1. The Adaptive Immune System and Humoral Immunity
Immune System Part IV:
The Adaptive Immune System and Humoral Immunity

2. Adaptive Immune System (Specific Immune System): Humoral Immunity
Selected B cells produce copious amounts of antibodies that interact with antigens found on pathogens.
Needs the support of helper T cells.
The graphic on the left is a naïve B cell and the one on a right is a transformed B cell or plasma cell producing antibodies.
Graphic 2

3. Adaptive Immune System: Humoral Immunity
An antigen is any material that stimulates selected B cells to produce copious amounts of antibodies.
Antigens include bacterial cell walls, viral parts, flagella, etc.
An epitope is the part of an antigen to which the antibody attaches. An antigen can have more than one epitope or type of epitope.
Point out that any one antigen can have a number of different epitopes to which different antibodies can attach. Epitopes are also called antigenic determinants. In the illustration, the antigen shown has three different epitopes or antigenic determinants.
Antigens can be proteins or carbohydrates but not lipids.
Point out the clumping ability of antibodies by possessing two receptor sites.
Graphic Campbell. 3

4. Adaptive Immune System: Different Epitopes on Different Antigens
Graphic Raven and Johnson
Different epitopes found on different types of antigens. 4

5. Humoral Immunity: Selecting B cells
Naïve B cell receptors are different for each B cell.
Antigens attach to a receptor site on the B cell.
Antigens are brought into the cytoplasm of the B cell.
Antigens attach to MHC II proteins and are transported to the cell membrane.
Humoral Response involves the arousal of B cells and antibody formation. On each of the naïve B cell receptors there are two receptor sites. This is because the receptors are actually antibodies inserted into the plasma membrane of the B cell. The receptor site is specific for a particular antigen or AG. All the receptor sites (10,000 or so) on a given B cell are identical to one another. During any given infection on a few naïve B cells are selected and cloned.
The receptor site captures the free floating AG which is then taken into the cell.
Once inside the cell, the AG combines with a MHC II protein and now the MHC complex migrates to the surface of the plasma membrane and is tagged for selection.
Remind students that MHC II proteins are used in communication between immune cells. These are the markers that allow B and T cells to “recognize” each other as both being immune cells. They are different from MHC I proteins which are found on all nucleated cells and are used in distinguishing self from nonself. 5 5

6. Humoral Immunity: Cloning Selected B cells
An activated helper T cell makes a match with MHC II/AG complex.
Helper T cell secretes cytokines which causes the B cell to reproduce and making plasma B cells and memory B cells.
The helper T cell with its T cell receptor site finds B cells with the MHC II protein and attached AG.
The activated helper T cells act much like the macrophages and dendrites did in activating naïve T cells.
An accessory protein is used to hold these two cells together as cytokines are secreted (called CD 4 or cluster of differentiation). Different lymphocytes have different CD proteins on them.
The two join and the helper-T-cell secretes a certain type of cytokine. This causes the B-cell to reproduce, forming a large clone of genetically identical B-cells.
Two different types of B cells are produced: Plasma cells and memory cells.
Plasma cells which will produce copious amounts of free floating AB for a specific AG.
The receptor sites on the free floating AB are identical to the receptor sites found on the plasma B cell.
Memory B cells for the secondary immune response and will be referred to later. 6

7. Humoral Immunity: Cloning Selected B cells
For this particular selected B cell, thousands of B plasma cells are cloned. They are identical to the original B cell.
Each plasma B cell can synthesize 2,000 identical AB per second.
The helper T cell has a T cell receptor or TCR that is match for MHC/AG complex. Once the two cells are connected, the T cell secretes cytokines which causes the B cell to be cloned and transformed into plasma cells.
Once cloned, the plasma cells start producing AB with receptor sites identical to the B cell receptor site. These AB are specific for a particular AG that stimulated the response.
The function of memory B cells will be addressed later. 7

8. This illustrates how out of thousands of different naïve B cells, only the one with the correct receptor site is selected and cloned.
This process is sometimes called “clonal selection.” 8

