1. Chapter 43:The Immune System Benjamin Stanonik Santhosh Ganesan Isaias Mendez Period 5

2. OverviewOverview The job of the immune system is to protect the body from foreign particles, microorganisms, and parasites called pathogens The body uses two main kinds of defense against pathogens:  Innate Immunity-Protection from pathogens that begins from birth, nonspecific, consists of the skin, the mucous membranes, the phagocytic cells, antimicrobial proteins, Killer Cells and the inflammatory response  Acquired Immunity-Protection that is brought about by exposure to pathogens and the production of antibodies against a specific pathogen

3. Innate Immunity: External Defenses Skin prevents most pathogens from entering the body, and mucous membranes surrounding the digestive and respiratory organs trap pathogens Saliva and tears, for the most part, prevent microbial colonization from occurring by washing microbes off the surfaces of exposed epithelial tissue Secretions of the skin and mucous membrane contain antimicrobial proteins, notably lysozyme, an enzyme that lyses bacteria by digesting their cell walls

4. Phagocytes Many of the microbes that break through the body’s external defenses are ingested by certain types of white blood cells upon entering the blood stream, called phagocytes, by a process called phagocytosis Phagocytes produce antimicrobial proteins and initiate inflammation, which limits the spread of microbes before the body can mount acquired, specific immune responses

5. Phagocytic Cells: Phagocytosis Phagocytes use surface receptors that are present on many microorganisms that aren’t present in normal body cells to attach to microbes and engulf them The microbe is then trapped in a newly formed vacuole that is fused with a lysosome Upon fusing with the lysosome, the microbe is either destroyed by toxins, or enzymes such as lysozyme digest it

6. Phagocytic Cells: Neutrophils Four types of white blood cells (also called leukocytes) are phagocytic. The most common are neutrophils, which are 60-70% of all white blood cells Neutrophils enter infected tissues and engulf them, but tend to self-destruct during phagocytosis, rendering their life span to only a few days

7. Phagocytic Cells: Macrophages Macrophages (“big eaters”) are a more effective defense. They have a long life span and are developed from monocytes, which are about 5% of white blood cells Monocytes circulate in the blood for only a few hours before they are migrated into tissues and transformed into macrophages Some macrophages migrate throughout the body, while others are permanent residents in the spleen and lymph nodes, whose net-like architecture traps microbes so they can be engulfed by the macrophages

8. Phagocytes: Eonsinphils and Dendritic Cells Other types of phagocytes are less abundant and play a more limited role Eosinphils are low in phagocytic activity but are critical to defense against multicellular parasites Dendritic cells, the fourth type of phagocyte, can ingest microbes but are mainly used to stimulate development of acquired immunity

9. Antimicrobial Proteins Antimicrobial proteins include about 30 serum proteins that make up the complement system, which can be triggered by substances on the surfaces of microbes Two types of interferons (α and β) provide innate defense against viral infections. These proteins are secreted by virus-infected body cells that signal neighboring cells to produce substances that inhibit viral reproduction (this mechanism is not virus-specific) Certain lymphocytes (white blood cell that mediates acquired immunity) secrete a third type of interferon (γ) that enhance their phagocytic ability

10. The Inflammatory Response Damage to tissue by injury or entry of pathogens leads to the release of chemical signals that trigger the inflammatory response The most active of these chemicals is histamine, which is stored in mast cells. Histamine triggers dilation and increased permeability of nearby capillaries, promoting blood flow to the injured site

11. Inflammatory Response (continued) The heat and swelling accompanied by inflammation help deliver antimicrobial proteins and clotting elements to the injured area Small proteins called chemokines direct the migration of phagocytes and signal them to increase production of microbe-killing compounds Neutrophils and macrophages engulf the pathogens and cell debris at the site, and the injured tissue eventually heals

12. Natural Killer Cells Natural killer (NK) cells patrol the body and attack virus-infected cells and cancer cells NK cells find harmful body cells and release chemicals that lead to the death of the cell by apoptosis, or programmed cell death While not 100% effective, NK cells are crucial in the destruction of cells that otherwise seem like normal body cells

13. Acquired Immunity: Antigen Recognition Any foreign molecule that is specifically recognized by lymphocytes and provokes a response from them is called an antigen Antigens are mostly large molecules, either proteins or polysaccharides Lymphocytes bind to small portions of antigens called epitopes

14. B Cells and T Cells There are two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells) B and T cells recognize antigens using antigen receptors Each lymphocyte recognizes a specific epitope on an antigen and defends against that antigen

