CHAPTER EIGHT: THE IMMUNE SYSTEM AND IMMUNOLOGY
I. Introduction to Immunology Immunology is the study of the immune system. The immune system is the body's defense against foreign substances, organisms and invaders. It consists of a group of defense mechanisms associated with different body systems that work together to protect the body against harm. The immune system must be able to recognize:
Pathogenic organisms: organisms with the ability to cause cell injury and
illness. Pathogens are often microscopic and therefore are pathogenic
microorganisms (microbes). Abnormal body cells: cells that begin to show abnormal or dangerous
changes, such as cancer cells. Cells introduced to the body from an outside source: such as tissue and
organ transplants. Normal body cells: in order to leave them alone and not attack them.
The body's ability to ward off disease is called resistance. A lack of resistance is susceptibility.
A. Two Types of Immunity (Resistance) There are two types of resistance: innate or non-specific immunity and adaptive or specific immunity (acquired immunity).
Non-specific resistance (innate immunity) employs a wide range of defensive measures against a wide range of foreign substances.
Specific resistance (adaptive or acquired immunity) deals with each foreign substance uniquely. The production of a specific molecule (called an antibody) or specific defense cell will be made against a specific bacteria, virus or toxin. This one-on-one reaction to each particular invader is known as specificity.
The two types of immunity work together during an immune response to rid the body of pathogens, cancer cells, and unwanted tissues. Their functions are intimately intertwined and overlapping. These two types of immunity will be further explored in subsequent sections of this chapter.
Pathogens are disease causing organisms. An infection is when the body is invaded by pathogens. There are many types of pathogens. Two main types are:
1. Bacteria: primitive unicellular organisms with no nucleus. Bacteria cause more human disease than any other class of pathogen. They multiply rapidly, competing with the body's cells for nutrients. Some bacteria will destroy cells by adhering to them and breaking them down. Sometimes it is the waste products of bacterial metabolism which are toxic to the body. 2. Viruses: usually contain DNA and a number of enzymes surrounded by a protein coat. Viruses cannot reproduce by themselves. To reproduce they must attach themselves to a body cell's membrane and inject their contents into the cell. Once inside the cell, the virus uses the cell's own machinery to replicate viral particles over and over again. Eventually, the cell is full of viral particles and cannot function. Then it ruptures, spreading viral particles throughout the tissue area and allowing the virus to spread further throughout the body.
Retroviruses contain RNA (instead of DNA) and enzymes that allow
them to make a DNA template to insert into the host cell's DNA. The
result is that every time the host cell duplicates the virus is also
duplicated inside the cell, making the infected cells very difficult for the
immune system to recognize and destroy. These types of viruses can
lie dormant for long periods of time before they activate to replicate
themselves. Once activated (usually in times of stress) they reproduce
viral particles until the host cell ruptures ad dies. HIV (human
immunodeficiency virus) is a retrovirus.
Other types of pathogens include fungi, protozoa, worms, spiders, insects, and proteins (called prions). These cause many fewer infectious diseases.
C. Antigens and Antibodies
In understanding the immune system, two terms are especially important: antigens and antibodies. Antigens are things that give rise to the production of antibodies. Antibodies are protein molecules produced in response to the presence of antigens. In more detail:
1. Antigens: The adaptive immune system is designed to defend our body against foreign substances, organisms and invaders. It is also programmed to recognize our own cells and leave them alone. Substances that elicit an adaptive immune response are called antigens. The term antigen comes from "antibody generating." Antigens may be parts of our own cells or come from outside the body.
An antigen can be anything (cell, molecule, chemical substance, or organism) that lymphocytes recognize (have receptors for) and which causes the body to produce an adaptive immune response, namely antibodies. Normally, the immune system learns to recognize self-antigens and not react to them. This is called self-tolerance. For our purposes on we will focus on foreign antigens.
