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Immune System Part III:

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1 Immune System Part III:
Adaptive Immune System & Cell Mediated Immunity

2 Adaptive Immunity (Specific Immunity) Third Line of Defense
Develops after exposure to pathogens Involves very specific response to pathogens Much slower than innate immunity Requires support of innate immunity to function Two parts: humoral immunity and cell mediated immunity Updated Information: There has been an explosion regarding emerging new information about the workings of the immune system. It is important that AP biology teachers keep current by obtaining new editions of university first year biology texts. Publishers will send you a “review copy” if you fill out their on-line form. Even the framework is outdated when it comes to certain terminology. Make your students aware of this and familiar with both the old and new terminology since AP test questions are often in development for two years and circulation on AP exams for far longer! Outdated Terminology Specific immunity or specific immune system is now referred to in all the new text books as adaptive immunity or the adaptive immune system. (Reece/Campbell, Raven and Johnson, Starr and Taggart, Hillis, & Solmon and Berg). The framework refers to the specific immune system rather than the adaptive immune system. Additionally, for a short while the specific immune system was called the acquired immune system. This was prior to the term adaptive immune system coming into our vocabulary. Nonspecific immunity or nonspecific immune system is referred to in new text books as innate immunity or the innate immune system. (This was addressed in the second power point of this series.) Virgin B and T cells are now called naïve B and T cells. MHC receptors are now call T cell receptors. Examine the EK 2.D.4.b and EK 2.D.4.b .1: 2.D.4.b Mammals use specific immune responses triggered by natural or artificial agents that disrupt dynamic homeostasis. Evidence of student learning is a demonstrated understanding of each of the following:  1. The mammalian immune system includes two types of specific responses: cell mediated and humoral. This might give one the impression that only mammals possess an adaptive immune system. This EK is misleading as the adaptive immune system (specific immune system,) so far, has been found in all jawed animals. Cartilage fish do have lymphoid tissue (primitive compared to mammals) and do synthesize T cells. Jawless vertebrates such a hagfish and lampreys do not have an adaptive immune system. 2 2

3 Lymphocytes—Specialized Cells
Adaptive Immunity Lymphocytes—Specialized Cells B cells- are synthesized and mature in the red bone marrow with characteristic plethora of rough E.R. T cells- are synthesize in bone marrow but mature in the thymus with an abundance of free floating ribosomes Immature B and T cells are virtually indistinguishable. There are two types of lymphocytes involved in the adaptive (specific) immune response, B cells and T cells. When immature, the two cells are indistinguishable. Both originate in the red bone marrow. Naïve lymphocytes are those that have not been exposed to a matching antigen. Each lymphocyte is programmed to match a particular antigen to be activated. Until that match occurs and the lymphocyte is activated, it is termed a naive lymphocyte. T cells mature in the thymus and have a large number of ribosomes. The thymus gland is located just above the heart. As an infant, the thymus is large but as time passes on, the thymus gland begins to shrink in size until adulthood. Adults retain their thymus but it is smaller in size than the thymus gland in infancy. There are different populations of T cells; including cytotoxic T cells, helper T cells, and memory T cells. T cells function in the cell-mediated response and are also important in the humoral response. (Humoral immunity is so named because it involves substances found in the humours, or body fluids.) Different types of T cells Naive T cells are those T cells that have not be activated or presented a matching antigen. Helper T cells (TH) activate the B cells in the humoral response Cytotoxic T cells (TC) destroy infected body cells Memory T cells (TM) are long lived T cells that have been initiated to a particular pathogen and kept in reserve. They are easily activated if the pathogen invades once again. Effector cells are lymphocytes that have been selected and transformed to “fight” a pathogen. B cells mature in red bone marrow and have a large amount of rough E.R. They are important in the humoral response production of antibodies, which is why they need so much rough ER. Types of B cells Naïve B cells are B cells that have not been activated or presented a matching antigen Plasma B cells are activated B cells that produce copious amounts of free floating antibodies. Memory B cells are long lived B cells that have been initiated to a particular pathogen and are kept in reserve. They are easily activated if the pathogen invades once again. The cell on the left is an immature lymphocyte. The middle cell is a mature B cell with extensive E.R. The cell on the right is a mature T cell with its extensive amount of ribosomes. Graphic 3

4 Adaptive Immunity and Primary Lymphatic Tissue
All lymphocytes originate in the red bone marrow. T cells then migrate to, and mature in, the thymus. B cells remain in the marrow to mature. Lymphocytes, like the phagocytes, originate in the red bone marrow. They are descendants of lymphoid stem cells rather than the myloid stem cells that give rise to the red blood cells, platelets, and phagocytes. Refer back to the innate immune system information regarding the origin of cells of the immune system. Graphic and Campbell 4 4