15. B Cell Receptors Each B cell receptor for an antigen is a Y-shaped molecule consisting of four polypeptide chains: two heavy chains and two light chains linked by disulfide bridges A region in the tail portion of the molecule, the transmembrane region, anchors the receptor in the cell’s plasma membrane, and a short region at the end of the tail extends into the cytoplasm At the tips of the Y are the light and heavy chain variable regions that vary extensively from one B cell to another due to their amino acid sequences Remainder of the molecule is made up of constant regions, whose amino acid sequences vary little from cell to cell

16. Antibodies Antibodies are Y-shaped, defensive proteins produced by plasma cells (antibody- secreting B cells) that bind to pathogens and mark them for elimination Antibodies can occur in two forms: as a secretion of a plasma cell or in a membrane-bound form on the surface of B cells Secreted antibodies, called immunoglobulins, are structurally similar to B cell receptors, but they lack the transmembrane regions that anchor receptors into the plasma membrane

17. T Cell Receptors T Cell receptors are similar in structure to B Cell receptors, however each T cell receptor for an antigen consists of two different polypeptide chains and is essentially “double L” shaped T cell receptors recognize fragments of antigens that are bound to normal cell surface proteins called MHC molecules MHC molecules are so named because they are encoded by a family of genes called the major histocompatibility complex As a newly synthesized MHC molecule is transported toward the plasma membrane, it binds with a fragment of protein antigen within the cells and brings it to the cell surface, a process called antigen presentation

18. MHC Molecule Classes There are two ways in which foreign antigens can end up inside cells of the body:  Class 1 MHC Molecules  Found on almost all nucleated cells, Class 1 MHC molecules bind peptides derived from foreign antigens that have been synthesized within the cell  Any body cell that is infected or cancerous can display these peptide antigens by its Class 1 MHC molecules, and are recognized by T cells called cytotoxic T Cells Because every person’s MHC alleles are unique, the immune system can use Class 1 MHC molecules as a “cell marker” to determine “self” from “nonself”

19. MHC Molecules Classes (continued)  Class II MHC Molecules  Made by just a few cell types  Bind peptides derived from foreign materials that have been fragmented through phagocytosis  Dendritic Cells, Macrophages, and B Cells are known as antigen-presenting cells because they engulf pathogens, break them up, and take some of their “antigen” components and “present” class II MHC molecules of that antigen on their surface to alert other leukocytes of the antigen’s existence in the body

20. Lymphocyte Development and Self Reactive Lymphocytes Lymphocytes originate in the bone marrow and later develop into T cells or B Cells depending on where they mature Lymphocytes that go to the thymus (gland in the thoracic cavity above the heart) develop into T Cells, and lymphocytes that stay in the bone marrow develop into B cells Genetically, lymphocytes are diverse and the source of this diversity comes from the unique genes that encode their antigen receptor chains Because the rearrangements of antigen receptor genes are random, a developing lymphocyte may end up with antigen receptors that target “self” molecules As they develop, B cells and T cells are tested for potential self reactivity, and the ones that are self reactive are usually either destroyed by apoptosis or rendered nonfunctional

21. Clonal Selection An antigen encounters a large number of B cells and T Cells in the body, however a given antigen interacts only with the few lymphocytes receptors specific for that antigen The selection of a B cell or T cell by an antigen stimulates the lymphocytes to divide many times and form to clones of daughter cells  One clone consists of a large number of short-lived effector cells that combat the same antigen  The other clone consists of memory cells, long-lived cells bearing receptors for the same antigen. Can reproduce and use antibodies again if the same pathogen that has the antigen reenters the body  Core of immune system’s ability to “remember” pathogens that enter the body This antigen-driven cloning of lymphocytes is called clonal selection, and it is the cornerstone of acquired immunity

22. Primary and Secondary Immune Response The selective production and differentiation of lymphocytes that occur the first time the body is exposed to the antigen is called the primary immune response, which involves the production of plasma cells that produce antibodies to neutralize the antigen  A person can become ill as this process is occurring, but symptoms diminish once the antibodies take action If a person is exposed to that same antigen again, the response is quicker and greater; it is the secondary immune response  Antibodies are more numerous due to the memory of the antigen already being recorded in the immunological directory by memory cells, and they overwhelm the antigen and the pathogen it belongs to as a result

23. Hormonal and Cell-Mediated Response Acquired immunity includes two branches: the humoral immune response and the cell mediated immune response  Humoral response activates clonal selection of B cells that secrete antibodies that circulate in the blood  Cell-Mediated response activates clonal selection of cytotoxic T cells, which directly destroy target cells Helper T cells are central to this network of interactions, as they respond to peptide antigens on antigen-presenting cells and signal B cells and cytotoxic T cells to act to destroy the antigens

