UPDATED: 01/12/00 UPDATED: 01/12/00
MICROBIOLOGY | CHEMISTRY | MEDICAL
Worm diet encourages immune system
Use of New Vaccines to Fight Common Diseases; Flu Vaccine Improvements; Malaria Vaccine
Use of Umbilical Cord Blood to Repair Immunity; Stem Cells to Grow Organs
Designer Babies: Eliminating Bad Genes
Eating pizza helps the immune system 4/99
The principle of molecular recognition. Ligand/receptor interaction of . Biological molecules interact by recognizing and binding with one another in a highly specific manner. Pairs of molecules that interact in this way are called RECEPTORS or BINDING SITES and LIGANDS respectively. Specific regions of atoms (molecular domains) on a receptor molecule have the characteristic of binding or attaching (docking) specifically to unique molecular domains on specific ligands. In this chapter we will discuss how the human immune system works and make our lives possible. You will come to understand how antibodies and other immune components can act to specifically to protect you even against small changes in your own cells, such as those on cancer cells. Permission to use this cartoon was granted by Sigma Chemical Co.
The UNDERLYING UNIVERSAL PRINCIPLE of the immune system deals with recognizing (FOREIGN) based on the principle of ligand/receptor binding described in the figure above. In a competitive and deadly world, self is usually GOOD and nonself is usually BAD. This LAW defines both the strengths and the weaknesses of the immune system and foreshadows its inherent problems. It is like the predicament one often sees portrayed in the movie plots where the hero/heroine find themselves in a dangerous situation with a weapon in hand and surrounded by people of unknown character, each claiming to be their friend ("trust me") while warning the hero/heroine that the others are their enemies. The dilemma is "how do you know who to trust and who is telling the truth?"; There is a scene in "Indiana Jones and the Last Crusade" where Jones has to chose between a beautiful woman and his father that illustrates the complexities of this problem. The immune system can thus be viewed from two perspectives:
How is SELF recognized?
How is NONSELF (foreign) recognized?
Clearly these are two sides of the same coin and the answer to one inevitably leads to understanding the other. Consider the DEVELOPING EMBRYO in a #multicellular organism like a mammal; in a real sense to the mother the embryo is !! With immunity a multicellular organism must take into account the fact that its cellular constituents, except for identical twins, belong to a very unique gene pool of ONE. However, although a fetus is not SELF, it can not be attacked as nonself if the species is to survive. Once self recognition is achieved the multicellular organism must now differentiate between self and ALL the other NONSELF material on the planet, including its own progeny; clearly a formidable task.
As has been described previously, the problem of COMMUNICATION between biological molecules such as #enzymes, their substrates, and their regulatory molecules, as well as in #phage/virus binding etc. has been solved through the principle of SPECIFIC LIGAND/RECEPTOR INTERACTION. Thus the problem of differentiating between self and nonself is not one of developing a "specific recognition system", since that already exists, but how does a multicellular organism design a system for discriminating self from the millions of NONSELF substances in the environment throughout its life time? It turns out that the immune response depends upon the process of genetic #recombination to solve this problem.
One final point: 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.
To recognize the various types and levels of immunity
To learn the basic components of the immune system
To understand how the immune system works at a fundamental level
To gain an understanding of the future of immune research and its
potential impact on OUR LIVES.
Women in a number of undeveloped
countries put breast milk in the infected eyes of their
infants. Why might they do that? If you were a health worker would you advise them to
continue this "treatment" or would you warn them that milk is a great medium
from the growth of microbes and advise them to stop doing this?
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 (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 PARTICULAR UNIQUE
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. To view the structure of an antigen, antibody and epitope
see the RasMol:Gallery
and view the section on Antibody and antigen binding. Also take a look at the following:
What the heck is an antibody? | More pictures of antibodies | Index of antibody movies. You'll have to have the right "Helper Applications" and a lot of memory to see these so take care.
This site contains the best tutorial on antibody structure I've seen (Go to INDEX>ARCHITECTURE OF PROTEINS>LECTURE 5>STRUCTURE OF HUMAN IMMUNOGLOBULIN G). It requires the helper application Chime, Netscape 3.0 or better and a fast computer. It is fantastic, although it is advanced for Micro 101/102 students, if however you go through this & learn it, I guarantee that you'll understand what antibodies are and how they work.