5 T cell receptor sites T cells have T cell receptor (TCR) sites that can attach to an antigen that is presented by another cell such as a macrophage or dendritic cell. Emphasize: TCR (T cell Receptor) sites have the ability to bind to a specific antigen and body cell protein (will be explained in the next slide) T cells bind to only one antigen TCR sites have two polypeptide chains that are different from one another (alpha, and beta, chains) and each polypeptide chain has a constant region and a variable region. The variable region is different for different T cells and it is that part that interacts with the pathogen. There are over 100,000 identical T cell receptors on a typical T cell. The constant region is anchored into the membrane of the T cell Neighboring T cells are different from one another because they have different receptors Graphic Campbell 5 5

6 B Cell Receptor Sites and Antibody Structure
B cell receptor (BCR) sites Each one can attach to two antigens. Made of four poly-peptide chains held in place by covalent bonds known as disulfide bridges. Graphic Campbell Emphasize: Antigens are foreign particles that invade the body and cause B cells to make antibodies. B cell receptors are actually antibodies with the ability to bind to two specific antigens (same antigens). [We will talk about antibodies in future slides but most students have at least heard of antibodies.] Held together by disulfide bonds (actual covalent bonds, not just IMFs). B cell receptors have four polypeptide chains. Two light chains that are identical and two heavy chains that are identical. Each chain has a variable region and a constant region. The constant region of the heavy chain is anchored into the plasma membrane region. There over 100,000 identical B cell receptors on a typical B cell. Each B cell receptor is different from a neighboring B cell because they have different receptor sites or variable regions. Two identical heavy chains and two identical light chains with variable and constant regions. Antibodies also have this same construction. 6 6

7 Secondary Lymphatic Tissue Where Lymphocytes are Activated
Once B cells and T cells mature, they migrate to secondary lymphoid tissue where they wait to be activated. B cells and T cells that have never been activated are called naïve B and T cells. The secondary lymphatic tissue/organs include lymphatic vessels, lymph nodes, spleen, tonsil, adenoid, appendix, and Peyer’s patch (small intestine). Emphasize that this is where lymphocytes reside until they are activated. Terminology Lymph is mostly clear fluid that contains materials that were not returned to the circulatory system. It contains ions, fatty acids, triglycerides, white blood cells, water, and dissolved gases and is similar to interstitial fluid (clear fluid that baths the organs). Lymphatic capillary is a capillary bed that collects lymph. It is connected to lymphatic vessel or vein. There are no lymphatic arteries. Lymphatic vessel or lymphatic vein Lymphatic veins are vessels that are connected to lymphatic capillaries. Like circulatory veins, these vessels have one way valves that continuously move the lymph in one direction. Lymphatic vessels will often direct the flow of lymph through lymph nodes or glands. Also, other secondary lymphatic organs drain material into lymphatic vessels. Lymphatic vessels empty into the vena cava near the heart where the filtered lymph rejoins the circulating blood. Lymph node or lymph gland is a small nodule of tissue that is compacted with T cells and B cells waiting to be activated as the lymph passes through the lymph node. These may be swollen or enlarged if pathogens pass through the node and T cells and B cells become activated. The same can be said for other secondary lymph organs like the tonsil. Originally, it was thought that these glands did not participate in the immune response but only became infected and enlarged. Tonsils were routinely removed for the slightest indication of infection. This is no longer the case. Tonsillectomies are only performed on patients with chronic cases of tonsillitis. 7

8 Four Characteristics of Adaptive (Specific) Immunity
Self/Nonself Recognition - T cells and B cells have the ability to recognize one’s own cells versus a pathogen (invader). Specificity - Lymphocytes are tailored to combat specific antigens due to the great diversity of B cells and T cells. Diversity - There are potentially billions of different antigen receptors on B cells and T cells that recognize billions of different antigens. Memory - Immune system is capable of “remembering” a pathogen once exposed. Emphasize that the memory characteristic will be discussed after going over the primary immune response of the cell mediated and humoral responses. Both cell mediated and humoral immunity have a “memory” to quickly respond to a second exposure to a certain pathogen.

