT cells), and suppressor T cells (sT cells). Some of these cells have other names: hT cells are CD4+ cells; cT cells are CD8+ cells.

Langerhans cells act like macrophages except that they do not produce IL-1. However, neighboring keratinocytes produce IL-1, and so similar immune activities occur in the skin. Besides stimulating T cells, IL-1 evokes inflammation and fever, two nonspecific defense mechanisms.

In the rest of this section, note that IL-1 and several specialized T-cell secretions (IL-2, lymphokines) cause positive feedback effects that amplify the immune response until sT cells come into play.

Helper T-Cell (hT-Cell) Activities

There are two main types of hT cells. TH-1 hT cells produce signaling substances that stimulate cT cells and that promote inflammation. These substances from TH-1 hT cells include IL-2, interferon-γ (IFN-γ), and tumor necrosis factor (TNF). Macrophages also produce TNF and stimulate inflammation. TH-2 hT cells produce signaling substances that stimulate B cells. Examples include IL-4, IL-5, IL-6, and IL-10. Many cell types including monocytes, macrophages, endothelial cells, mast cells, keratinocytes, and osteoblasts produce IL-6. IL-6 promotes inflammation, bone matrix removal, and other body activities. The signaling substances from hT-cells and from other cells regulate the hT-cells and other immune response cells so immune system activities remain balanced.

The hT cells that are produced bind to the original presenting macrophage or to any other macrophage that presents the same antigen. Then the hT cells then secrete interleukin-2 (IL-2). IL-2 initially enhances the developing immune response in several ways (Figure 15.4).

Figure 15.4 Activation and activities of hT cells. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

(1) Macrophages (M) ingest antigen.

(2) Macrophages digest and present the antigen.

(3) hT cells with specific receptors for the antigen join the presenting macrophage, using HLA receptors and antigen-specific receptors.

(4) hT cells produce IL-2, which stimulates macrophages, hT cells, cT cells, and B cells that are joined to the antigen.

(5) hT cells produce lymphokines.

First, it stimulates macrophages to phagocytize more antigen, leading to the digestion and presentation of more antigen and the activation of more T cells specific for that antigen. Second, it stimulates the production of more hT cells and cT cells. Third, it stimulates the proliferation and activity of any B cells that have bound to the original undigested antigen.

While the hT cells are producing IL-2, they also secrete other helpful defense substances called lymphokines. These substances increase macrophage phagocytosis in several ways and protect normal body cells from viruses.

Cytotoxic T-Cell (cT-Cell) Activities

Unlike hT cells, which bind to antigen and HLA protein on macrophages and Langerhans cells, cT cells bind to antigen and HLA protein on other body cells (Figure 15.5).

Figure 15.5 Activation and activities of cT cells. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

(Figure 15.5) Activation and activities of cT cells.

(1a) Antigen invades body cells (bc).

(2a) cT cells (cT) with specific receptors for the antigen join to the infected body cell, using HLA receptors and antigen-specific receptors.

(3a) cT cells produce lymphokines (jagged arrow) against infected cells.

(4a) Infected cells and enclosed antigen are destroyed.

(5a) cT cells produce more identical cT cells to attack other body cells that are infected with the antigen.

(1b) Body cells become cancer cells (cc) and produce antigens.

(2b) cT cells with specific receptors for the antigen join to the cancer cells, using HLA receptors and antigen-specific receptors.

(3b) cT cells produce lymphokines against the cancer cells.

(4b) Cancer cells are destroyed.

(5b) cT cells produce more identical cT cells to attack other identical cancer cells.

Such combinations occur on cells infected with viruses, fungi, or bacteria; certain types of cancer cells; and cells transplanted into the body from a person with different HLA protein or from an animal. When a cT cell binds to an antigen-bearing cell, it is activated and proliferates, producing a clone of cT cells that bind to other cells with the same antigen. With the assistance of IL-1 and IL-2, each cT cell destroys the cell to which it binds, using secretions that damage the cell membrane. This type of immune response is called a cell-mediated response because the cT cells make direct contact with each antigen-bearing cell they attack. It contrasts with the humoral response by B cells, which secrete antibodies that attack antigens at a distance (see below).