IMMUNE CELLS or LYMPHOCYTES= These are the VARIOUS CELLS of the specific
immunity system that respond to SPECIFIC foreign or nonself antigens.
FAQ: "Exactly what are ANTIGENS and how can they cause problems like allergies?"
Antigens are usually MACROMOLECULES like #proteins and #polysaccharides; small molecules usually make POOR antigens, but they can be antigenic under certain circumstances. For example, antibodies against hormones are how pregnancy tests work.
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 HIGHLY 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. Epitopes. 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 ATOMS 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 immunity an
organism is BORN WITH.
Part of this immunity is the NATURAL DEFENSE SYSTEM described in the
previous chapter. 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. Some
examples are:
Within a species there may exist SUBGROUPS that are STATISTICALLY immune or resistant to particular pathogens. For example:
INNATE immunity is different from the SPECIFIC immunity discussed in this section. However, both system interact so as to provide better protection to the host.
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). ACTIVE ARTIFICIALLY ACQUIRED IMMUNITY
= This occurs when individuals are actively vaccinated with an antigen that confers
immunity. 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. 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. PASSIVE acquired immunity is short lived as the antibodies eventually die off or are
themselves removed from the body as foreign protein. Since the person receiving the
passive dose DOES NOT PRODUCE their own antibodies, the immunity is TRANSIENT.
The ACTIVE forms of immunity are generally long lived,
particularly in the case of recovery from a CLINICAL INFECTION. Sometimes this immunity is
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.
FAQ: "Are vaccines safe to use?"
Should we bother to immunize ourselves and our children? Isn't the US so safe that vaccinations are not needed anymore?
The future of vaccination looks very promising due to three emerging technologies. These are, the use of DNA to vaccinate animals, including humans, new injection devices and novel drying techniques that convert vaccines into dry forms that can be stored for long periods without refrigeration:
NEW DRYING TECHNOLOGIES
Most vaccines require constant refrigeration to remain functional. This makes vaccination in remote areas of the world difficult and expensive, and is called the "refrigeration element". Maintaining a "cold chain" to remote areas like central Africa costs over $200 million per year. Recently it has been found that a number of living organisms can protect themselves from damage by drying if they contain a high concentration of the simple disaccharide sugar trehalose. Such organisms (cryptobionts) that have been completely dried can be returned to life, without apparent harm, by the addition of water.
This trehalose-based drying and stabilization technology is being applied to vaccine antigens. Measles vaccine dried with trehalose suffered no loss of activity after two months at room temperature compared with commercially dried material that lost >90% of its activity in the same period. Trehalose-dried DT&P vaccine could be stored at 60oC for 12 weeks without loss of activity.
EXTRA CREDIT COMMENTARY: 15A
Do you plan to have your children vaccinated against the common childhood diseases? Explain your reasons for your choice.
DLS: Luke Heath 1/12/00
Our government is made up of individuals whom the American citizens have elected democratically. The government was set up to protect its citizens and to provide a safe environment at the interest of the people. At times, the publics best interest is not honored (i.e. Jim Crow Laws, Slavery, etc.), but the American people have contended for the rights to freedom, peace and the pursuit of happiness. When the instuition of government is underattack (i.e. World War II), individuals have gathered together in support and set aside their freedoms to protect their hertiage and their future. Many people would call it honor or even duty, but the reality of these actions stood for self preservation.
Even though we are not being bombarded by Japan or Germany, there is a smaller and potentially more dangerous enemy. Diseases like HIV, polio, measles and whooping cough are very serious and can be detrimental to our society. A wide spread epidemic of TB or HIV could literally destroy the people that make up our nation. When asked on whether or not the government has the right to levy taxes and mandate immunizations, I ask, "Is this going ensure are freedom and existence at our nations best interest?" If so, I would not have a problem to guarentee a better health and standard of living at the expense of the taxpayer. The government should use the benefits of society to protect its existence. What I mean, is that the discovery of vaccines to battle against virulent diseases should be used to prolong life. Finding the facts and forcing doctors to report the cases of the diseases like HIV, should be done to further promote awareness and control on the problem. If no one reports the disease, how are going to fight it. We pay the government money to spend money on research and developement of drugs that can inhibit the mortality rates.