9 Major Histocompatibility Complex (MHC)
Self Versus Non-self Major Histocompatibility Complex (MHC) Major Histocompatibility Complex (MHC) Proteins are cell surface proteins that are unique for each individual (except for identical twins). May be helpful to translate the term “Histocompatibility” into English: “Histo” refers to tissue so this important (“Major”) group of proteins (“complex”) determines whether or not tissues are compatible with one’s self. MHC proteins are unique to an individual. The adaptive immune system determines whether or not any given tissues really belong to an individual. If the tissues are from the same individual then the MHC markers are identical and they are also compatible. The immune system will ignore the tissue. If the MHC markers are not the same, and the immune system recognizes the tissue as not being “self.” The tissue is not compatible and needs to be removed. (Ex: The rejection of transplanted organs. Bad reaction to a blood transfusion of the improper blood type.) This primarily applies to MHC I markers, but you can think of it in the same way for MHC II markers which are used by certain white blood cells to determine whom they are “talking to” when communicating between B and T cells, for instance. Identical twins have the same MHC proteins because they have the same genome. No two people have exactly the same MHC proteins unless they are identical twins. MHC I proteins are found in on every cell MHC II proteins are found on antigen presenting cells (T cells, B cells, macrophages, and dendritic cells) MHC III proteins have a somewhat different function. They are involved in the inflammation process of the innate immune system and include the complement proteins. Graphic Three classes of MHC proteins - MHC I, II, and III. MHC I proteins are on ALL cells and MHC II proteins are on antigen presenting cells (B cells, macrophages, dendritic cells).

10 Major Histocompatibility Complex (MHC)
Four polypeptide chains with cleft to attach to antigens which are small polypeptide chains. Extremely polymorphic with some classes having as many as 500 different alleles. Antigens can attach to the cleft. The genes for the MHC proteins are found on chromosome #6. Emphasize that the MHC I and II proteins have four polypeptide chains and there are as many as 500 different alleles for one of those proteins in the human population. The genes are said to be polymorphic. An example of polymorphic alleles is blood typing which has three alleles (A,B,O). So, it makes sense that each individual (except identical twins) are unique with regard to MHC proteins. This is also the reason that transplanted organs will often be rejected. Emphasize that there is a cleft in the MHC protein where foreign peptides/molecules can bind (think of a hotdog in a bun). Unlike T cell receptors and B cell receptors, the binding site for the MHC protein is very general and binds to most foreign small polypeptides or most likely bits and pieces of viruses. Graphic

11 Major Histocompatibility Complex (MHC)
MHC I and II proteins have the ability to attach to foreign material (small polypeptides) and transport the foreign polypeptides to the surface of the infected cell. Antigen presenting cells (APC) are mostly phagocytes. As APC are in the process of cleaning up an infection, bits and pieces of the pathogens are displayed on the MHC proteins. Compare the two diagrams. MHC I proteins are found on all cell and only antigen presenting cells have both MHC I and MHC II proteins on the surface of the cell. In the first diagram, the cell is infected however, it has the ability to combine the MHC I protein and bits of foreign peptides. In the second diagram the cell is involved in cleaning up the infection. The cell is not infected, however, it is in the process of destroying the pathogen. Majority of the time this process involves a virus that is the invading pathogen. The antigen has to be bits and pieces of proteins or small polypeptides that are the remains of the virus. Graphic

12 Recognizing Self from Non-self for T cells
T cells migrate to and mature in the thymus with interaction of dendritic cells. Graphic Raven and Johnson

13 T Cells Recognizing Self from Non-self
Three possible outcomes: TCR binds to a dendritic cell with body’s own proteins and MHC protein. Apoptosis is induced and T cell dies TCR weakly binds to a dendritic cell with MHC with no proteins. T cell survives. TCR does not bind to any MHC protein. Apoptosis is induced and the T cell dies. Emphasize that in the second outcome, a T cell that can only interact with its own MHC protein coupled with a foreign peptide attached. Apoptosis is programmed cell death. (The cells within a tad pole’s tail make a good example) Naïve T cells are T cells that have matured but have not been activated or selected and participated in the immune response. (Formerly called virgin T cells). To be activated it must be presented with a MHC protein with a specific antigen. Graphic Raven and Johnson

14 T Cells Recognizing Self from Non-self
Surviving T cells (called naïve T cells) can recognize MHC proteins that have some foreign protein in the cleft. It must be a double match. T cells ignore MHC proteins without any foreign material in the cleft or healthy cells. “Double Match” means that the T cell must bind to both the MHC I marker and the foreign material. Sort of like a double-handshake. Graphic Raven and Johnson

