Chapter 15 Immunology Part I

I The Immune System is Specific

II Overview of the Immune System

1. Antigens and Antibodies

2. Cells and Tissues of the Immune System

3. Immune Recognition of Self versus Non-Self

4. Specificity of the Immune System

5. Immune Memory

III Humoral Immunity and Antibodies

1. Structure of Antibodies (Immunoglobulins)

2. Primary and Secondary Responses

3. Kinds of Antigen-Antibody Reactions

4. Monoclonal Antibodies

IV Cell-Mediated Immunity

1. Helper and Suppressor T Cells

2. Targets of Cell-Mediated Immunity

3. The Cell-Mediated Immune Reaction

4. The Role of Activated Macrophages

V Kinds of Immunity

1. Innate Immunity (or Innate Resistance)

2. Acquired Immunity

3. Naturally Acquired versus Artificially Acquired Immunity

4. Active versus Passive Immunity

VI Immunity to Various Kinds of Pathogens

1. Bacteria

2. Viruses:

3. Fungi:

VII Factors that Modify Immune Responses

I The Immune System is Specific

The immune system differs from the various nonspecific defenses in being specific. The immune system remembers exposure to particular specific microorganisms and diseases. [There is some specificity in the action of interferon against viruses, but they act against viruses in general, not just one kind.]

Strictly speaking the immune system remembers foreign molecules, rather than whole microorganisms. These foreign molecules are known as antigens and are component parts of infectious agents such as bacteria or viruses. Not surprisingly, antigens are usually molecules that are found on the outside of intruding microorganisms where they can be detected by the immune system.

The immune system includes protein molecules called antibodies, which recognize and bind to the antigens. Each antibody recognizes only one specific antigen. So antibodies against, say measles will not protect against mumps. In addition there is a family of white blood cells, the T cells, that also specifically recognize intruders.

The immune system must also be able to distinguish between SELF and NON-SELF (Foreign intruders). Non-self must be destroyed and "self" must not be harmed. In practice the immune system is not perfect and/or may be damaged and this may result in attacking your own molecules &emdash; auto-immune diseases &emdash; see later.

1. Antigens and Antibodies

Antigens = foreign molecules which provoke a response from the immune system. Antigens are normally foreign &emdash; i.e. from outside the body. They must be big enough to be regarded as cell components e.g. proteins with molecular weights over 10,000 work well as antigens but molecules that are too small do not work. Other macromolecules also work as antigens e.g. polysaccharides. Proteins with other types of molecule attached also work e.g. glycoproteins and lipoproteins.

Epitopes = separate recognition sites on the surface of a large molecule. A large protein may have several separate sites on its surface which the immune system recognizes and binds to. These are different epitopes although they are parts of the same antigen. Epitopes are also called antigenic determinants.

A whole bacterial cell or virus will have several different proteins and/or polysaccharides on its surface. Each of these may act as an antigen. Therefore any intruding microorganism will have multiple antigens and many of these will have several epitopes.

Hapten = a molecule that will not stimulate an immune response by itself. However, if it is attached to a larger or more immunogenic molecule, it can. This is how penicillin can cause an allergic response. Penicillin is too small to trigger an immune response by itself. If penicillin binds to another, larger molecule, then the immune system may respond. This may immunize the body against all parts of the aggregate, including the penicillin. After that, if penicillin is used again, the immune system recognizes it & responds.

Antibodies = proteins made by the immune system which recognize and bind to antigens. Each kind of antibody is specific for a certain antigen. One of the important characteristics of the immune system is specificity.

2. Cells and Tissues of the Immune System

Leukocytes refers to all white blood cells.

Lymphocytes are the sub-group of white blood cells that are responsible for immunity. There are two main kinds of lymphocytes:

B cells make antibodies. They mature in the bone marrow (B for bone). Plasma cells are large mature B cells that make large amounts of antibody and are found in blood plasma. (Plasma = blood fluid without the blood cells).