The government was set up order and to prohibit chaos. As a result, certain laws are passed to stop pandimoum and needless destruction and death. Again, people elected officials to set up rules that would promote order, but there was check and balances to make sure the officials did not step out of line. For the most part, there has been little trouble with protecting peace and order. As a result, our country has established a life of 200 years and hopefully continue to live on even after I pass on. Religion is one of those check and balances, but even within religion there are checks and balances. Religion promotes morality and virtues and gives life and hope to a nation. Much of the constituition was set up by the hertiage of Christianity. I believe that most religions promote order and self-preservation, like love your neighbor as yourself. Therefore, it should not be much of a problem for a religion to support its government and vice a versa.
I plan to have my children vaccinated for three reasons. First, I would do it for them so they could be immune to a potential killer. Second, I would not want to feel the pain or guilt if they did come down with the disease. Last, I would do it to help eliminate the virus or disease to promote a safer environment.
The specific immune system exists throughout the body, but a major portion of it circulates in the blood and lymphatic systems, as they flow throughout the body. The human specific immune system is a two level or DUAL SYSTEM consisting of soluble antibodies and special immune cells. The two systems work intimately as a coordinated unit. Foreign material is dealt with by both components of this dual system. The cellular components of the specific immune system includes a host of specialized cells; new ones are being discovered all the time. The entire process of specific immunity is initiated by non-specific immune cells, the phagocytic cells of the nonspecific defense system, which act as general scavengers and a kind of "attack dogs". These cells engulf or ingest any material they perceive as foreign/nonself. Once inside these phagocytic cells the engulfed material is digested and its chemical components are processed for use by the specific immune system. The two components of the specific immune system are described in greater detail below.
Shown in Figures 2 & 3 are some of the various white blood cells involved in the immune system. Some are part of the nonspecific defense system and some are components of the specific immune system. Telling the difference between these cells is difficult, but because their individual form (morphology) and relative numbers of the different types are important tools in disease DIAGNOSIS, they are carefully studied. A variety of #different stains are used to help the medical technologist and pathologist distinguish between the different cell types. However, many are indistinguishable morphologically and can only be differentiated by antigenic differences. Click here to view immune cells.
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One of the professions open to Microbiologists is that of Medical Technology. Medical Technologists are responsible for analyzing patient's fluids, including determining the types and numbers of the various different cells present in a patient's blood. Thus a Medical Technologist would be expected to identify each of the blood cells shown in Fig. 2 & 3. However, as computer imagery gets better slides will be scanned by computers and diagnoses only verified by medical personnel.
THE HUMORAL IMMUNE
SYSTEM One part of the dual level specific immune system is called the HUMORAL system. The humoral system involves the soluble ANTIBODIES described above. These antibodies circulate through the blood and lymph system. When blood is spun in centrifuge (or allowed to sit quietly in the refrigerator), the red blood (RBC) & white cells (WBC) settle or PELLET to the bottom of the tube, leaving behind a straw-colored liquid called the SERUM. The antibodies, and other soluble components of the blood, are located in the blood serum. Antibodies are made by SPECIAL B-CELLS, called PLASMA CELLS that make and excrete huge quantities of antibody molecules.(Fig.3).
THE
CELL-MEDIATED IMMUNE SYSTEM The second component of the specific immune system involves a special class of cells called T-cells. There are many different types of T-cells and new ones are being discovered frequently. Each population T-cells has a unique role in the immune process. Although T-cells do not produce antibody, they contain antibody-like receptors on their cell surfaces that specifically bind to foreign ligands in exactly the same way that antibodies do. Further, they also have other receptors on their surfaces that identify other cells within the body with which they are designed to interact. They have many roles. One important role is to act as the HIT-MEN of the immune system. When a foreign cell is pointed out to these "killer cells" 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).