24. Helper T Cells The main job of the helper T cell is to alert the immune system When a helper T cell recognizes an class II MHC molecule- antigen on an antigen-presenting cell, it divides and creates clones of activated helper T cells and memory T cells A protein called CD4 is used to bind the helper T cell to the antigen-presenting cell  Helps keep the helper T cell and the antigen-presenting cell joined while activation of the Helper T cell continues Activated helper T cells secrete cytokines that stimulate other lymphocytes, which creates a hormonal and cell- mediated response

25. After a dendritic cell engulfs and degrades a bacterium, it displays bacterial antigen fragments (peptides) complexed with a class II MHC molecule on the cell surface. A specific helper T cell binds to the displayed complex via its TCR with the aid of CD4. This interaction promotes secretion of cytokines by the dendritic cell. Proliferation of the T cell, stimulated by cytokines from both the dendritic cell and the T cell itself, gives rise to a clone of activated helper T cells (not shown), all with receptors for the same MHC–antigen complex. The cells in this clone secrete other cytokines that help activate B cells and cytotoxic T cells. Cell-mediated immunity (attack on infected cells) Humoral immunity (secretion of antibodies by plasma cells) Dendritic cell Dendritic cell Bacterium Peptide antigen Class II MHC molecule TCR CD4 Helper T cell Cytokines Cytotoxic T cell B cell 1 2 3 1 2 3

26. Cytotoxic T Cells Cytotoxic T cells are the core of cell-mediated immunity A surface protein, called CD8, greatly enhances interaction between a target cell and a cytotoxic T cell (a target cell in this case can be a virus, a bacterium, a cancer cell, or transplanted tissue), and it allows the activation of the cytotoxic T cell Once a cytotoxic T cell is bound to a target cell and is activated, it becomes an active killer, secreting proteins that result in the destruction of the target cell  Deprives pathogens of places to reproduce and exposes them to antibodies  Important in destroying cancerous cells and malignant tumors

27. Cytotoxic T cell Perforin Granzymes CD8 TCR Class I MHC molecule Target cell Peptide antigen Pore Released cytotoxic T cell Apoptotic target cell Cancer cell Cytotoxic T cell A specific cytotoxic T cell binds to a class I MHC–antigen complex on a target cell via its TCR with the aid of CD8. This interaction, along with cytokines from helper T cells, leads to the activation of the cytotoxic cell. 1 The activated T cell releases perforin molecules, which form pores in the target cell membrane, and proteolytic enzymes (granzymes), which enter the target cell by endocytosis. 2 The granzymes initiate apoptosis within the target cells, leading to fragmentation of the nucleus, release of small apoptotic bodies, and eventual cell death. The released cytotoxic T cell can attack other target cells. 3 1 2 3

28. Antibody Classes There are five major types of heavy-chain constant regions, and these determine five major classes of antibodies (Ig stands for immunoglobulin):  IgG is the most abundant antibody in the blood  IgA is found in fluids such as saliva, tears, and intestinal fluids, provides localized defense  IgM is the largest antibody, effective in complement activation  IgD is found on the surface of certain B cells that have not been exposed to antigens  IgE binds to masts cells to release histamine

29. First Ig class produced after initial exposure to antigen; then its concentration in the blood declines Most abundant Ig class in blood; also present in tissue fluids Only Ig class that crosses placenta, thus conferring passive immunity on fetus Promotes opsonization, neutralization, and agglutination of antigens; less effective in complement activation than IgM Present in secretions such as tears, saliva, mucus, and breast milk Triggers release from mast cells and basophils of histamine and other chemicals that cause allergic reactions Present primarily on surface of naive B cells that have not been exposed to antigens IgM (pentamer) IgG (monomer) IgA (dimer) IgE (monomer) J chain IgD (monomer) Promotes neutralization and agglutination of antigens; very effective in complement activation Provides localized defense of mucous membranes by agglutination and neutralization of antigens Presence in breast milk confers passive immunity on nursing infant Acts as antigen receptor in antigen-stimulated proliferation and differentiation of B cells (clonal selection)

30. Antibody-Mediated Disposal There are several ways that antibodies help lead to the destruction of pathogens:  Viral Neutralization- antibodies prevent viruses from binding to a host, marks it for elimination by phagocytes  Agglutination- antibodies clump bacteria and viruses and makes it easier for them to be recognized and engulfed by phagocytes  Use of a membrane attack complex (MAC)- antibodies and complement proteins work together to create pores inside the cell membranes of pathogens  Ions and water to rush into the pathogen and cause it to lyse