T cells carry out the cell mediated response. They mature mostly in the thymus gland (T for thymus). [Also maybe in bone marrow as thymus becomes less active in adults]. There are several major kinds of T cells:

Cytotoxic or killer T cells function to kill foreign cells.

Helper T cells are needed for the production of antibodies by B cells.

Suppressor T cells regulate the immune system.

Delayed-type hypersensitivity T cells cause some allergic responses.

Natural killer cells (NK cells) are a specialized type of T cell.

There are two main divisions of the immune system.

I The humoral response = antibody production by B cells.

"Humoral" refers to soluble proteins &emdash; i.e. the antibodies in your body fluids. These work best on bacteria and viruses that have not yet entered human cells and on toxins.

II Cell-mediated immunity = T cells.

More complex and less well understood. Cell-mediated response works best against eukaryotic cells:

a) Your own cells that have been invaded by viruses, or by bacteria that enter host cells or that have gone cancerous.

b) Cells from another person received by organ transplantation

c) Invading parasites that are eukaryotic &emdash; including protozoans, fungi, worms, etc.

Heterogeneity of the immune system. This refers to the fact that there are many different kinds of cells in the immune system. It refers not just to the different types of B cells and T cells but also to the fact that many sub-types of B cell and T cell exist that recognize many, many different kinds of antigens.

3. Immune Recognition of Self versus Non-Self

The immune system must be able to tell apart foreign microorganisms from the bodies own cells. If is going to defend the body by destroying invaders, it is vital that it does a good job of recognizing what is foreign and needs to be destroyed. It is even more essential that it recognizes cells that belong to the body otherwise it will end up attacking the bodies own cells.

Autoimmune disease = when self-recognition fails. This happens occasionally. Autoimmune diseases includes a set of poorly understood conditions including systemic lupus erythrematosis, multiple sclerosis, rheumatoid arthritis, and juvenile diabetes.

Complicated changes are made in the DNA of lymphocytes as they mature. This generates a vast number of different lymphocytes (both B cells and T cells) that each recognizes and responds to a different antigen. Those lymphocytes which recognize molecules that belong to the body itself ("self antigens") are prevented from developing.

Tolerance = when the immune system does not recognize or respond to the sort of molecule which would otherwise be an antigen &emdash; except that it is one of your own molecules. (That is, "self antigens" are tolerated.)

However, when a lymphocyte does recognize and respond to an antigen, that lymphocyte is stimulated to divide. These lymphocytes continue dividing until there are a lot of them. These include the B cells that produce antibodies and the T cells. This is called clonal selection, because each original lymphocyte gives rise to a group of identical descendents (i.e. clones) that recognize the same antigen.

4. Specificity of the Immune System

DNA changes happen in B cells and T cells DNA their maturation. This results in each line of immune cells recognizing just one specific antigen. (Strictly, each recognizes one specific epitope belonging to a particular antigen).

Because there are so many lymphocytes some of them will be bound to recognize similar or identical antigens. So more than one line of B cells or T cells will recognize any one particular antigen.

Despite this the antibodies made by the different B cells that recognize the same antigen will not be identical. Some will bind more tightly, others less well. If an antigen enters the body, a few B cells will recognize it. They will then divide and make antibodies. Most of the antibodies will be made by the B cell that recognized the antigen best. Those that bind the antigen less well will not be stimulated so much and will divide less.

Cross reaction: Suppose that a very similar antigen enters the body. That is, if we look at the chemical structure of this antigen, it looks a lot like the first antigen. Consequently it will bind to the antibodies to the first antigen. But not so well. The more closely it is related, the better it will bind. This is called a cross reaction. As a result, if you gain immunity to one strain of, say, influenza, you will be protected against other closely related virus strains to some extent.

5. Immune Memory

The B cells that actually make antibodies don't last for a long time - less than one week. But the immune response also produces some special B cells that last for a very long time. These are called memory cells. These have the special ability to recognize the same antigen if it appears again and to respond very quickly. If you are immunized and then get exposed to the antigen again much later, your immune system responds quickly. You start making new antibodies in time to prevent infection (or damage by a toxin).