Every cT cell can move from cell to cell, selectively destroying each antigen-bearing cell that binds to both of its types of receptors. The cT cells also release lymphokines, which activate macrophages and other types of T cells while protecting normal cells from viruses. Certain cT-cell lymphokines also stimulate natural killer cells (NK cells), nonspecific lymphocytes that destroy cancer cells.

Delayed-hypersensitivity T-cell (dT cell) Activities

Delayed-hypersensitivity T cells are similar to cT cells in the way in which they identify abnormal cells. However, these cells do not kill cells directly. Rather, the lymphokines produced by these cells stimulate other immune system cells (e.g., macrophages) to destroy cells with surface antigens. These lymphokines also cause inflammation, which increases the defense of the affected area (Chapter 3). The inflammation is evident during excessive dT-cell reactions, such as those resulting from poison ivy or positive skin tests for tuberculosis (e.g., tine tests). Delayed-hypersensitivity cells received their name because at least 1 day is required for them to cause significant inflammation. By contrast, allergic reactions caused by B cells are called immediate-hypersensitivity reactions because they produce significant effects within minutes or hours. Examples of immediate-hypersensitivity reactions include forms of asthma and allergic reactions to penicillin, bee stings, and foods.

Suppressor T-Cell (sT-Cell) Activities

We have seen that IL-2 stimulates immune activity by acting on hT cells, cT cells, and dT cells. However, IL-2 also stimulates the proliferation of sT cells. Since this occurs slowly, it takes approximately 1 week to develop a large number of sT cells specific for the antigen being attacked. When enough sT cells have developed, their secretions overpower and quell the immune activities of the attacking immune system cells and the immune response to that antigen subsides. By this time the antigen usually is being reduced or has been eliminated.

Suppression of the immune response helps prevent the adverse effects that may accompany excessive or prolonged immune activity. Examples include discomfort and damage from accidental immune injury to normal body components and from inflammation. Therefore, sT cells help maintain homeostasis by providing timely negative feedback that reverses the positive feedback effects of other immune system cells.

Though some sT cells are antigen-specific and therefore suppress specific immune responses, others suppress immune responses to many different antigens simultaneously. This provides ongoing regulation of the entire immune system. One benefit is a reduction in autoimmune reactions, which are immune responses against normal parts of the body, such as rheumatoid arthritis and insulin-dependent diabetes mellitus. Another benefit is a reduction in allergic responses, which are excessive immune responses against foreign antigens, such as hay fever, asthma, and food and drug allergies.

B-Cell Participation

Most aspects of the immune response mentioned up to this point result in nonspecific defense reactions against an antigen (e.g., phagocytosis, inflammation, fever). Only the portion of the antigen bound to cells bearing HLA protein is specifically attacked. To understand how unbound antigen, such as antigen suspended in body fluids, is attacked, we must examine the operations of B cells and the antibodies they produce.

B-Cell Activation

Since antigen-specific receptors on B cells are more complete than antigen-specific receptors on T cells, B cells can bind to an antigen even when HLA protein is not present (Figure 15.6).

Figure 15.6 Activation and activities of B cells. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

(Figure 15.6) Activation and activities of B cells.

(1) Antigen binds to B cells (B) that have specific receptors for the antigen.

(2) B cells with bound antigen join hT cells (hT) that have specific receptors for the antigen, using HLA receptors and antigen-specific receptors.

(3) hT cells release IL-2 which stimulates B cells to reproduce.

(4) Stimulated B cells produce mB cells (mB) and plasma cells (p).

(5) Plasma cells produce antibodies that have specific bonding sites for the antigen.

(6) Antibodies bind to the antigen.

No macrophages or other cells are needed to process or present the antigen to B cells, and B cells specific for the antigen bind to it wherever they meet it. This stimulates the attached B cells to proliferate and produce two special types of B cells-memory B-cells (mB cells) and plasma cells-both of which continue to reproduce. All the mB cells and plasma cells have the same antigen specificity as the B cells from which they were derived. Memory B cells are described below in connection with memory. The plasma cells manufacture and secrete antibodies (immunoglobulins), which combat the antigen in several ways (see below). However, the original antigen-bound B cells and their progeny usually function inadequately unless they are stimulated by IL-2. The hT cells provide a concentrated application of IL-2 to the antigen-bound B cells, plasma cells, and mB cells by binding to them. This cell-to-cell binding is similar to other types employed by various T cells. That is, the two types of hT-cell receptors bind simultaneously to their corresponding HLA proteins and antigens on the surfaces of the B cells and their progeny.