Cells of the #nonspecific defense system, known as macrophages, neutrophils and polymorphonuclear neutrophils, are involved in a complex relationship in which they recognize and then ATTACK NON-SELF MATERIAL, destroy it and process it for use by the specific immune system. All the components of the immune system are intimately tied together much like the members of a smooth running sports team or an army. They use chemical signals to each other to coordinate their defense of the host. This entire process is only partly understood and is so exceedingly complicated that it should keep a lot of biological scientists off the streets for a long time into the future (just ask their mates). But these scientists seem to need to eat (every time we train one not to eat they die on us) so they will be coming to you citizens FOR MONEY to pursue this research.
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 in 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.
Now we come to the issue brought up in the introduction, namely: How does the body distinguish the good-guys from the bad-guys?
The steps in the immune system development are:
Stem cells, which are the PARENT CELLS of all immune cells,
enter the liver of the fetus and develop to a point there.
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.
Other stem cells move from the liver
into the thymus gland located in the middle of your chest.
The thymic stem cells differentiate into
a variety of T cells.
Other stem cells go on to differentiate
into other blood cell lines such as macrophages.
Immunologists are making rapid headway in unraveling the complexities of these various differentiation's, but the differentiation process is extremely complex and subtle. From my perspective of >40 years in microbiology I have observed tremendous progress in the area of immunology. However, my guess would be that we are not even half way to a full understanding of the entire system. I am optimistic that the immune system will be completely understood in your lifetimes.
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)
Consider the problem an immune system faces. It must defend its host against thousands of unknown , each a MOSAIC of different antigens (#epitopes). Further, it must distinguish between millions of self antigens and other millions of foreign antigens; the penalty for failure is DEATH by a pitiless nature. What makes this goal even more difficult is that many of the self-antigens are chemically very similar to the nonself-antigens. As the early immunologists defined this incredible diversity they were awestruck and puzzled as to how this could possibly be. It was one of these situations that was demonstrability true, but seemed impossible to achieve; but then life itself fits in that category doesn't it? As usual in science the answer came from the brilliant reasoning of a few people. The thought process that broke the "case" went something like this.
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 make billions of different SPECIFIC-EPITOPE-BINDING
ANTIBODIES and then let the antigens that accidentally stumbled
into the host choose 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 hypothesized:
This theory, which has come to be called the CLONAL SELECTION THEORY, has been shown to be correct.
If you take the time
to understand the following information and the Figs. 5-8, understanding the immune system
is relatively easy & you'll be able to figure out most of the answers to exam
questions on this material.
1. During fetal development the body
randomly produces millions of B & T CELLS, each of which produces only a .
2. The B cells that produce self
antibodies (antibodies against self antigens) are DESTROYED, leaving only lines or CLONES of B cells that produce
random antibodies to foreign epitopes.
3.When a particular foreign #epitope (e.g. antigen No. 2,025) is introduced into 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 (No. 2,025) which binds to ANTIGEN No. 2,025.
4. These events trigger a RAPID PROLIFERATION of that PARTICULAR B (and T-cell) cell
population (No. 2,025),
producing a large number of clones. These No.
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 No. 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 system (complement and PMNs etc.).
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So at this point we know that there are millions of B-cell-antibody-producing types, just waiting to be "triggered" by contact with their respective antigen, but we still don't know how we get these millions of different B-cells in the first place. To understand how this occurs you have to know something about antibody structure.
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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 (requires Chime). IgG does most of the humoral immune work. Figure 7 shows the physical structure of the IgG molecule. This site shows mobile models of IgG (requires Chime)
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 (Fig. 10).
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 DIFFERENT for 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.
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It may help you to understand Fig. 11 if you think of each of the L.C. and H.C. colored rectangles as different cards and then each of the light and heavy chain combinations of 3 cards each as "HANDS" of cards dealt to the players. Let me know if you like this analogy or send me a better one.
Click here to see a series of views of antibody molecules.