Again, antigens often are not the same thing as a whole pathogen (disease-producing microbe). Antigens are usually just a part of a microbe, like a molecule in the cell membrane, or a cilium or flagellum, or toxins released by the microbe. Antigens can also be a non-microbial substance like pollen or gluten. The specific portion of the antigen that is recognized by the body as being "foreign" is called the antigenic determinant. It is the portion that the immune system recognizes as foreign and leads to an adaptive immune response by activating a population of B-cells and T-cells that recognize the antigen. Specific receptor molecules on the B-cells and T- cells recognize the antigenic determinants. An area of common confusion for students is the way the term "antigen" is used. All cells have protein markers, and generally these markers are called antigens. Recall that RBC antigens allow for blood typing in the ABO and Rh systems. With the exception of red blood cells, each cell in a person's body has its own unique set of protein markers (except identical twins). These markers on our own cells are called major histocompatibility complex antigens or MHC antigens (self-antigens). "Histo" means "tissue" and "compatibility" means "existing in harmony with another." MHC antigens are the markers that let our own cells know they belong to the same body and are of the same person, living in harmony together - and therefore should not be attacked by our immune defenses. But when these markers on our own cells get into another person's body, they cause tissue rejection because the receiver's body perceives them as foreign and does attack them.
In your own body, your MHC antigens help immune cells recognize antigens. That is, these "self-antigens" aid in the detection of foreign antigens. So, the MHC antigens have two roles: they give cells in your body an identification tag and they help to present foreign antigens to cells of the immune system to initiate an adaptive immune response. 2. Antibodies: Antibodies are protein molecules produced by the immune response generated by B-cell activity. Antibodies are produced in response to an antigen and react specifically to that antigen by binding or locking on to it in a lock and key manner. Antibodies are present in the body fluids. When an antigen and antibody are locked together they form an antigen/antibody complex. The formation of antigen/antibody complexes leads to a number of
immunological responses that eliminate the antigen (and the pathogen that it is part of.) Antibodies belong to a group of proteins collectively called immunoglobulins or Igs.
II. The Innate Immune Response The innate immune response is also known as non-specific resistance or general resistance. It employs defense mechanisms that provide a general response to a wide range of pathogens and antigens. The defense response is the same regardless of the pathogen. There is no specific or unique defense response (no specificity). Non-specific resistance can be either mechanical (physical) or chemical.
A. Non-specific Mechanical Protection
1. Skin - keratinized epithelial cells provide a watertight physical barrier to pathogens. Continual shedding of the outer layer of the skin helps eliminate pathogens. Skin has a low pH (3-5) which inhibits microbial growth, and fatty acids released in sebum also have an antimicrobial action. 2. Mucous Membranes - line all the entrances to the body: the digestive, respiratory, urinary and reproductive tracts. The epithelial layer secretes a sticky mucus which traps microbes and debris. Mucous membranes are often ciliated to propel trapped particles out. They are full of diffuse lymphatic tissue and antibodies. Mucus contains antibodies secreted by cells in the mucosa lymphatic tissues.
3. Other Secretions - such as gastric juice (pH 1-2, strongly antibiotic, dissolves pathogens); perspiration (contains lysozyme to break down bacteria and flush skin); tears (physically wash the eyeball, and contain lysozyme); saliva (washes teeth and mouth and contains lysozyme); urine (flushes microbes); vaginal secretions (low pH - acidic). Also, breast milk contains antibodies and several molecules that impede growth of pathogens.
4. Phagocytosis - by macrophages and neutrophils. Nonspecific ingestion of pathogens by these white blood cells is an important step in the initiation of more adaptive immune responses.
5. Inflammation - is the body's chief response to tissue injury. There are five main signs and symptoms of inflammation: heat, redness, swelling, pain, and loss of function. Injured tissue stimulates the release of a chemical called histamine, which will trigger the inflammatory response. Inflammation is characterized by arteriole vasodilation and
increased capillary permeability, which brings more blood to the area and encourages diapedesis.
6. Fever - higher temperatures speed up the healing process (cell's internal metabolism is faster), inhibits pathogen growth and intensifies the effects of interferons (see below).
7. Natural Killer Cells - also play a role in the innate immune response. They roam the body looking for cells that are in trouble and should be eliminated. Unlike T-cells and B- cells, which we'll look at shortly, NK cells are nonspecific in their activity. They attack and destroy cells that don't display MHC antigens or cells that are coated with antibodies. They eliminate these cells using many of the same chemical mechanisms as cytotoxic T cells (see below). NK cells are especially effective against cancer cells and virus-infected cells.