9. Antibodies Can Inactivate Antigens
Antibodies (AB) are also called immunoglobulins (Igs). There are different classes of AB or Igs. (Students are not responsible for the different classes of AB or Igs).
AB or Igs can be isolated from the blood serum. Blood serum is the liquid that remains when all blood cells and blood clotting factors are removed from the blood. Serum contains water, electrolytes, nutrients, antibodies, and other non-clotting proteins.
How AB work:
Neutralization: AB will coat the epitopes so that the pathogen cannot interact with the receptor sites of cells. Also in certain cases the “tail” of the AB is constant and can attach to a receptor site on a macrophage causing the macrophage to literally roll over and engulf the pathogen. This process is called opsonization (loosely translates as “make tasty”) and is illustrated on slide 13.
Agglutination: AB bind to several AG clumping them together so phagocytes can devour them.
Precipitation: AB will attach to soluble AG so that it will precipitate out and can be easily engulfed (phagocytosis).
Certain interaction with AB and AG trigger complement system, the complement proteins cause holes in invading cells, water rushes in, and the cell bursts.
Graphic Campbell 9 9

10. Opsonization and Inactivating an Antigen
Opsonization: Certain bacterial cells have so many AG determinants that the antibodies coat the bacteria cell. The constant regions stick out (called the FC region). The phagocytes have FC receptors. This interaction allows the phagocyte to roll over the pathogen and phagocytosis occurs.
Antibody opsonization is the process by which a pathogen is marked for ingestion and destruction by a phagocyte. Opsonization involves the binding of an opsonin, e.g., antibody, to a receptor on the pathogen's cell membrane. After opsonin binds to the membrane, phagocytes are attracted to the pathogen. The Fab (fragment, antigen binding) portion of the antibody binds to the antigen, whereas the Fc (fragment, constant) portion of the antibody binds to an Fc receptor on the phagocyte, facilitating phagocytosis. 10 10

11. Activation of B-Cells
Another drawing of B cell selection and activation of plasma cells. 11 11

12. Homeostasis: Halting the Attack
Regulatory T cells (Treg) help to halt the immune response.
Do not know how they are activated; possibly through antigens.
Thought to stop any further naïve B or T cells from being activated. The immune response then stops because activated immune cells die due to their short life span.
This slide is a repeat of halting the cell mediated response which is the same as halting the humoral response. There is still a lot that is unknown about the halting of the adaptive immune response.
Emphasize
Homeostasis is maintaining a constant internal environment in an external environment that is in constantly changing.
Pathogens and toxins are a threat to homeostasis resulting in disease and cellular death.
The immune system is a response to that threat.
Once the immune system has been activated, there must be a way to halt the response.
In the innate immune system, as phagocytes remove the pathogens, the response is halted. It is the presence of the pathogen that triggers the innate system, and it is the removal of the pathogen that halts the innate system.
The adaptive immune system is triggered by pathogens or toxins being presented to B and T lymphocytes.
The response includes selected T cells that recognize and destroy the body’s own infected cells.
The response includes selected B cells that produce free floating antibodies in the response to antigens.
The halting of this response is still being investigated however it seems to involve T-reg cells. 12

13. This is a summary of the humoral response.
The first exposure to a specific antigen represents the primary immune response
During this time, effector B cells called plasma cells are generated, and T cells are activated to their effector forms.
Effector cells with regard to the immune system are those B and T cells that have been activated and are in the process of defending the body from pathogens. Effector cells include plasma B cells, activated helper T cells, cytotoxic T cells. They do not include naïve B and T cells or memory B and T cells.
Memory B and T cells are made and stored in lymphatic tissue during the primary immune response.
A subsequent exposure to that same antigen activates a secondary immune response.
Graphic Campbell 13 13

14. Secondary Immune Response
Memory B cells and T cells are selected for when exposure to a subsequent pathogen occurs and the memory cells are a match for the antigen.
Memory B cells and T cells quickly reproduce, making plasma B cells, helper T cells and cytotoxic T cells (effector cells).
Plasma B cells begin to make AB and cytotoxic T cells begin to destroy infected cells. 14

15. Secondary Immune Response
Memory cells live for many years. If there is a subsequent exposure to the AG, the B and T memory cells are selected for and begin to synthesize plasma B cells, cytotoxic T cells, and helper T cells.
The graph shows that it may take two weeks from the initial exposure for plasma cells to be at their maximum production level producing AB.
Look at the response by inoculating the person with a second antigen. This demonstrates that the exaggerated response to the second exposure of antigen A is due that the fact that it is not due second first time exposure to an antigen.
Upon subsequent exposure though it only take two days to be at the same AB production level that it took the first exposure two weeks to attain.
In only seven days the number of antibodies in the blood stream is 100 times the amount produced by the primary response.
This is because of rapid activation memory cells B and T cells. 15