Several days after the antigen is detected by the T cells and B cells, many fully activated plasma cells are produced and secrete antibodies profusely. Each plasma cell may continue antibody production for up to 1 week, after which it dies. Exhausted plasma cells may be replaced by new ones.

Antibodies

All antibodies from a plasma cell have the same antigen specificity as did the B cell that first bound to the antigen. Therefore, these antibodies also bind to the antigen wherever the two meet. However, different classes of antibodies are produced and concentrated in different places in the body.

The different antibody classes are designated by different letters. IgA antibodies are concentrated in the secretions from mucous membranes lining body systems (e.g., respiratory system, digestive system). When they bind to antigens, they help block the entry of the antigens into the body. Most antibodies in the IgM and IgG classes are found in blood and lymph. IgM and IgG prevent injury from antigens in several ways. For example, they cause some antigens to become more easily phagocytized by clumping them together and coating them with phagocyte-stimulating substances. IgM and IgG chemically neutralize other antigens. They also lead to the destruction of other antigens by activating a group of substances in the blood called the complement system. Complement substances can kill antigenic cells such as bacteria directly and intensify defense activities by promoting phagocytosis and inflammation. IgE antibodies bind to mast cells. When antigen later binds to this IgE, the mast cells release histamine and cause inflammation. Antibodies assist only in fighting antigens; they do not destroy antigens.

Memory

We have seen that an antigen causes the production of a large number of specialized T cells, plasma cells, and antibodies that have specificity. It takes several days to produce enough of these cells and antibodies to combat a large dose of antigen the first time it is encountered. This is called a primary immune response. (Figure 15.7)

Figure 15.7 Primary immune response. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

Secondary Immune Response

Many specialized T cells and plasma cells produced during the primary immune response are eliminated once the antigen has been reduced. The remaining specialized T cells constitute a cadre of memory T cells (mT cells). The mB cells and much of the antibody produced during the primary immune response also remain, though the amount of antibody declines over a period of weeks. Since memory cells are abundant and specialized, they swiftly produce many specialized T cells and plasma cells if the antigen is detected again. Furthermore, the antibody level rises precipitously, reaching a valve far above the peak level attained during the primary immune response. Therefore, the old antibody, along with the new specialized T cells and the antibody from new plasma cells, produces a more rapid and intense attack on the antigen if it appears in the body again. An immune response to an antigen encountered a second or subsequent time is called a secondary immune response. This response may effectively eliminate an antigen within 1 day of its detection by the immune system (Figure 15.8).

Figure 15.8 Secondary immune response. (Copyright 2020: Augustine G. DiGiovanna, Ph.D., Salisbury University, Maryland. Used with permission.)

With each subsequent secondary immune response to an antigen, additional memory cells and antibody for that antigen may accumulate and the antibody level may decline more slowly. When this happens, each subsequent secondary immune response is faster and more effective than the previous one. This further decreases the risk of sustaining injury from the antigen each time it is present. It can also cause allergic responses to become worse with repeated exposure to certain antigens (e.g., penicillin, bee stings).

Acquired Active Immunity

Sometimes the formation of memory is so effective that only one exposure to an antigen prompts complete and permanent resistance. For example, most people have measles or chickenpox only once. Once the secondary immune response is strong enough to prevent significant adverse effects from the next encounter with an antigen, the person has an acquired active immunity against that antigen. Such immunity may result when the first dose of antigen is sufficient to cause serious illness, as occurs with full-blown measles. However, this immunity is sometimes acquired after a person receives an antigen in one or more doses that are not strong enough to cause significant illness. Acquired active immunity against antigens such as polio, tetanus, diphtheria, and influenza can be intentionally induced in this way, using vaccines that contain the antigen.

Though acquired active immunity against antigens such as polio usually lasts indefinitely, the memory cells and antibodies for other antigens may diminish substantially if the cells do not encounter the antigen again for months or years (e.g., tetanus). Then the antigen may cause approximately the same degree of injury that it did when it was first encountered because several days may be required to produce enough of an immune response to eliminate it. This sometimes can be prevented by receiving a vaccine again (a booster dose) at appropriate intervals.