How is SELF recognized? How is NONSELF (foreign) recognized?

We CAN NOT SURVIVE without a functioning immune system. Without it, no amount of antibiotics or medical treatment can keep us alive for more than a brief time. This is painfully illustrated by the death of AIDS victims.

THE SPECIFIC IMMUNE SYSTEM = Previously we have discussed the nonspecific defense system that protects us, more or less, from all pathogens. The specific immune system (or often called the IMMUNE SYSTEM) protects us against SPECIFIC NONSELF ORGANISMS and substances. It is an INDUCED response; that is it must be TAUGHT which things to attack.

ANTIGEN = An antigen is anything that elicits the formation of a specific immune response. Older definitions limits the definition of an antigen to ".....formation of an antibody.", however, as you will learn there are two levels (duality) to the immune system.

EPITOPES = These are the unique regions (or chemical groups) on a molecule that are antigenic; i.e., that elicit a specific immune response.

ANTIBODY = A special group of soluble proteins that are produced in response to foreign antigens.

IMMUNE CELLS or LYPHOCYTES= These are the VARIOUS CELLS of the specific immunity system that respond to SPECIFIC foreign or nonself antigens.

Antibodies are a group of soluble, proteins that have unique binding sites on them which recognize and bind to the epitopes of antigens. As previously described with enzymes, allosteric sites and other binding site-situations, the antibody binding sites are higly specific. There are several types of antibodies with a variety of different functions in the specific immune response which will be discussed as appropriate. Figure 1 illustrates the relationship between an antigenic molecule, its epitopes and the soluble antibodies produced against it.

Figure 1. On the left is illustrated a folded, functional protein. It might be an enzyme, or a cell wall receptor site protein or a ribosomal protein etc. On this protein there are certain groups of amino acids  that comprise epitopes. These groups are defined as epitopes because they elicit an immune response and for no other reason. Since each of the epitopes is a different and unique chemical cluster, each one of them induces a unique antibody. Each antibody will bind tightly to its particular epitope and not to any of the others. Within this cartoon lies the core information one needs to understand how the immune system works. That is, if you know how one car works, you have the core information on how all cars work, only some details differ.

INNATE IMMUNITY = This can best be described as GENETIC IMMUNITY or that immunity an organism is BORN WITH. This type of immunity can be an immunity that applies to the vast majority of the members of a species (SPECIES IMMUNITY), or it can be an immunity that applies to only a certain subgroup within a species down to a few individuals within that species. For example, cattle suffer from the cowpox virus, but appear to have a SPECIES IMMUNITY to the closely related smallpox viruses, whereas smallpox is a deadly disease to humans , but cowpox is a mild localized skin infection. Humans are susceptible to the HIV virus, but most of our related primates are immune to HIV, but they suffer from HIV-like viruses to which we appear to be immune. Within a species there may exist SUBGROUPS that are STATISTICALLY immune or resistant to particular pathogens. For example, the Northern Europeans appears to be more resistant to tuberculosis than are most Africans, whereas Africans are naturally resistant to a variety of African diseases that readily kill the "whites". Finally, because of the genetic variation within every species INDIVIDUALS are statistically more resistant to some diseases, and more susceptible to other diseases. Most of you know those within your own families that "rarely" get colds or the flu, while other family members catch one respiratory infection after another. While there are many factors (diet, stress etc.) that could explain these individual differences, one of them is that certain COMBINATIONS OF GENES render some more resistant to the common cold viruses, whereas others of us are very susceptible. This type of immunity has NOTHING TO DO WITH the type of specific immunity we are discussing in this section.