16. Preventing Disease with Vaccines
Immunity-Subsequent exposures to pathogens do not result in the disease. Active immunity causes memory B and T cells to be made. Passive immunity results from obtaining pre-made antibodies with no memory cells being made.
Vaccines are a way of stimulating the immune system to produce memory B and T cells against nonvirulent pathogen. The nonvirulent pathogen cannot cause a disease but is very similar to a virulent pathogen that does causes a disease. The vaccine tricks the immune system into responding to a pathogen that has not invaded the body. The end result is the production of memory B and T cells that are ready to attack a specific antigen.
Live or attenuated vaccine uses a pathogen that is intact but does not cause a disease. For example, there might be a mutation in the receptor site so that the pathogen can no longer attach to the cell to infect it.
Killed vaccines use a pathogen that has been disassembled. These pathogens are killed or disassembled most commonly by heat or formaldehyde.
The most effective vaccine is the live attenuated.
Historical note:
Edward Jenner is credited with the first vaccine. Smallpox was a very devastating disease with a % mortality rate. People who survived were often left blind; limbs suffered arthritis and at the very least disfigured people with small circular scars. It was noticed that milk maids who were exposed to cowpox (caused by a related virus) were not very likely to come down with smallpox. The symptoms of cowpox were not nearly as devastating or lethal as smallpox. Edward Jenner inoculated an eight year old boy with pustules fluid from a cowpox lesion.
The child had very mild symptoms of cowpox and the child recovered. Later the child was inoculated with smallpox, and he did not come down with the disease. In 1840, Great Britain offered cowpox vaccinations free of charge. Other countries followed suit.
With a world vaccination effort, the World Health Assembly declared the smallpox virus to be eradicated in May of 1980.
Ask students if they know anyone that has been vaccinated against smallpox. More importantly how do they know?? (My scar is on my upper left arm from prior to entering public school.)
Routine vaccination of the American public against smallpox stopped in 1972 after the disease was eradicated in the United States. Until recently, the U.S. government provided the smallpox vaccine only to a few hundred scientists and medical professionals who work with smallpox and similar viruses in a research setting. After the events of September and October, 2001, however, the U.S. government took further actions to improve its level of preparedness against terrorism. For smallpox, this included updating a response plan and increasing the amount of smallpox vaccine in the stockpile. We now have enough vaccine in the stockpile to vaccinate every person in the United States in the event of a smallpox emergency. 16 16

17. Type of Immunity
Natural active immunity- (ex. mumps) organism is exposed to the actual pathogen and gets the disease. Memory cells are made. Subsequent exposure to the pathogen does not cause the disease.
Artificial active immunity- (vaccine) person is given inactive parts of the pathogen so that memory cells are made. Exposure to the pathogen does not cause the disease.
Natural passive immunity- AB in breast milk and the antibodies of a pregnant woman cross the placenta to her fetus. Lasts a few weeks to a few months. No memory cells made. Can succumb to the disease later.
Natural active immunity results from being exposed to a pathogen and activating the primary immune response. The person experiences the disease. This results in the synthesis of B and T memory cells which can be called into action due to subsequent exposure to the pathogen. Many childhood diseases result in natural active immunity like mumps, measles, and chicken pox.
Artificial active immunity results from a vaccination. The vaccination contains inactive pathogens, however memory cells are made so that exposure to an active pathogen does not result in the disease. There are many vaccines for certain diseases. Children are required by law to be immunized for certain diseases so that they will not come down with the disease or pass it on to other.
Example: Polio is caused by a virus that attacks the nervous system and quite often results in paralysis. It was a serious disease Jonas Salk announced the development of a killed polio vaccine Albert Sabin announced the development of an oral attenuated polio vaccine. Dr. Sabin spearheaded a mass immunization of people in the U.S. He also encouraged other countries to follow suit. This disease is close to being eradicated like small pox.
Natural passive immunity This applies mainly to infants. The baby receives only the AB and does not make memory cells. The reception of the AB can be through breast milk or from crossing over from the placenta. 17 17