15 B cells Recognizing Self from Non-self
Mature in the bone marrow. If the receptor site on a B cell matches a surface protein found on bone marrow cells, apoptosis occurs. The B cells that survive (naïve B cells) are those that will ignore the body’s own surface proteins but will recognize foreign material. Receptors are antibodies and are very specific for a particular antigen. Receptors that are a match for its own surface proteins are destroyed. Graphic Raven and Johnson

16 A Few Self-Reactive B and T Cells Do Survive
NOT all self-reactive B and T cells are destroyed. Those few that do survive, are suppressed to insure that the self-reactive B and T cells DO NOT react with the body’s own tissue. More on this later. Once mature, naïve B and T cells migrate out of the secondary tissue to wait to be selected. If self-reactive B and T cells do react with the body’s own tissues it can cause an autoimmune response and auto immune diseases. Naïve B and T cells are those that are mature but have not been activated. They are found in the secondary lymphatic cells. Graphic Raven and Johnson

17 Specificity and Diversity of Immune System
The specificity and diversity of adaptive immunity lies in the receptor sites on B and T cells and production of free floating antibodies. Emphasize Each of these receptors has variable and constant regions. The variable regions are different on each individual B cell and T cell. The variable regions are the part that interacts with the different types of pathogens or antigens. The constant region remains the same for each class of receptor sites. Graphic Campbell

18 Structure of Antibodies Are Like B Cell Receptors
B cells produce proteins called antibodies that interact with pathogens. The basic structure is similar to that of the B cell receptors. The function of antibodies will be discussed in the humoral response but are identical in fundamental structure to B receptor site. Both B cell receptors and antibodies are made in the same method. Emphasize that when B cell receptors and antibodies interact with pathogens, it is really bits and pieces of the pathogen it is interacting with. Those bits and pieces are called antigens. Graphic Campbell Antibodies are a part of the humoral response

19 Genes of Receptor Sites and Antibodies
Emphasize There are billions of different types of B and T cells due to differences in their receptors sites yet there are only approximately 20,000 genes in the entire human genome. There are regions on various chromosomes that code for the receptor sites. For example on the light chain there is a variable and a constant region. Look at the chromosome where this part of receptor site is coded for. There are 40 segments that code for the variable region, V, there are 5 regions that code for the joining region, J, and a constant region, C, depending on the class of antibody. Enzymes recombine the DNA with V, J regions so there is just one of each. The gene is transcribed and alternate RNA splicing occurs so that there is only one C region in the transcript. The mRNA is translated to produce a functional protein with one variable and one constant region. Two polypeptides are produced one for each side of the receptor. A similar process is used to make the heavy chain and also the T cell receptor. Alternative splicing of the DNA and RNA and recombination allow for huge variation of the receptor sites and antibodies. It is estimated that there are 1010 different type of polypeptides for variable regions. Graphic Campbell

20 Adaptive Immune System: Two Components
Adaptive Immune System (Specific Immune System): Cell Mediated Immunity Adaptive Immune System: Two Components Cell Mediated Immunity- Selected T cells recognize and destroy infected body cells and cancer cells. Humoral Immunity- Selected B cells produce copious amounts of antibodies to fight pathogens. Graphic

21 Cell Mediated Immunity-Needs the Support of Innate Immunity (Nonspecific Immunity)
The cell mediated immunity needs the support of the cells involved in the innate immunity. The dendritic cells and macrophages are used to present antigens to select and clone T cells in the secondary lymph tissues. The secondary lymph tissue includes tonsils, adenoids lymph nodes, etc. Emphasize that 3 of the 4 characteristics of the adaptive, specific, immune system have been addressed Self/Nonself Recognition-T cells and B cells have the ability to recognize your own cells versus a pathogen. Specificity- Lymphocytes are tailored to combat specific antigens due to the great diversity of B cells and T cells. Diversity- There is potentially billions of different antigen receptors on B cells and T cells that recognize billions of different antigens. Remind the students that adaptive/specific immune system has two parts Cell mediated immunity Humoral immunity

22 Cell Mediated Immunity
Macrophages and dendritic cells arrive at the site of infection. Phagocytosis occurs. Both types of cells have MHC I and MHC II proteins. Emphasize Macrophages and dendritic cells are called antigen presenting cells because their function is to present antigens to T cells. Both of these cells have MHC I and II proteins. The cells are constantly making the MHC proteins and the MHC migrate out to the cell membrane.