ACQUIRED IMMUNITY = This refers to immunity that one acquires in one of two ways, active or passive. These are subdivided into the following further categories:

a) ACTIVE NATURALLY ACQUIRED IMMUNITY = This occurs when individuals suffer from
    a natural infection of a pathogen and become immune to that pathogen upon recovery (e.g.
    chickenpox)
b) ACTIVE ARTIFICIALLY ACQUIRED IMMUNITY = This occurs when individuals are
    actively vaccinated with an antigen that confers immunity.

c) PASSIVE NATURALLY ACQUIRED IMMUNITY = This occurs when individuals receive
    antibodies from their mother by a natural process, such as in BREAST MILK or in-utero transfer of
    antibodies from mother to fetus. In mammals, mother's milk is know to contain a large concentration
    of antibodies and other antiviral and antibacterial substance that protect the newborn infants. Further,
    the mother's antibodies cross the placental barrier, particularly near the end of term. In both these
    circumstances the infant is only resistant to whatever the mother is resistant to.
d) PASSIVE ARTIFICIALLY ACQUIRED IMMUNITY = This occurs when individuals are
    injected with POOLED serum from immune individuals that contain antibodies against a large number
    of pathogens. In the case of humans, a fraction of blood serum, GAMMA GLOBULIN, that is
    highly enriched in antibodies is injected into individuals that have been exposed to certain pathogens.
    The GAMMA GLOBULIN is obtained from pooled sera from many individuals and thus contains a
    broad spectrum of antibodies.

• Gamma globulin is the material was given to people who have been exposed to the hepatitis A virus in the contaminated strawberries in the Spring of 1997.

The ACTIVE forms of immunity are generally long lived, particularly in the case of recovery from a CLINICAL INFECTION. Sometimes this immunity it lifelong, but in other cases it is not. Vaccinations may induce long-lived immunity, but recent data indicate that vaccinations may not last as long as once was hoped. For example, there is a very effective vaccine against tetanus, but it lasts only a few years and every year hundreds of people who have been vaccinated against this bacterium die because they have not gotten their BOOSTER SHOTS (vaccinations given periodically to booster the immunity of previous vaccinations) every three to five years.

II. THE CELL-MEDIATED IMMUNE SYSTEM.
The second component of the specific immune system involves a special class of cells called T-cells. There are several important types of T-cells, each with unique responsibilities in immunity. The T-cells do not produce antibody, but they react directly with other cells. They might be thought of as the HIT-MEN of the immune system; point out a foreign cell and they gang up on it, beat the dickens out of it until there is nothing left but a few bit 'n pieces of garbage floating around. Once in while they go crazy and decide to attack their own host cells and then there is a serious problem (e.g. arthritis).

III. THE PHAGOCYTIC COMPONENTS OF THE IMMUNE SYSTEM.
Cells of the nonspecific defense system, known as macrophages, monocyte and neutrophil, are involved in a complex relationship in which they recognized and then ATTACK FOREIGN MATERIAL, destroy it and process it for use by the specific immune system. They use chemical signals to each other to coordinate their defense of the host.

IV. COMPLEMENT.
Another important component of the specific immune system is a group of proteins called the COMPLEMENT SYSTEM. Complement is a GROUP OF PROTEINS that, like the antibodies, are soluble and reside in the serum. Complement is a COMPLEX OF ENZYMES that mainly act on foreign cells by punching holes their membranes to cause their LYSIS AND DEATH. Complement works in concert with the SPECIFIC ANTIBODIES that "point out" the cells to be attacked by the complement; i.e., the antibodies act to "FINGER" (identify) a target cell and the complement acts as the "HIT MAN" that kills the targeted cell. In addition complement, plus antibody, designate which cells are to be engulfed by the phagocytic cells. Complement can also result in immunological damage to ones own cells in the case of diseases caused by faulty immune systems. One such reaction is the serious allergic response known as ANAPHYLACTIC SHOCK.

The steps in the immune system development are:

a) Stem cells, which are the PARENT CELLS of all immune cells, enter the liver of the fetus and
    develop to a point there.
b) From the liver some stem cells move into the bone marrow (at the center of the bones) where
    they differentiate into B CELLS and NATURAL KILLER CELLS.
c) Other stem cells move from the liver into the thymus gland located in the middle of your chest.
d) The thymic stem cells differentiate in a variety of T cells.
e) Other stem cells go on to differentiate into other blood cell lines such as macrophages.

