Fragile X Mutations Affect Boys and Their Grandfathers
17.2 The Human Immune System
The immune system is a network of vessels called lymphatics that transport lymph fluid to bean-shaped structures through- out the body called lymph nodes. The spleen and thymus gland are also part of the immune system ( figure 17.3 ).
Lymph fluid carries white blood cells called lympho- cytes and the wandering, scavenging macrophages that capture and degrade bacteria, viruses, and cellular debris. B cells and T cells are the two major types of lymphocytes.
The genetic connection to immunity is the proteins required to carry out an immune response. The immune response attacks
MHC self protein
Macrophage Bacterium Phagocytosis of
the microbial invader 1
2
MHC proteins and their attached antigens are displayed on macrophage surface 3
Helper T cells recognize antigens and MHC proteins and bind to the macrophage, initiating a series of immune events 4
Lymphocyte (helper T cell) Bacterial antigen
Nucleus
Antigens from the dismantled invader are attached to MHC self proteins
Macrophage Lymphocyte
Figure 17.2 Macrophages are antigen-presenting cells. A macrophage engulfs a bacterium, then displays foreign antigens on its surface, which are held in place by major histocompatibility complex (MHC) self proteins. This event sets into motion many immune reactions.
pathogens, cancer cells, and transplanted cells with two lines of defense—an immediate generalized innate immunity, and a more specific, slower adaptive immunity. These defenses act after various physical barriers block pathogens. Figure 17.4 sum- marizes the basic components of the immune system, discussed in the following sections.
Physical Barriers and Innate Immunity
Several familiar structures and fluids keep pathogens from entering the body in the innate immune response: unbroken skin, mucous membranes such as the lining inside the mouth, earwax, and waving cilia that push debris and pathogens up and out of the respiratory tract. Most microbes that reach the stomach perish in a vat of churning acid or are flushed out in diarrhea. These physical barriers are nonspecific—that is, they keep out anything foreign, not just particular pathogens.
If a pathogen breaches these physical barriers, innate immunity provides a rapid, broad defense. The term innate refers to the fact that these general defenses are in the body, ready to function should infection threaten. A central part of the innate immune response is inflammation, a process that creates a hostile environment for certain types of pathogens at an injury site. Inflammation sends in cells that engulf and destroy pathogens. Such cells are called phagocytes, and their engulfing action is phagocytosis ( figure 17.5 ). Certain types of white blood cells and the large, wandering macrophages are phagocytes. Also at the infection site, p lasma accumulates, which dilutes toxins and brings in antimicrobial chemicals.
Increased blood flow with inflammation warms the area, turn- ing it swollen and red.
growth indirectly, because higher body temperature reduces the iron level in the blood. Bacteria and fungi require more iron as the body temperature rises; a fever-ridden body stops their growth. Phagocytes also attack more vigorously when the tem- perature rises. Tumor necrosis factor is another type of cytokine that activates other protective biochemicals, destroys certain bacterial toxins, and attacks cancer cells. Many of the aches and pains we experience from an infection are actually due to the immune response, not directly to the actions of the pathogens.
Adaptive Immunity
Adaptive immunity must be stimulated into action. It may take days to respond, compared to minutes for innate immunity.
Adaptive immunity is highly specific and directed.
B cells and T cells carry out adaptive immunity. In the humoral immune response, B cells produce antibodies in response to activation by T cells. (“Humor” means fluid; anti- bodies are carried in fluids.) In the cellular immune response, T cells produce cytokines and activate other cells. B and T cells differentiate in the bone marrow and migrate to the lymph nodes, spleen, and thymus gland, as well as circulate in the blood and tissue fluid.
The adaptive arm of the immune system has three basic characteristics. It is diverse, vanquishing many types of patho- gens. It is specific, distinguishing the cells and molecules In addition to inflammation, three classes of proteins par-
ticipate in innate immunity. These are the complement system, collectins, and cytokines. Mutations in the genes that encode these proteins increase susceptibility to infection.