23 Role of the Macrophage or Dendritic Cell
The antigen (AG) combines with either a MHC I or MHC II protein Complex migrates to the cell surface to become antigen presenting cell. Emphasize Phagocytosis occurs. The vacuole fuses with a lysosome and pathogen is broken down. Small peptides are inserted into the cleft of the MHC proteins MHC proteins migrate to the surface of the AG presenting cell. Now the AG presenting cells migrate to secondary lymphoid tissue looking for a match with the TCR found on the T cell.

24 Cytotoxic T cells are Selected and Cloned
APC cell migrates to secondary lymphoid tissues. Begins searching for a match with a T cell. If the match is with MHC I protein, the T cell becomes cytotoxic cell or memory cell. There must be a dual match with the T cell receptor site to the MHC protein and AG. It is specific. If the MHC I and AG of the APC bind with a T cell, then the following will occur. A substance called cytokine is secreted. Cytokines are cell-signaling molecules used in this case to communicate between the immune cells (the APC and the T cell). The cytokine causes the selected T cells to reproduce making both cytotoxic T cells and T memory cells. In this diagram, it binds with MHC I proteins and cytotoxic T cells and memory cells that are made. Memory cells will be referred to later. An accessory protein is used to hold these two cells together as cytokines are secreted (called CD 8 or cluster of differentiation). Different lymphocytes have different CD proteins on them.

25 Helper T Cells If the MHC II protein makes a match with the T cell, the T cell is destined to become a helper T cell and memory helper T cells. More on this later. Meanwhile if a MHC II protein and antigen makes a match with a TCR on a T cell, then the T cell becomes a helper T cell. In this diagram the match is with a MCH II protein. More on helper T cells later on. 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. 25

26 Dendritic Cells Dendritic cells are found in skin and other tissues that interact with the environment. Involved in being APC to T cells Most pathogens will probably encounter a dendritic cell prior to encountering a macrophage. Graphic 26

27 T Cells and Cell Signaling
There are a couple of things the student can explain: In the case of the macrophage, the macrophage or dendritic cell has signals from TLR that informs the cell that there is a pathogen. The macrophage engulfs the pathogen. The response is to attach bits and pieces of the pathogen to the MHC protein and display it. Secondly, the macrophage or dendritic cells (APC) now has a signal molecule to present to the T cell. The signal transduction pathway results in the naïve T cell reproducing and making helper T cells, cytotoxic T cell and memory T cells. Continue this sort of analysis in the next slide with the interaction and communication of T cells and infected body cells. Explain how the previous slides illustrate the process of cell signaling or cell communication. 27

28 Pathogens Invade Body Cells
While appropriate T cells are being selected and cloned, body cells are becoming infected. Bits and pieces of the pathogen end up on the MHC I protein of the body cell. While appropriate T cells are being selected and cloned, other cells are becoming infected. Only the T cells with the correct receptor site were selected. Once body cells are infected, bits and pieces of the pathogens are inserted into the MHC I protein. Uninfected body cells will not have bits and pieces of the pathogens on the MHC I protein and will be ignored by activated T cells. 28 28

29 Matching T Cells with Infected Cells
The body cell is tagged as infected. Selected cytotoxic cell recognizes the infected body cell and attaches to the cell. This body cell is identified as infected because of the MHC I is tagged with the bits and pieces of the pathogen. 29

30 Cytotoxic Cells Destroy Infected Cells
Once attached, the cytotoxic cell secretes perforin which makes pores in the membrane of the infected cell. The cytotoxic cell also secretes granzymes which cause the infected cell to die. Once the cytotoxic cell has completed its job, the cytotoxic cell can continue searching other infected cells. Cytotoxic cells can also kill cancer cells because cancer cells change and produce new proteins. Some of these new proteins combine with MHC I proteins and appear on the surface of the cancer cell. Cytotoxic cells recognize these cells as foreign and destroy it. Every once in a while the cells will escape the cytotoxic-T-cell because the MHC I protein has also changed. There is no longer a dual match. T cells do not recognize the cancer cell as foreign. The cancer cells continue to replicate or metastasize. The granzymes induce apoptosis once they enter the infected cell. 30

31 Cytotoxic Cells Destroy Infected Cells
This is another rendition of how a cytotoxic cell kills in infected cell. Below is a cytotoxic cell (orange) killing a cancer cell (purple) 31 31

32 Homeostasis 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. Then the immune response stops because activated immune cells die due to their short life span. In summary, 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 and maintaining a constant environment. 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, then the response is halted. It is the presence of the pathogens that triggers the innate system, and it is the removal of the pathogens 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. 32

33 Created by: Carol Leibl Science Content Director National Math and Science

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