Antibody variability comes about through an unusual SHUFFLING of the genes that code for the variable portions of the IgG molecule (Fig. 11). The antibody genes are inherited as GENE FRAGMENTS. During lymphocyte development these gene fragments are joined together in RANDOM ARRANGEMENTS that form the COMPLETE GENES in the individual B & T cells. The fact that the IgG molecules are composed of two proteins, each with its independently produced variable regions adds increased variability to the whole process. It is estimated that >100 million distinct antibodies can be made by this process. In addition the genes for receptors of B lymphocytes MUTATE extremely rapidly when the B cell is activated by binding to a foreign substance or antigen. Once a B lymphocyte binds antigen to its receptor, it differentiates and secretes specific antibody molecules that have been specified by the genes that created the receptor on the parent B cell.
The basic reaction of all Ab's with their epitopes is the same (a binding of #ligand and receptor), but the physical MANIFESTATIONS of that reaction differs depending on the PHYSICAL NATURE of the antigen. The point to remember is that the Ab has TWO binding sites so a single Ab molecule can bind to two independent antigen molecules or particles. You see one of these manifestations in #Lab exercise 21.
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- 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 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.
We use to allow students to use the
agglutination test to determine their own blood type, but because of the danger of AIDS it
now must be done under supervision by someone who has been especially trained to handle
blood safely.
Does this raise a concern in your mind about having sex with someone whose HIV status you don't know if it is considered unsafe to test blood types in a controlled laboratory setting?
The second component of the adaptive immunity system involves a set of special immune cells called T cells. We will only deal with three of the T cell types. The T cells develop in the thymus gland (#Fig. 7), but the process is not completely understood. Briefly, the stem cells in the thymus undergo differentiation's that form two major groups of T cells, the KILLER T CELLS (Tc or Tk) and the HELPER T CELLS (Th). The process of immunological diversification through DNA fragment shuffling is the same as that which was described for the B cell development so that EACH Tk and Th cell responds only to a unique epitope (#Fig. 3). T cells that react with self antigens DIE OFF during the early stages of differentiation. The T cell clones migrate throughout the lymphatic system. When a T cell encounters its antigen (epitope) it goes through a series of changes that convert it into its final immunological defense posture.
The special role of the T-helper (Th-cell) in developing immunology is described below:
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Therefore, the Th helper cell acts as a MASTER CONTROL CELL of the immune system. It is 
REQUIRED for both the humoral and cellular immune systems
to function. When Th cells are not present the host's fate is
sealed because the correct B-cells will not proliferate and the correct antibody will not
be produced (like a football team without a quarterback) with the result that death
ensues. (See discussion on #AIDS)
The T killer cells (Tc) have a different function. The Tc cells are designed to recognize foreign antigens on the SURFACE OF HOST CELLS. Foreign cell epitopes appear on host cells mainly in two types of situations, in viral infection and in cancer cells. In both these case there are changes in the composition of the host's cells that cause foreign antigens to be PRESENTED ON THE SURFACE of the modified cell. The Tc cells recognize these foreign epitopes and are stimulated to attack and destroy the infected or modified (e.g. cancer) cell.
Figure 10. Activation of & 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 they become more complex as time goes on.
The adaptive immune system can, on occasion, make antibodies against the body's own cells. These antibodies activate #complement which damages or destroys the targeted self-cells. When this happens you have an AUTOIMMUNE disease. Examples of autoimmune diseases include multiple sclerosis, juvenile diabetes, myasthenia gravis, Graves disease and rheumatoid arthritis. Autoimmune diseases are as insidious and terrible as cancer as they represent the BETRAYAL OF THE BODY by something that is intended to be of benefit to the body. Five percent of adults in Europe and North America, 2/3 of them women, suffer from autoimmune disease and this is likely to be a low estimate.
Since you've been paying attention, you should suspect by now that autoimmune disease is complex. In many autoimmune illnesses, genetic factors play a crucial role. For example, identical twins have a high chance of suffering from the same autoimmune disease. The causes of autoimmune diseases are virtually unknown, but the human genome is sequenced we will begin to learn about the genetics of these diseases. A significant amount of data indicates that infections can trigger them (e.g. Strep-throat/rheumatoid arthritis), or they can be provoked simply by an injury or stress. There are some hopeful signs of treatment for some of these autoimmune disease, but much more needs to be learned about them.