The immune system is spread throughout the entire body and includes the following (a partial listing):

• Adenoids & tonsils
• The lymph nodes & lymphatic system
• The Spleen, appendix and small intestine
• The bone marrow
• The thymus gland

Figure 4. This figure shows the location in the body of various components of the nonspecific and specific immune systems. The B cells and a variety of other lymphatic cells are made in the bone marrow. The lymph nodes contain the macrophages, B cells and T cells, which is why your lymph glands swell up and become tender to the touch when you have an infection. The thymus gland is the gland where the differentiation of the T cells occurs. Other macrophages, monocytes and phagocytes reside in the liver, spleen and lungs. Special immune cells have been found in the brain, in the skin and in the cells lining the intestine. Breast milk contains a variety of the mother's white blood cells that kill microbes in the infant's gut and stimulate the development of the infant's immune system as well as antibodies and 10 other microbial inhibitors (Sci. Am. Dec. 1995)

Instead of thinking that the immune system had to be INSTRUCTED AHEAD OF TIME as to which antibodies would be required throughout a life time, clearly an impossible task, N.K. JERNE suggested that the immune system was SELECTIVE rather than instructive. Jerne reasoned that the immune system must randomly made billions of different specific-epitope-binding antibodies and then let the antigens that accidentally stumbled into the host chose or select which antibodies would be produced in quantities large enough to be protective. In a sense this is just another twist on the "survival of the fittest" process in evolution. Burnet in Australia and Talmage in CO then hypothesized that antibodies SIT ON THESURFACE of lymphocytes and that each lymphocyte manufactures only a SINGLE ANTIBODY (which recognizes and binds to only a SINGLE epitope). This theory has been shown to be essentially correct by a number of brilliant experimentalists.

2. The B cells that produce self antibodies are DESTROYED, leaving only lines or CLONES of B cells that produce random antibodies to foreign epitopes.

3.When a particular foreign epitope (for example, antigen 2,025) appears in the host's body it is PROCESSED by lymphocytic cells of the nonspecific defense system. This sets off a sequential series (cascade) of events that eventually acts on a small population of randomly-produced B/T cells that happen (by chance) to have on their surface, antibody (2,025) which binds to ANTIGEN 2,025.

4. These events trigger a RAPID PROLIFERATION of that PARTICULAR B (and T-cell) cell population (2,025), producing a large number of clones. These 2,025 B cell-clones differentiate into PLASMA CELLS (Fig. 3) which are ANTIBODY-PRODUCING-FACTORIES that spew out prodigious quantities of ONE ANTIBODY-#2,025, that binds to the specific antigen-epitope 2,025 that stimulated it.

5. The specific antibody floods through the host and wherever it binds to its epitope it MARKS IT FOR ATTACK and destruction by the appropriate cells and associated components of the immune tem (complement and PMNs etc.).

Figure 3. The process of B & T cell differentiation and CLONAL SELECTION. The parental STEM cells migrate to the bone marrow and to the thymus gland where they differentiate into B and T cells which make random epitope binding proteins. When a foreign epitope binds to the appropriate site on the B & T cells, they replicate into clones that, in the case of the B cells differentiate into PLASMA cells that produce prodigious quantities of specific antibodies. The T cell clones further differentiate into several different T cell types with specific functions.

Figure 4. The response to an antigen (Ag) in terms of the production of a specific antibody over time. Initially the levels of each unique antibody are extremely low, however as soon as the stimulation events occur (Fig. 7) and the plasma cell clone begins producing antibodies the TITER (concentration or quantity/volume) of the unique antibody begins to rise. It takes about 2 weeks for the Ab level to peak. Once the foreign antigen is removed, antibody production slowly returns to a low level, however MEMORY PLASMA CELLS remain in the system. When the original antigen again appears in the host these memory cells respond rapidly and produce even higher levels of antibodies. This "REMEMBERING RESPONSE" is why we remain immune to many diseases for a long time. The secondary exposure to the antigen may be natural or it may be artificial in the case of booster vaccinations. As parents we are responsible for seeing to it that our children are initially vaccinated and that their booster shots are given at the appropriate ages.

There are five different types of antibodies, however in this course we will discuss only the most common one, IgG, in detail. However, note that the other 4 types physically resemble the basic structure of IgG. IgG does most of the humoral immune work. The figure below shows the physical structure of the IgG molecule.