The complement system consists of plasma proteins that assist, or complement, several other defenses. Some comple- ment proteins puncture bacterial plasma membranes, bursting the cells. Others dismantle viruses or trigger release of hista- mine from mast cells, another type of immune system cell that is involved in allergies. Histamine dilates blood vessels, send- ing fluid to the infected or injured area. Still other complement proteins attract phagocytes to an injury site.
Collectins broadly protect against bacteria, yeasts, and some viruses by detecting slight differences in their surfaces from human cells. Groups of human collectins correspond to the surfaces of different pathogens, such as the distinctive sug- ars on yeast, the linked sugars and lipids of certain bacteria, and the surface features of some viruses.
Cytokines play roles in both innate and adaptive immu- nity. As part of the innate immune response, cytokines called interferons alert other components of the immune system to the presence of cells infected with viruses. These cells are then destroyed, which limits the spread of infection.
Interleukins are cytokines that cause fever, temporarily triggering a higher body temperature that directly kills some infecting bacteria and viruses. Fever also counters microbial
Thymus
Bone marrow T cells, B cells, and macrophages originate in the bone marrow and migrate into the blood.
Macrophages engulf bacteria and stimulate helper T cells to proliferate and activate B cells.
B cells are released from lymphoid tissues, such as the spleen and lymph nodes, and secrete antibodies.
Plasma cells
Memory cells T cells mature in
the thymus gland, in the small intestine, and the skin.
Cell-mediated immunity Cytotoxic T
cells attack cells directly.
Humoral immunity Antibodies Helper T cells
Lymph nodes
Spleen
Interleukins
Figure 17.3 The immune system produces diverse cells. T cells, B cells, and macrophages build an overall immune response. All three types of cells originate in the bone marrow and circulate in the blood.
that there is almost always one or more available that corre- sponds to a particular foreign antigen. Turnover of these cells is high. Each day, millions of B cells perish in the lymph nodes and spleen, while millions more form in the bone marrow, each with a unique combination of surface molecules.
Once the activated T cell finds a B cell match, it releases cytokines that stimulate the B cell to divide. Soon the B cell gives rise to two types of cells ( figure 17.6 ). The first, plasma cells, are antibody factories, each secreting 1,000 to 2,000 iden- tical antibodies per second into the bloodstream. They live only days. These cells provide the primary immune response. Plasma cells derived from different B cells secrete different antibodies.
that cause disease from those that are harmless. The immune system also remembers, responding faster to a subsequent encounter with a foreign antigen than it did the first time. The first assault initiates a primary immune response. The sec- ond assault, based on the system’s “memory,” is a secondary immune response. This is why we get some infections, such as chickenpox, only once. However, upper respiratory infections and influenza recur because the causative viruses mutate, pre- senting a different face to our immune systems each season.
The Humoral Immune Response—B Cells and Antibodies
An antibody response begins when an antigen-presenting mac- rophage activates a T cell. This cell in turn contacts a B cell that has surface receptors that can bind the type of foreign anti- gen the macrophage presents. The immune system has so many B cells, each with different combinations of surface antigens,
Bacteria Viruses
Cytokines Macrophages present antigens
Fever
Antimicrobial proteins Phagocytosis
Inflammatory response Mucous membranes Skin
Infection-fighting chemicals Flushing action of urination, tears, diarrhea, saliva
Innate immunity Physical barriers
Adaptive immunity
Cellular response
Humoral response
T cells B cells Memory B cells
Cytotoxic T cells Plasma cells
Antibodies
Figure 17.4 Levels of immune protection. Disease-causing organisms and viruses (pathogens) first must breach physical barriers, then nonspecific cells and molecules attack in the innate immune response. If this is ineffective, the adaptive immune response begins:
Antigen-presenting cells stimulate T cells to produce cytokines, which activate B cells to divide and differentiate into plasma cells, which secrete antibodies. Once activated, these specific cells “remember”
the pathogen, allowing faster responses to subsequent encounters.