B. Non-specific Chemical Protection
Cytokines are molecules that control many of the mechanisms of innate and adaptive immune responses. Cytokines are cell-signaling molecules that aid in cell-to-cell communication in immune responses. They also stimulate the movement of cells toward sites of inflammation, infection, and trauma. Two important groups are:
1. Interferons - are a large variety of chemicals produced by virus-infected cells, which then diffuse to non-infected cells to induce them to produce enzymes that will inhibit viral replication. Some interferons can inhibit cell growth and suppress tumors.
2. Complement - a group of about 20 proteins mostly produced in the liver that act to enhance the immune system and which are activated by antigen-antibody complexes. Opsonization is the coating of microbial surfaces with complement proteins which then encourages the phagocytosis of the complex. Cytolysis is when the proteins bore holes in the cell membrane, causing the cell to rupture and die.
III. The Adaptive Immune Response The adaptive immune response is also known as specific resistance or acquired immunity. Here, a specific cell or molecule will respond to a specific bacterium, toxin or other antigen. There is a one-on-one response. Adaptive immunity means that the body
can adapt (adjust) its immune response to respond specifically to each specific antigen encountered.
The adaptive immune response manifests in the body in two ways:
Antibody mediated immunity (or humoral immunity or blood-borne immunity)
involving B-lymphocytes and the production of antibodies that circulate
throughout the body and bind with the antigen. Cell-mediated immunity (or cellular immunity) involving T-lymphocytes, and a
certain type of T-cell that can attach to the antigen and destroy it.
Therefore, antibody mediated immunity is about B-cell response whereas cell-mediated immunity is about T-cell response.
A. Antibody Mediated Immunity (Humoral Immunity or Blood-Borne Immunity)
B-lymphocytes are preprocessed in the bone marrow before birth to recognize more than a million different antigens. There are millions of differently programmed B-cells in the body, each capable of responding to a specific antigen.
Mature B-cells reside in lymphoid organs and tissues, especially the lymph nodes, spleen, and gastrointestinal tract. They do not leave these sites but send out their antibodies to circulate in the blood and lymph. Blood, lymph and other body fluids are called humors in older medical language. As the antibodies travel through the blood and lymph they are known as free-floating antibodies. Hence, we have humoral immunity or blood-borne immunity ("borne" means carried or transported by), or antibody mediated immunity.
1. Activation of B-cells When a B-cell meets the specific antigen it is programmed for, it becomes activated or sensitized. Generally speaking, activation occurs when a macrophage engulfs an antigen and displays the antigenic determinant on its surface next to its MHC marker. Then the macrophage "presents" (shows, or introduces) the antigen to the B-cell that is preprocessed to recognize that specific antigen. This is called macrophagic presentation. B-cells may also become activated directly, without the work of the antigen-presenting cell.
When the antigen is presented to the B-cell, the B-cell is then activated to reproduce itself profusely, forming many, many duplicate B-cells of that specific type (programmed to fight that specific antigen).
Activation causes proliferation but also differentiation of that B-cell line. As the B cell line increases in number the daughter cells differentiate into two different types called plasma cells and memory B-cells. All of these differentiated cells are derived from the same unique B-cell line and therefore will recognize the same antigen and produce the same antibody.
2. Differentiation of B-cells
In B-cell sensitization, B-cells differentiate into plasma cells and memory B-cells. Plasma cells make and release antibodies specific to that antigen. These antibodies are released into blood and lymph and circulate around the body.
Plasma cells can produce and release tremendous amounts of antibody (2000 antibodies a second for 4-5 days). When the free-floating antibodies encounter the antigen, the antibodies bind with the antigen forming antigen-antibody complexes. As a result, the antigen is neutralized, complement proteins are activated, and macrophages are drawn in to phagocytose the complex. These processes lead to the destruction and elimination of the antigen.
Memory B-cells do not release antibodies during this first encounter with the antigen. They do nothing during this first time of exposure (called the primary response), except to be produced. But they are programmed to recognize the specific antigen should it return at a later date. During the primary response it can take several days to weeks for the immune system to make enough antibodies to shut down the antigen. The infected person usually has signs and symptoms of illness during these first days until the concentration of antibodies has increased to the levels necessary to rid the body of the antigen. Then the sick person begins to get better.
Large numbers of memory cells are produced during the primary response so that during a second encounter with the same antigen (called the secondary response) they can be activated swiftly and quickly react to the antigen. The secondary response is faster than the primary response because now there are so many memory B-cells in the body, and there may also be elevated antibody levels. The secondary response is generally so fast that the person does not get sick again from the same antigen, or has a much milder illness.