 
Figure 5. The IgG molecule. IgG is composed of two protein subunits, a LIGHT (blue) and a HEAVY CHAIN (orange) named appropriately according to their relative sizes. The various chains are bonded together to form the IgG molecule with disulfide bonds (S-S bonds). Note the two arms & the heavy 'n light chains.

The Y-shaped structure is real as electron microscopic pictures show. However, even before they viewed IgG in an electron microscope immunologist had discerned its basic shape. They knew that each antibody had to have two equivalent binding sites for its specific epitope. It turns out that those two binding sites are located at the end of the short arms of the Y.

The IgG molecule is further divided into CONSTANT and VARIABLE REGIONS OR DOMAINS. The constant regions have mostly the SAME amino acid sequence in all IgG molecules (we won't discuss the differences here), whereas the amino acid sequences in the variable regions are DIFFERENCE for each unique antibody produced by a clone of plasma cells. The amino acid sequence in the variable domains are such that they tightly bind to particular epitopes. Thus they show the same lock-key relationship as do enzymes/substrates and enzymes/allosteric molecules and viruses/target cell receptors.
 

NEUTRALIZATION = When the antigen is a soluble toxin, the addition of an Ab against it will usually render the toxin INEFFECTIVE (nontoxic), that is it NEUTRALIZES it. Such neutralized toxins are called TOXOIDS and can be used as vaccines. For example, if you were suspected of suffering from either tetanus or botulism poisoning the treatment would involve giving you a shot of the appropriate antitoxin, which is a common name for the Ab against a toxin. The antitoxin circulates through your body and binds and neutralizes any toxin it contacts.

PRECIPITATION = Under the proper conditions a soluble antigen can be precipitated in the presence of its Ab because of the of antigen-antibody net-work that forms gets large enough to form masses that SETTLE OUT (precipitate) on their own.

AGGLUTINATION = When the antigen is a large PARTICLE, like a whole bacterium or a RBC, the addition of its Ab will form an Ab-antigen net work that causes the particles to CLUMP IN LARGE MASSES like milk coagulating when it spoils. This agglutination is easy to see and is useful for diagnostic purposes. For example, if you want to see if a person is making Ab against a particular bacterium, mix the person's serum with the suspected bacterium; if the bacteria clump into large globs it means that Ab are present. Both precipitation and agglutination are illustrated below.

Figure 7. Antibody/antigen complex forming a larger complex. These nets can grow so large that they become insoluble and visible to the eye. The network forms because of the dual-binding characteristic of the antibody which allows it to attach to two different antigen molecules at the same time.

1. A macrophage engulfs a virus or bacteria & breaks down their proteins. Antigenic fragments of these proteins are presented on the surface of the macrophage.

 
2. The few Th-cells, which contain receptors on their surface that recognizes a particular presented foreign antigen, INTERACTS WITH that unique-foreign antigen. This interaction triggers a series of events that ACTIVATES the Th-cell.
3. The activated Th-cells are stimulated to proliferate, producing a population of this class of Th-cells (clonal selection). The activated Th-cells interact physically (have contact with) with only those rare B-cells that make antibody that recognizes the SAME antigen molecules that have activated the Th-cell. During this interaction the Th- & B-cells recognize each other
4. by their common recognition of the unique antigen.

1. The B- and Th-cell interaction stimulates the Th-cells to produce chemicals (CYTOKINES) that, in turn, stimulate the appropriate B-cells to proliferate (clonal selection) and to DIFFERENTIATE into Ab-producing plasma cells that produce the Ab that bind the antigen that the Th-cell originally reacted to. 

Figure 8. Activation  & killing by Tc killer cells of cells displaying a unique surface antigen. Note the virus particles in the cell on the right and the presence of unique viral proteins on its surface to which the Tc cells bind.

Other T cell types exist and probably more types will be found. The above is an incomplete and simplified explanation of what is currently known about the immune system. Some of it will undoubtedly be modified as new facts come to light and we will surely find that it is even more complex and subtle than previously imagined. It's like human relationships which usually start out simple, but the become more complex as time goes on.