Figure 17.5 Nature’s garbage collectors. A human phagocyte engulfs a yeast cell.
Figure 17.6 Production of antibodies. In the humoral immune response, B cells proliferate and mature into antibody- secreting plasma cells. Note that only the B cell that binds the antigen proliferates; its descendants may develop into memory cells or plasma cells. Plasma cells greatly outnumber memory cells.
Plasma cells Proliferation
Proliferation
Memory cell
Antigen-presenting cell (macrophage) Antigens
Stimulates Stimulates Helper T cell
B cells
B cells Antigen
disulfide (sulfur-sulfur) bonds, forming a shape like the letter Y ( figure 17.8 ). A large antibody molecule might consist of three, four, or five such Ys joined.
In a Y-shaped antibody subunit, the two longer polypep- tides are called heavy chains, and the other two light chains.
The lower portion of each chain is an amino acid sequence that is very similar in all antibody molecules, even in dif- ferent species. These areas are called constant regions, and they provide the activity of the antibody. The amino acid sequences of the upper portions of each polypeptide chain, the variable regions, can differ greatly among antibodies.
These parts provide the specificities of particular antibodies to particular antigens.
Antibodies can bind certain antigens because of the three-dimensional shapes of the tips of the variable regions.
These specialized ends are antigen binding sites, and the parts that actually contact the antigen are called idiotypes. The parts of the antigens that idiotypes bind are epitopes. An antibody contorts to form a pocket around the antigen.
Antibodies have several functions. Antibody-antigen bind- ing may inactivate a pathogen or neutralize the toxin it produces.
Antibodies can clump pathogens, making them more visible to macrophages, which then destroy them. Antibodies also activate complement, extending the innate immune response. In some situations, the antibody response can be harmful.
Antibodies are of five major types, distinguished by where they act and what they do ( table 17.2 ). (Antibodies are also called immunoglobulins, abbreviated Ig. ) Different anti- body types predominate in different stages of an infection.
The human body can manufacture seemingly limitless varieties of antibodies, though the genome has a limited number of antibody genes. This great diversity is possible because parts of Each type of antibody corresponds to a specific part of the
pathogen, like hitting a person in different parts of the body. This multi-pronged attack is called a polyclonal antibody response ( figure 17.7 ). The second type of B cell descendant, memory cells, are far fewer and usually dormant. They respond to the foreign antigen faster and with more force should it appear again. This is a secondary immune response. Memory B cells are what enabled survivors of the 1918 flu pandemic to resist infection.
An antibody molecule is built of several polypeptides and is therefore encoded by several genes. The simplest type of antibody molecule is four polypeptide chains connected by
Bacterium
Antibodies
Plasma cell Plasma
cell
Plasma cell
Figure 17.7 An immune response recognizes many targets. A humoral immune response is polyclonal, which means that different plasma cells produce antibody proteins that recognize and bind to different features of a foreign cell’s surface.
Antigen binding site
a. An antibody subunit Variable
region (idiotype)
Constant regions
Hinge mechanism
Heavy chain
Disulfide bond Light chain Antigen
Epitope
SS SS
SS SS
b.
IgA
c.
IgM
Figure 17.8 Antibody structure. The simplest antibody molecule (a) consists of four polypeptide chains, two heavy and two light, joined by pairs of sulfur atoms that form disulfide bonds. Part of each polypeptide chain has a constant sequence of amino acids, and the remainder varies. The tops of the Y-shaped molecules form antigen binding sites. (b) IgA consists of two Y-shaped subunits, and IgM (c) consists of five subunits.
different antibody genes combine. During the early development of B cells, sections of their antibody genes move to other chromo- somal locations, creating new genetic instructions for antibodies.