31. Active Immunity (Vaccines) Immunity gained by natural exposure to a pathogen and activation of lymphocytes is active immunity  Can develop following immunization or vaccination  Vaccines are derivations of nonfunctional or weak viruses and bacteria that stimulate the immune system into producing antibodies against the antigens in the vaccine  Memory cells “remember” the antigen and save it in the immunological directory so that if the body is infected by the actual pathogen, it can immediately produce antibodies against it  Newer vaccines are being produced using anti-antibodies, which are used by the immune system to neutralize antibodies Stimulate the immune system to produce antibodies against an “imaginary” antigen

32. Passive Immunity Antibodies that are transferred from one individual who produced them to another who didn’t is passive immunity Antibodies immediately neutralize the pathogen it was designed to fight, and they are then destroyed by the recipient's immune system and aren’t used again Example: Antibodies can be injected into a person that was bitten by a rabid dog to fight the rabies virus

33. Blood Transfusions Since the immune system can recognize “self” from “nonself,” the opportunities to transplant tissues and organs and transfuse blood are limited Red blood cells present either the A antigen, the B antigen, both antigens, or neither antigen A person with type A blood does not produce antibodies for the A antigen, because they are self-tolerant; however, they do have antibodies against the B antigen, which prevents blood transfusion involving type B or AB blood A person with the O blood type must transfuse their blood with blood only of the O type, as they have antibodies for both the A and the B antigen

34. Tissue Transplants A rejection reaction is caused by the vast majority of tissue transplants because at least some of the MHC molecules in the donated tissue are foreign to the recipient Solutions to this dilemma include donating tissues that are as closely related to the MHC molecules of the recipient as possible, and giving the recipient medicines to suppress immune responses (although this can cause the recipient to become more susceptible to infection) Bone marrow transplants are done to produce B and T cells in someone with a weakened immune system

35. Allergies Allergies are hypersensitive responses by the immune system to certain antigens called allergens Most common allergies involve the IgE antibodies Mast cells degranulate and send large amounts of histamine into the bloodstream to stimulate the immune system to fight against relatively harmless particles such as pollen A strong allergic response can lead to anaphylactic shock, which is caused by histamine dilation of blood vessels, causing a dramatic drop in blood pressure and possibly death

36. Autoimmune Diseases When the immune system loses tolerance for itself and attacks one’s own body cells, that individual has an autoimmune disease Autoimmune diseases likely arise from failure to regulate self-reactive cells The immune system produces autoantibodies that attack a wide range of “self” molecules, including histones and DNA released by normal breakdown of body cells Examples include lupus, rheumatoid arthritis, and multiple sclerosis, the most common chronic neurological disease in developed countries

37. Immunodeficiency Diseases: Primary An individual whose immune system is unable to protect the body against garden-variety pathogens that it would normally be able to deflect has an immunodeficiency disease There are two types of these diseases: primary and secondary Primary immunodeficiency diseases are caused by genetic defects that prevent the formation of an immune or an impaired immune system (example: severe combined immunodeficiency or SCID)

38. Immunodeficiency Diseases: Secondary Secondary immunodeficiency diseases are caused by biological or chemical agents that impair a previously operational immune system Most well-known example of this type of disease is acquired immunodeficiency syndrome (AIDS)  Human immunodeficiency virus (HIV) is the agent that causes AIDS  Currently, there is no cure, but there are drugs that can slow HIV reproduction; however, they are very expensive  New, prototype vaccines have been recently produced that can help the immune system fight against certain forms of the virus

39. How can we help strengthen our immune systems? Having a positive attitude actually helps strengthen the immune system; stress weakens it, due to hormones that are released as a result of depression or stress that can weaken leukocytes Vitamins (particularly Vitamin C) contribute to the production and fortitude of leukocytes Eating a balanced diet and getting exercise keeps the immune system active and ready to fight pathogens

40. Bibliography Campbell, Neil A., and Jane B. Reece. "Chapter 43: The Immune System." Preparing for the Biology AP Exam with Biology, Seventh Edition. San Francisco, Ca.: Pearson/Benjamin Cummings, 2005. Print. Friedlander, Mark P., and Terry M. Phillips. The Immune System: Your Body's Disease-fighting Army. Minneapolis, MN: Lerner Publications, 1998. Print. Pack, Phillip E. "Animal Structure and Function: The Immune System." CliffsAP Biology. New York: Wiley, 2001. Print.