Humoral immunity is the system that makes antibodies. Long before the body sees any invading antigens, the immune system has already generated a vast number of different B cells each capable of making a single type of antibody. The idea is that you possess at least one antibody that can bind any possible antigen that you might ever encounter. Each of this colossal number of antibodies is made by just a handful of B cells.

When an antigen enters it is recognized by whichever B cell carries the corresponding antibody on its surface. When the antigen binds, the B cell divides many times, eventually giving many larger plasma cells that secrete the one chosen antibody in large amounts. Helper T cells are also needed to help B cells get activated. In addition macrophages are involved. See below. Later on the response is turned off by the action of suppressor T cells. See below.

1. Structure of Antibodies (Immunoglobulins)

Antibodies are proteins. Also known as immunoglobulins (Ig). The basic unit is 4 chains - 2 identical copies of a heavy chain plus 2 identical copies of a light chain. Together these make up a Y shaped molecule.

The ends of the arms of the Y are highly variable in their amino acid sequence from one antibody to another. This part of the antibody is called the variable region and recognizes the antigen. The rest of the antibody is the constant region. Each original B cell makes antibody with a different variable region.

The constant region has several functions - it is involved in activating complement, in phagocytosis, and in allergic reactions.

There are 5 classes of antibody (M, G, A, E, D) and there are five corresponding classes of heavy chain. The antibodies in each class share the same type of heavy chain. There are 2 kinds of light chain. Both kinds of light chain may be found in any class of antibody. The classes of antibodies:

1) IgM is the first antibody made. It is present on B cells before antigen stimulates them to divide. IgM is attached to cell membrane of B cells. Structure is unusual &emdash; it is the only class of antibody that consists of 5 antibody units joined together (i.e. 5 lots of 2H plus 2L). Together with IgG, it is important in protection against bacteria and viruses (before they enter human cells). IgM activates complement and also causes microorganisms to clump together.

2) IgG is the main blood antibody. IgG is made next after IgM. Therefore it is very important in protecting us against foreign antigens. Made in especially high amounts in secondary response. Structure = one basic unit = 2H plus 2L. IgG crosses the placenta to provide protection before an infant's immune system becomes fully functional. IgG activates complement and promotes phagocytosis.

3) IgA is mostly present in secretions, like saliva, milk, colostrum, tears, even mucus, but is also found in small amounts in blood. In secretions IgA consists of 2 basic units held together (i.e. structure = 2 lots of 2H plus 2L). [In blood IgA consists of a single basic unit, i.e. = 2H plus 2L].

4) IgE is a mixed blessing. It helps with defense against bacteria, etc. but is most important against larger parasites, such as worms. But it is also the antibody responsible for allergies to things like pollen, animal dander, insect venoms, penicillin, some foods, mites in house dust - what is called immediate type hypersensitivity (see later). IgE structure = one basic unit = 2H plus 2L.

5) IgD is the mystery antibody - function unknown. Structure = one basic unit = 2H plus 2L.

2. Primary and Secondary Responses

Primary response = when antigen is first encountered:

When an antigen enters, B cells respond and in a few days antibodies are being made, mostly IgM at first, later also IgG. Then, if the antigen is eliminated the response levels off.

Secondary response = when same antigen is encountered again:

If the same antigen enters the body again, later on, the response is much faster and there is much more IgG made. Usually the intruder is overwhelmed quickly by the vigorous response. There is a smaller IgM response and a faster bigger IgG response. Due to having memory cells that recognize antigens introduced by immunization or by having the disease.

3. Kinds of Antigen-Antibody Reactions

There is a variety of ways in which antibodies react with antigens. Not all antibodies do all of these with every kind of antigen. The kinds of reactions that can occur:

1) Agglutination: bacterial cells clump together.

2) Opsonization: antibodies help phagocytes recognize and bind to the antigen so that phagocytosis is stimulated.

3) Stimulation of the complement system [IgG and IgM].

4) Bind to toxins, therefore making them inactive [IgG].

5) Bind to viruses, preventing them from infecting cells [IgM, IgG, and IgA].