18. Artificial Passive Immunity
Artificial passive immunity- Patients exposed to a serious pathogen maybe given a shot with pre-formed AB against the disease.
The AB are found in the plasma of a person who has had the disease. The plasma is processed so that all the blood clotting proteins are removed forming serum.
Artificial passive immunity A person is given preformed AB or Igs usually through a shot. This is usually done when a person has been exposed to a serious disease and does not have time to make AB or the disease is lethal. For example when a person has been exposed to rabies, it is important to stop the pathogen as soon as possible. While the person who has been exposed is given a rabies vaccine, that is not enough. They are also given human rabies immunoglobulin (HRIG) to deactivate the rabies virus.
AB come from people or animals that have been exposed to the pathogens. The AB are found in the blood. A person with the AB donates blood. The blood is separated into its components into blood cells and plasma. The blood clotting proteins are removed from the plasma forming serum. The serum is processed removing any pathogens. Serum that has been processed with the desired AB is called antiserum. 18 18

19. When the Innate Immune System Goes Awry
Certain bacterial infection can induce an overwhelming inflammatory response.
Too many mast cells and phagocytes release huge cytokines and histamines. Too much fluid leaks from the capillary bed into the tissues. Blood pressure drops dangerously low and the tissues swells. Can be fatal.
The graphic above shows a normal inflammatory response. Have students imagine this response either happening all over the body at the same time, as when a wasp injects poison into a person’s blood stream, or when someone eats food to which they are allergic. The flood of inflammatory chemicals in multiple locations results in a reaction called systemic shock and the release of cytokines is called a “cytokine storm.”
Ask if they’ve ever seen the “allergy scene” from the movie Hitch as well! 19 19

20. When the Adaptive Immune System Goes Awry
Not all self-reactive lymphocytes are destroyed in development. Those that survive are suppressed.
Autoimmune diseases happen when certain suppressed lymphocytes are activated and attack the body’s own tissue.
Emphasize that the first point we made in this section was determining how lymphocytes could determine self from non-self.
Example: Grave’s Disease - B-cells produce antibodies that attack the stimulatory receptor sites on the thyroid gland. The thyroid gland then responds to being stimulated and over-produces thyroxin resulting in hyperthyroidism.
Diabetes mellitus type 1 or juvenile diabetes - results from B cell antibodies attacking proteins found on certain islet cells of the pancreas. This destroys the cells responsible for making insulin.
Rheumatoid arthritis-Results from B cell antibodies attacking the joints, resulting in arthritis.
Multiple sclerosis attacks myelin proteins found on the myelin sheath of nerves in the central nervous system, spinal cord or optic nerve. Can result in permanent nerve damage.
What exactly causes the suppressed immune cells to become activated is still being investigated. Suspected connections at this time include viruses, environment, and gene regulation.
Graphic 20 20

21. A,B,O and AB Blood Groups and the Immune System
Red blood cells have a number of different surface proteins called antigens, including A and B. These determine the four different blood types A, B, AB, and O (complete absence of A or B antigens) blood types. It turns out that shortly after birth a person has antibodies for the blood surface proteins not found on their blood. For example, a person with type B blood has type A antibodies circulating in their blood.
This has implications for transfusions. A person who is given a transfusion of blood with antibodies for their own blood type will cause the blood to coagulate and could be fatal.
The next question is how can someone who has never been exposed to blood with different antigens actually possess antibodies for those antigens?
Answer- There are bacteria in the environment that happen to have antigens that are very similar to the A and B antigens found on red blood cells. When these bacteria enter the body (very soon after birth), the body will make antibodies for any A or B antigen that is not found on one’s own blood type.
For example a person with type A antigen on the red blood cell will be exposed to bacteria carrying the A and B antigen. That person will not make A antibodies because the body recognizes it as self but will make B antibodies. If the person with type A blood is given a transfusion of B blood, that blood will coagulate due to the free floating B antibodies found in the blood stream.
Everyone has circulating antibodies for A and B antigens that a person does not possess. This makes blood typing important in transfusions. Also, these antibodies for the A and B blood group are of a type that does not cross the placenta. This is fact is important for having babies with different blood types than the mother’s blood type.
Graphic Campbell 21 21