The assembly of antibody molecules is like putting together many different outfits from the contents of a closet containing 200 pairs of pants, a drawer containing fifteen different shirts, and four belts. Specifically, each variable region of a heavy chain and a light chain consists of three sections, called V (for variable), D (for diversity), and J (for joining). The V, D, and J genes—
several of each—for the heavy chains are on chromosome 14, and the corresponding genes for the light chains are on chromo- somes 2 and 22. C (constant) genes encode the constant regions of each heavy and light chain. A promoter sequence precedes the V genes and an enhancer sequence precedes the C genes. These control sequences oversee the mixing and matching of the V, D, and J genes. Figure 17.9 shows how the genetic instructions for the antibody parts are combined in different ways to encode the heavy and light polypeptide chains.
Enzymes cut and paste the pieces of antibody gene parts.
The number of combinations is so great that virtually any anti- gen that a person with a healthy immune system might encoun- ter will elicit an immune response.
The Cellular Immune Response—T Cells and Cytokines
T cells provide the cellular immune response. It is called “cel- lular” because the T cells themselves travel to where they act, unlike B cells, which secrete antibodies into the bloodstream.
T cells descend from stem cells in the bone marrow, then travel to the thymus gland (“T” refers to thymus). As the immature T cells, called thymocytes, migrate toward the interior of the
HEAVY CHAIN GENES
ANTIBODY STRUCTURE
LIGHT CHAIN GENES V1
V1 V2 V3 V4
V1 V2 V3 V4 V5 V6 Vn J1J2J3J4J5 C
V J J C
VH
VL JL DH JH
s s V2 V3 D1D2D3
VDJ C
Gene rearrangement
Gene rearrangement Heavy chain Antigen
binding site
Antigen binding site
Light chain J1J2J3J4 C
s s
V5 n 1 2
s s s s
Figure 17.9 Antibody diversity. The human immune system can produce antibodies to millions of possible antigens because each polypeptide is encoded by more than one gene. That is, the many components of antibodies can combine in many ways.
Type* Location Functions IgA Milk, saliva, urine, and
tears; respiratory and digestive secretions
Protects against pathogens at points of entry into body
IgD On B cells in blood Stimulates B cells to make other types of antibodies, particularly in infants IgE In secretions with IgA and
in mast cells in tissues
Acts as receptor for antigens that cause mast cells to secrete allergy mediators IgG Blood plasma and tissue
fluid; passes to fetus
Protects against bacteria, viruses, and toxins, especially in secondary immune response IgM Blood plasma Fights bacteria in primary
immune response; includes anti-A and anti-B antibodies of ABO blood groups
*The letters A, D, E, G, and M refer to the specific conformation of heavy chains characteristic of each class of antibody.
Table 17.2 Types of Antibodies
thymus, they display diverse cell surface receptors. Then selec- tion happens. As the wandering thymocytes touch lining cells in the gland that are studded with “self” antigens, thymocytes that do not attack the lining cells begin maturing into T cells, whereas those that harm the lining cells die by apoptosis—in great numbers. Gradually, T cells-to-be that recognize self per- sist while those that harm body cells are destroyed.
Several types of T cells are distinguished by the types and patterns of receptors on their surfaces, and by their func- tions. Helper T cells have many functions: they recognize for- eign antigens on macrophages, stimulate B cells to produce antibodies, secrete cytokines, and activate another type of T cell called a cytotoxic T cell, (also called a killer T cell). Cer- tain T cells may help to suppress an immune response when it is no longer required. The cytokines that helper T cells secrete include interleukins, interferons, tumor necrosis factor, and colony stimulating factors, which stimulate white blood cells in bone marrow to mature ( table 17.3 ). Cytokines interact with and signal each other, sometimes in complex cascades.
Distinctive surfaces distinguish subsets of helper T cells.