4. Monoclonal Antibodies

Monoclonal antibodies = antibodies all made from a single kind of B cell and therefore all identical.

Natural antibodies isolated from blood consist of a very complex mixture. Monoclonal antibodies were developed to obtain large amounts of pure antibodies against a single antigen.

The problem is that B cells live only a few days and will not grow and divide in culture. Cancer cells continue to grow and divide when they should have stopped. To make monoclonal antibodies an antibody producing B cell is fused with a cancer cell to give a hybridoma. The hybridoma cells continue to grow and divide in culture and also produce antibodies. So you get a large population of cells all making exactly the same kind of antibody. Monoclonal antibodies are used in clinical diagnosis to identify antigens that are characteristic of a particular disease. They are being experimentally tested as possible therapeutic agents against certain infections and cancers.

In cell-mediated immunity the invader is attacked by a whole cell (instead of just an antibody molecule). T cells are responsible. T cells mature in the thymus. They do not make antibodies but have receptors similar to antibodies on their surfaces (T cell receptors). This way, T cells can also recognize and respond to specific antigens. Just as there are vast numbers of B cells each with different antibodies that were made before the antigen even appears, so there are vast numbers of T cells each with different T cell receptors.

1. Helper and Suppressor T Cells

Helper T cells are needed to allow a B cell to divide and produce antibody in large amounts. The story starts when macrophages swallow an infectious agent and degrade its components. Fragments of these (i.e. antigen fragments) are then moved to the cell surface of the macrophage. There they may be recognized by the T cell receptors of a helper T cell. This activates the T cell. The activated T cell can then go on to activate a B cell that recognizes the same antigen. Helper T cells also interact with cytotoxic T cells to activate them (see below).

Helper T cells are the kind of cells that HIV mostly infects. The HIV virus recognizes the CD4 receptor protein on the surface of T helper cells. When the helper T cell population is decreased or destroyed the immune system fails to work right and B cells are not stimulated to make antibodies.

T suppressor cells suppress the immune response so it does not go on forever.

2. Targets of Cell-Mediated Immunity

Cell-mediated immunity is most important in responding to eukaryotic cells that have a foreign antigen on the surface. Eukaryotic cells that are attacked include:

a) Fungi

b) Protozoa

c) Worms

d) Our own cells infected with viruses, because then they have viral antigens on the cell surface

e) Our own cells when they become cancerous, because they have "foreign" antigens on the surface. These are not really foreign antigens &emdash; they are our own proteins that should not be made by the cells in question.

f) Cells in organ transplants. When a patient gets a new liver or kidney they must be treated with immune suppressive drugs to keep the T cell response down. That makes the patient more susceptible to infection.

3. The Cell-Mediated Immune Reaction

When an infectious agent or toxin enters, a macrophage engulfs it, breaks it apart and transports some of the antigens to the surface of the cell where they are bound to special molecules known as histocompatibility proteins. This is called antigen processing. These antigen fragments are then "presented" to T cells, which then respond by dividing.

This produces: helper T cells, suppressor T cells, delayed-type hypersensitivity T cells, and cytotoxic T cells, which are all specific for the particular antigen. Memory T cells are also produced.

Cytotoxic T cells recognize foreign antigens and are particularly effective at killing virus infected cells but also attack tumor cells and transplanted cells.

Delayed type hypersensitivity T cells stimulate inflammation. They secrete substances that stimulate macrophages. They also are responsible for some kinds of allergic reactions such as contact dermatitis (e.g. poison ivy allergy) which does not happen immediately but maybe hours later.

Natural killer cells (NK cells) are not specific and don't require activation by macrophages, unlike other T cells. They are very effective at killing altered host cells that have "gone bad" and now have foreign antigens on the surface. These include: virus infected cells, cancer cells, transplanted cells (which are non-host but usually same species so very similar), cells infected by bacteria or other intracellular parasites. They can also attack fungi and bacteria.