22. Antibodies and the Rh Factor
The Rh antigen is another antigen found on red blood cells. There are several variations of this antigen. It is a protein. If one has the Rh antigen, then that person is Rh+ and if one does not, then that person is Rh-. Unlike the A,B,O blood antigens, there are no preformed antibodies for the Rh antigen.
Graphic
There is a problem for a pregnant women who is Rh- and a fetus is Rh+. During the first pregnancy, when birthing the child, some of the baby’s blood will mix with the mother’s. She will then make AB against the Rh antigen. This is not a problem for the first baby because it has now been born and will not come in contact with these new antibodies, BUT during the second pregnancy, if any of the blood mixes, the mother’s Rh antibodies will cross the placenta and agglutinate the baby’s red blood cells (called erythroblastosis fetalis). To prevent this, the mother is injected with anti-Rh antibodies shortly after giving birth to any Rh+ child. These antibodies will then eliminate any fetal blood cells that may have crossed into her body and prevent her from making AB against the Rh factor. Therefore, to her immune system, each pregnancy is like the first one. 22

23. The HIV Virus and Immunity
This is the HIV retro virus that causes AIDS. It contains RNA.
During replication, the RNA is transcribed to DNA. This process does not correct for transcription errors. This virus easily mutates.
The HIV (human immunodeficiency virus) that causes AIDS (acquired immunodeficiency syndrome) is an RNA retro virus. Its genome is RNA and not DNA. During replication the RNA is converted to DNA and integrated into the T-cell genome. The enzyme that transcribes the RNA into DNA is called reverse transcriptase. This process does not correct for transcription errors resulting mutations for this virus. This fact is making it difficult to synthesize a vaccine for the disease
During infection the virus attaches to CD4 protein of a helper-T cell and gains entry into the cell. The cytotoxic cells have CD8 proteins and the HIV virus does not infect these cells. Dendritic cells (DC) also have CD4 proteins and are also infected by the HIV virus. In fact, it is thought that the DCs are responsible for spreading the virus to the T cells after the initial infection. Remember DC are found in the skin and mucus membranes.
Once integration into the host cell is complete, the virus begins to make viral particles and copies of the viral genome.
The helper T cell dies because of the damaging effects of the virus. The destruction of the helper T cell affects both the humoral response and the cell mediated response. Usually people with AIDS die of secondary infections from opportunistic pathogens like a pneumonia caused by a fungi or Kaposi’s sarcoma, a rare cancer. There is no cure for AIDS only a combination of drugs that slows down the progress of the disease. 23

24. HIV Replication Infected helper T cells die because
as the new viral particles leave via exocytosis, the plasma membrane is disrupted enough that the cell dies
as the virus continually replicates and takes over the process of translation, it stimulates the cell to under apoptosis
as the T cell is infected, bits and pieces of the viral parts are now associated with MHC protein, cytotoxic T cells recognize the cell as infected and destroys the cell
Graphic 24 24

25. Progress of AIDS Three Phases of Infection
Acute Infection- 2-4 weeks after infection (some may take 3 months to appear). Symptoms are severe flu like.
Body is responding to infection
Copious amounts of HIV virus are being made
The body’s immune response tries to fight the disease
Note increase in helper-T-cells, AB for the HIV virus
Latency- Because of the body’s immune response, the concentration of the HIV virus declines but it is not irradiated.
HIV virus is still active but at a reduced level
Infected persons are said to be asymptomatic or HIV positive
T cells are being slowly destroyed
May last up to 8 years
AIDS-One is diagnosed with AIDS when the helper T cell count falls below 200 T cells/mm of blood. Most people have T cells/mm of blood.
The number of HIV viruses circulating in the blood increases
The number of helper T cells declines
Susceptible to opportunistic diseases like pneumonia caused by a fungi or Kaposi’s sarcoma, a rare cancer. There is no cure for AIDS only a combination of drugs that slows down the progress of the disease
Once diagnosed with AIDS, life expectancy is 1-3 years
The destruction of the helper T cell affects both the humoral response and the cell mediated response.
There is no cure for AIDS only a combination of drugs that slows down the progress of the disease.
Graphic Campbell 25 25

26. Helper T Cell and HIV virus
A T-cell being infected by the HIV virus (blue particles) 26

27. Created by:
Carol Leibl
Science Content Director
National Math and Science