To summarize, memory B-cells are not active during the primary response but work in the secondary response and secrete large amounts of antibodies very quickly.
It is this memory response that can keep us from getting sick from the same thing twice (or at least as sick). But you can get the same antigen twice, and if you have a deficient
immune system, then you may get sick from the same antigen twice. But normally, repeated exposures to the same antigen will lead to a stronger immune response. Summary of antibody mediated immunity:
B-cells are responsible for humoral immunity.
Plasma B-cells secrete large quantities of antibodies into the body fluids.
Antibodies bind with antigen to form antigen/antibody complexes.
Antigen/antibody complexes lead to the elimination of the pathogen.
Memory B-cells remember the antigen and become active during secondary
responses (subsequent exposure to the antigen). A person often gets sick during the primary response. Secondary response leads to mild or no disease.
B. Cell-Mediated Immunity (Cellular Immunity) Like B-cells, T-lymphocytes are also preprocessed to recognize more than a million different antigens. While B-cells are preprogrammed in the bone marrow, T-cells are preprogrammed in the thymus. Also like B-cells, mature T-cells reside in lymphoid organs and tissues. There are millions of differently programmed T-cells in the body, each capable of responding to a specific antigen. T-cells become activated (sensitized) by macrophagic presentation. Once activated, the T-cells proliferate and differentiate. Activated T-cells will differentiate into 4 subpopulations: 1. Killer T-cells (Cytotoxic T-Cells): Killer T-cells are the main kind of the four subgroups. They can leave the site of production in lymphoid tissues and travel to the area of the antigen/microbe invasion. When they encounter the antigen, or any cell displaying the specific antigen, they can attach to it and release powerful digestive enzymes called lymphotoxins, which kill the cells/antigens.
Lymphotoxins are a cytotoxic (cyto = cell; toxic = poison) substance, therefore killer T- cells are also called cytotoxic T-cells. Since it is the T-cell itself that is fighting the antigen (as opposed to protein antibodies), this immune response is called cellular immunity or cell-mediated immunity.
Cytotoxic T cells are most effective against intracellular pathogens, such as virus and some intracellular bacteria. They roam through the body looking for cells displaying
antigenic molecules derived from the pathogens that are bound to the MHC molecules on their cell membranes. 2. Helper T-cells (T4 cells, or CD4+ cells): release chemicals (cytokines) that help activated T-cells and B-cells proliferate. They also help B-cells turn into plasma cells and help activate natural killer cells. The "T4" designation refers to a type of protein on the surface of the cell, and is a designation often used in discussing the immune capacity of people with HIV/AIDS. The Human Immunodeficiency Virus attacks T4 cells. Low T4 cell counts are indicative of active HIV infection and weakened immune response. You will learn more about this in the Pathology course.
3. Suppressor T-cells: turn off the immune system in the end stages of the immune response by suppressing B-cell and T-cell proliferation after a period of time.
4. Memory T-cells: are activated during the second exposure to the same antigen. Again, like memory B-cells, they are not active in the primary response, and usually the patient experiences being ill until there are enough antibodies and killer T-cells produced to get rid of the antigen. Memory T-cells are active in the secondary response and produce a quicker, stronger immune reaction the second time the body is exposed to the antigen.
C. Active and Passive Immunity Active immunity is the immune response of our own body (endogenous) resulting from its own production of antibodies and lymphocytes when exposed to the antigen. It generally results in a strong and long-lasting immune protection. Active immunity may be naturally (by infection) or artificially acquired (such as in vaccination). Vaccination means introducing antigenic material into the body to stimulate the immune response. The introduced antigen/pathogen is usually inactivated in some way so the person does not get sick with the disease, although people can have a reaction to the vaccine. Vaccination usually requires repeating the exposure to the antigen to be effective. This is one of the reasons why vaccines are administered in multiple doses.
Passive immunity is immune protection provided by sources from outside of the body (exogenous), such as antibodies or white blood cells produced in medical laboratories or from another person or animal and then transferred to the patient through injections or transfusion. Passive immunity is not as effective and long-lasting as active immunity. Like active immunity, passive immunity may be naturally acquired (as from mother to fetus or infant) or artificially acquired (injection of exogenous antibodies).