Allergies and their more dangerous relative, hypersensitivity's, are very common. Basically they can be seen as OVER REACTIONS to foreign antigens by a HYPERACTIVE or misdirected specific immune system. These conditions include allergic rhinitis (hay fever), asthma, sneezing or fighting for air after inhaling certain chemicals. Asthma is a serious disease and a frequent cause of death of young adults; I have lost three friends, all under 40, in my life time to asthma and I have several relatives who suffer from this dreadful condition. The antigens that trigger allergy attacks are called ALLERGENS. We don't understand why allergies are so common, but one theory is that they are the results of our immune system evolving a way of dealing with parasites (worms, etc.).When the body is invaded by a parasite it responds by producing IgE, a form of antibody different from IgG. IgE is the antibody that is responsible for allergy reactions. The stages of an allergic reaction are:
An initial exposure of the immune
system to an ALLERGEN.
At this time there are NO SYMPTOMS as the immune system must first synthesize the IgE in
response to the unique allergen.
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On subsequent exposures to the
allergen, it binds to IgE molecules that are located on the surface of MAST CELLS.
This induces a CASCADE (series) of events that
cause the mast cells to release chemicals present in granules in the mast cells.
These chemicals include histamines,
leukotrienes and prostaglandins, which in turn INDUCE THE VARIOUS SYMPTOMS typical of an
allergic response.
This entire process can take JUST SECONDS, thus explaining the suddenness with which allergic and hypersensitive reactions can occur. Allergies include a WIDE VARIETY of diseases. For example chronic allergic rhinitis (runny nose, stuffed up sinuses) is commonly caused by the feces of the COMMON HOUSE LOUSE, to CAT & DOG allergens & to the COMMON COCKROACH all of which live in most of our homes. Seasonal allergies are often caused by pollens or mold spores in the air. Asthma effects approximately 5 to 10% of children, but another 5 to 10% acquire asthma in adulthood and others become afflicted in their 80s. There are numerous forms of asthma, only some of which may involve IgE-mediated activity. For recent (8/99) information on asthma and allergies visit this site.
Mast cells have recently been shown to have an important role in the bodies early defense against many pathogens. Mast cells serve as an early warning system at the body's borders that's equipped to kill some of the invading bacteria. Its main role is to alert the heavy artillery of the immune system that the body is under attack. An understanding of this role may allow mast cells to be manipulated so as to produce a more effective immune system.
BOTTOM WAR: After the end of the second world war some American service men in Japan suffered from painful and itchy blisters developing on their elbows and in a ring around their buns. Was this a subtle form of chemical warfare developed by the Japanese as retaliation for losing? No, it turned out that a common Japanese wood used to make toilet seats and bar tables contains a chemical that was very similar to poison ivy allergen and the Americans were reacting to it because of their exposure to poison ivy in the US. I suspect that few service men gave up the activities that brought them into contact with this allergen! |
One of the more dangerous allergic reactions is ANAPHYLAXIS. This frightening response to an allergen can KILL AN INDIVIDUAL in a few minutes. Typically, it occurs following an INSECT STING or the ingestion of a tiny bit of food (e.g. peanut butter). It is characterized by the allergen inducing an EXPLOSIVE RELEASE of chemicals from the MAST CELLS. The rush of these chemicals can induce shock which quickly leads to death. In some cases rapid swelling can close off the trachea causing the victim to suffocate. Less dangerous responses, often to foods, result in symptoms like hives or a transient swelling in the face or area effected. The danger with food anaphylaxis is that small quantities added in with the major food can induce this response. If you've even had even a mild response to a food or an insect bite, you are always in DANGER as the next one could kill you. Sensitive people should see an allergist and be tested. People who are in danger from anaphylactic reactions should carry kits with them containing drugs that they can inject quickly into themselves to stop the reaction.