After contact with the target cell, the NK cell secretes lytic proteins called perforins that penetrate the membrane of the target cell, resulting in lysis and death. They resemble cytotoxic T cells in their ability to kill foreign cells but differ in being able to kill in the absence of stimulation by specific antigens. NK cells are capable of destroying malignant and virus-infected cells in vitro without previous exposure to the foreign antigen.

4. The Role of Activated Macrophages

Delayed type hypersensitivity T cells secrete substances that activate macrophages. The activated macrophages differ from unactivated macrophages in secreting more hydrogen peroxide and other products that kill ingested cells. So activated macrophages are more likely to kill organisms that might otherwise be resistant and sometimes survive inside macrophages - cells like Mycobacterium, Listeria, Brucella. Activation is nonspecific. Macrophages may be activated by T cells stimulated by one organism but they will be activated against all intracellular bacteria.

1. Innate Immunity (or Innate Resistance)

Innate immunity = inborn resistance to a disease. Any particular infectious agent only infects a small range of hosts. You cannot catch feline leukemia even if the virus was injected into your bloodstream, and your cat cannot catch smallpox.

The inherent properties of each species, including humans, prevent most infectious agents from successfully infecting. For example, most viruses don't infect humans because we don't have the correct receptors on our cells.

Such inherent resistance also differs between human populations and between individuals. To a large extent this is due to genetic differences.

2. Acquired Immunity

This refers to the action of the immune system in providing specific immunity. Such immunity is usually acquired by exposure to the disease agent in some way.

3. Naturally Acquired versus Artificially Acquired Immunity

Naturally acquired immunity is when you catch a disease and your body makes an immune response. The immune system will remember and if you are infected with the same disease agent later, you will be protected &emdash; i.e. you have become immune.

The other way to get naturally acquired immunity is a special case. Antibodies can cross the placenta from mother to fetus and are also transferred from mother to baby through colostrum and breast milk. Colostrum is the first secretion of the mammary glands after birth. Milk is made later. Colostrum in particular has a lot of antibodies from the mother. Notice that in the mother to fetus or mother to baby transfer, the infant receives ready-made antibodies from somebody else.

Artificially acquired immunity is when a vaccine is injected, or when you receive serum with antibodies in it made by somebody else.

4. Active versus Passive Immunity

Active immunity is when you make your own antibodies and your own immune system remembers an infectious agent. If you have an infection, or if you are vaccinated, your immune system responds to the infectious agent. This response takes several days and is relatively slow compared to the non-specific defenses. However, the immune system gains the ability to recognize the agent if you ever infected again &emdash; this is immune memory. Upon later infection the immune system responds very quickly and very specifically. This gives you long term protection.

Passive immunity is when the antibodies are made by someone else and your own immune system does not respond. When an infant gets antibodies from its mother, or if an individual receives serum with antibodies in it, the immunity lasts only a short time, maybe a few weeks or months. In this situation the immune system does not learn to recognize the intruder and therefore the immunity does not last. If you are re-infected you will not be protected.

1. Bacteria

Nonspecific - includes mechanical barriers, acids, cilia, mucus, phagocytosis (which can be stimulated by specific immune responses). In addition special antibacterial substances like lysozyme and defensins.

Specific - mostly due to antibodies made by specific B cells.

2. Viruses:

Nonspecific - as above, plus interferon.

Specific - both cell-mediated and antibodies.

3. Fungi:

Nonspecific &emdash; largely as against bacteria.

Specific- probably mainly cell-mediated.

Our immune systems are not all exactly the same and even one person's immune system does not always work the same.

1. Age &emdash; the very young and very old have less vigorous immune responses. The very young do not have fully developed immune systems until age 2 or 3. They also have not yet acquired memory cells that respond quickly to many infectious agents.

2. General health - poor nutrition, alcohol abuse, drug abuse will all decrease the ability of the immune system to respond.

3. Stress - physical or emotional

4. Some chemical agents - smoking, air pollution, some medications. Specific medications are used to depress the immune system in people receiving transplants.

5. Radiation can also be used to depress the immune system.

6. Some infections &emdash; especially HIV, because it affects helper T cells.