Certain antigens called cluster-of-differentiation antigens, or CD antigens, enable T cells to recognize foreign antigens displayed on macrophages. One such cell type, called a CD4
Key Concepts
1. The immune system consists of physical barriers; an innate immune response of inflammation, phagocytosis, complement, collectins, and cytokines; and an adaptive immune response that is diverse, specific, and remembers.
2. In the humoral immune response, stimulated B cells divide and differentiate into plasma cells and memory cells. A plasma cell secretes abundant antibodies of a single type. Antibodies are Y-shaped polypeptides, each with two light and two heavy chains, each with a constant and a variable region. The tips of the Y form an antigen binding site with a specific idiotype. Antibodies make foreign antigens more visible to macrophages and stimulate complement. Shuffling gene pieces generates antibody diversity.
3. In the cellular immune response, helper T cells stimulate B cells to manufacture antibodies and cytotoxic T cells to secrete cytokines. Using T cell receptors, cytotoxic T cells bind to nonself cells and virus-covered cells and burst them.
17.3 Abnormal Immunity
The immune system continually adapts to environmental change.
Because the immune response is so diverse, its breakdown affects health in many ways. Immune system malfunction may be inher- ited or acquired, and immunity may be too weak, too strong, or misdirected. Abnormal immune responses may be multifacto- rial, with several genes contributing to susceptibility to infec- tion, or caused by mutation in a single gene. Or, susceptibility to an immune disorder may reflect abnormal gene expression, as the chapter opener describes for rheumatoid arthritis.
Inherited Immune Deficiencies
The more than twenty types of inherited immune deficiencies affect innate and adaptive immunity (table 17.5 ). These conditions can arise in several ways.
In chronic granulomatous disease, neutrophils can engulf bacteria, but, due to deficiency of an enzyme called an oxidase, they cannot produce the activated oxy- gen compounds that kill bacteria.
Because this enzyme is made of four polypeptide chains, four genes encode it, and there are four ways to inherit the disease, all X-linked. A very rare autosomal recessive form is caused by a defect in the part of the host cell that encloses bacteria.
helper T cell, is an early target of HIV. Considering the criti- cal role helper T cells play in coordinating immunity, it is little wonder that HIV infection ultimately topples the entire system, a point we will return to soon.
Cytotoxic T cells lack CD4 receptors but have CD8 receptors. These cells attack virally infected and cancerous cells by attaching to them and releasing chemicals. They do this by linking two surface peptides to form structures called T cell receptors that bind foreign antigens. When a cytotoxic T cell encounters a nonself cell—a cancer cell, for example—the T cell receptors draw the two cells into physical contact. The T cell then releases a protein called perforin, which pierces the cancer cell’s plasma membrane, killing it ( figure 17.10 ). Cyto- toxic T cell receptors also attract cells that are covered with certain viruses, destroying the cells before the viruses on them can enter, replicate, and spread the infection. Cytotoxic T cells continually monitor body cells, recognizing and eliminating virally infected and tumor cells.
Table 17.4 summarizes types of immune system cells.
Cytokine Function Colony stimulating
factors
Stimulate bone marrow to produce lymphocytes
Interferons Block viral replication, stimulate macrophages to engulf viruses, stimulate B cells to produce antibodies, attack cancer cells
Interleukins Control lymphocyte differentiation and growth, cause fever that accompanies bacterial infection
Tumor necrosis factor Stops tumor growth, releases growth factors, stimulates lymphocyte differentiation, dismantles bacterial toxins
Table 17.3 Types of Cytokines
Figure 17.10 Death of a cancer cell. A cytotoxic T cell binds to a cancer cell and injects perforin, a protein that pierces (lyses) the cancer cell’s plasma membrane. The cancer cell dies, leaving debris that macrophages clear away.
Cancer cell
T cell receptor
Cytotoxic T cell binds to cancer cell.
Foreign antigen
Perforin
Hole
Perforin breaks cancer cell apart.
T cell has lysed cancer cell.
Cytotoxic T cell