There are many myths and much misunderstanding about allergies. Profuse sums of money are spent on testing for allergies and for allergy treatments, but RIGOROUS PROOF is often lacking both for the cause of specific allergies or for the efficacy of the, usually expensive, treatments. The role of industrial pollutants in producing allergies is not clear, but considerable data suggests a relationship between air quality, asthma and other respiratory difficulties. Substantial work remains to be done before this relationship is resolved. There are treatments for eliminating the sensitivity to specific allergens, but they generally required a lifetime commitment to the treatment. Before embarking on a long series of expensive, sometimes painful injections to treat your allergies, it is a good idea to get a second opinion and to explore alternative treatments. For example, three of the most common causes of household allergies are the feces of a louse that lives in all our homes, cat and/or dog proteins (flakes of skin and the hair; even from the neighbors' pets) & cockroach proteins (feces). The following simple treatments may help an allergy problem:
The immune response is being used as a possible treatment against cancer. As described above, the Tc cells destroy cells that present nonself epitopes on their cell surface. This includes cancer cells. Some data suggests that many cancers arise throughout our lives but that they are routinely destroyed by the immune system. However, for unknown reasons it doesn't get all of them. There is evidence suggesting that if we could "turn on" the immune system properly it would destroy many cancers that escape destruction initially. Such experiments against the skin cancer melanoma are currently underway and we can only hope they will succeed.
The Rh factor is a concern to all pregnant women as it can result in the death or damage to a newly born infant. What happens is as follows:
Some children are born lacking the ability to make a functioning immune system. Without treatment these children are doomed to an EARLY DEATH. Some of the genes responsible for this deficiency have been identified and their defect known. Currently GENE THERAPY is underway to replace the missing genes with a functioning healthy gene. Although the experiment is far from being finished, the early results, although mixed are encouraging and several children are living normal lives today who would have surely died without this treatment. Of concern, however is the HIGH cost entailed to treat these children. These costs are generally borne by the TAXPAYER. The hope is that the experiments on these children (and on others with genetic diseases) will result in a treatment for this, and other, inherited diseases that can be applied at an acceptable cost.
EXTRA CREDIT
COMMENTARY 15B DLS: Luke Heath 1/12/00 I view genetic engineering kind of like the search for the fountain of youth. Only the rich and famous will get to enjoy the adventure, and probably be the only ones who will share in its secrets. I am willing to support the research and believe that there will be some very good benefits from this. However, I am skeptical about its future and I am worried about the power that genetic engineering holds. Human nature tells me that people are more likely to destroy each other than to help one another. Allowing people to say what a good gene and a bad gene may become very grey. If anything, there ought to be rules set up to protect us from a tradegy. What happens when the bad gene is based upon the color of your skin or your race? Is there going to be another Holocaust? What are we going to do when someone does have a bad gene, are they going to be treated as a human or as a mutation that needs to be destroyed? Maybe I am too skeptical, but I believe someone needs to be.
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Immunological testing is important in criminal and other legal circumstances, such as proving parenthood. Sensitive immunological tests along with techniques like DNA fingerprinting and related techniques provide added sensitivity and specificity to both disease and forensic diagnosis. Techniques are being developed to combine the two which will improve sensitivity even more.
If you are having trouble understanding my explanations give these sources at try:
This site contains a fantastic tutorial using Chime on antibody structure and Ab/Ag interaction. The best presentation I've seen so far of antigen/antibody reactions. Must load the following: RasMol, Chime and Shockwave. When on the INDEX page scroll click on the "Protein Domains". It may take a while to load (I've had trouble here). View the series of slides illustrating the structure of antibodies. Use the right mouse button to see different views of the molecules and the left button to rotate the molecules. If you study this material you will know than I do about antibodies.
Collection of antibody images.
Still another course on the immune system. Very good images and cartoons. Start with Chap. 6.
Even another course on the immune system.
Copyright © Dr. R. E. Hurlbert, 1999.
This material may be used for educational purposes only and may not be duplicated for
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Figure 8B. Random Ab formation. Each of the
colored squares in the light chain (L.C.) and heavy chain (H.C.) regions represent a GENE FRAGMENT. If three of these fragments are required to
make one gene for the VARIABLE REGION a large number
of combinations are possible, some of which are shown below each cluster of fragments.
Then on the far left are several examples of combinations between the variable light and
heavy chain genes that form the variable arms of IgG. As you can see from the limited
numbers of color bars used in the illustration many different combinations could be
formed. 
Figure 9. 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. 