Introduction to The Immune System

Transcription

1 Introduction to The Immune System Mohamed Farouk Elshal, Ph.D. Bldg.: 71 / Room:2008; melshal@kau.edu.sa References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology, 6th ed., Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology, 7th ed., 2006.

2 Keys toward Learning Immunology Lectures => Deliver the key concepts of Immunology. Workbook => Apply the knowledge from Immunology to the solution of clinical problems. Textbook reading => Help learn the details and build up comprehensive knowledge of immunology

3 Evaluation For the Immunology Section: Examination => 70 % Attendance & Class performance => 30%

4 What is Immunity?

5 Immunity Immunity The ability of the body to fight infection and/or foreign invaders by producing antibodies or killing infected cells. Immune System The system in the body responsible for maintaining homeostasis by recognizing harmful from nonharmful organisms and produces an appropriate response.

6 Foreign Invaders Called Pathogens Viruses, bacteria or other living thing that causes disease/immune response. Antigens Toxins that pathogens produce that cause harm to an organism. A molecule which elicits a specific immune response when introduced into an animal. More specifically, antigenic (immunogenic) substances are: Generally large molecules (>10,000 daltons in molecular weight), Structurally complex (proteins are usually very antigenic), Accessible (the immune system must be able to contact the molecule), and Foreign (not recognizable as "self").

7 Epitopes: Antigen Regions that Interact with Antibodies

8 Components of Human Immune System

9 Components of Human Immune System CELLS OF THE IMMUNE RESPONSE Cells: Blood - White Blood Cells in particular. 1. B-cells 2. T-cells [Helper T-cells (TH), Suppressor T-cells (TS), Cytotoxic T-cells (CTL) ] 3. Accessory cells [Macrophages, Dendritic cells, Polymorphonuclear cells (PMNs)] 4. Killer cells [NK cells, K cells] 5. Mast cells

10 Components of Human Immune System Lymphoid Tissues: Thymus Gland Produces T Lymphocytes Bone Marrow Produces B Lymphocytes Lymph nodes Spleen

11 LYMPHOID TISSUES

12 LYMPHOID TISSUES

13 How does the body fight infection/foreign invaders? Types of Immunity Nonspecific (innate) Specific (acquired) Naturally acquired Artificially acquired Intact skin Mucous membranes Phagocytic cells Examples Enzymes in secretions Cytokines (Interferon) Placental transfer of antibody (passive) Recovery from disease (active) Administration of antitoxin (passive) Vaccination (active)

14 How does the body fight infection/foreign invaders? The Body s THREE lines of Defense First Line of Defense The Skin Provides Physical and Chemical barriers Physical hard to penetrate, made of indigestible keratin Chemical tears, sweat

15 Second Line of Defense Nonspecific Immune Response These are defenses the body uses no matter what the invader may be. These defenses include: Phagocytosis done by Macrophages Natural Cell Killers Inflammation - caused by release of Histamine from leukocytes Fever caused by histamines. The fever (high temp) kills invaders by denaturing their proteins. Macrophage: A phagocytic cell found in the liver, spleen, brain and lungs. Travels to all areas of the body to find and eat pathogens.

16 Third Line of Defense Specific Immune Response This is a specific response to a specific pathogen/antigen. The response involves the creation of Antibodies.

17 Innate Immunity

18 Innate immunity Innate immunity is the older host defense system: - Existed in both Invertebrates & Vertebrates - Provides the initial defense against infections - Activates and shapes adaptive immune responses

19 Inflammation =>A hallmark of innate immunity =>Local accumulation of immune cells & molecules against microbes =>Function to eliminate infections but often cause tissue damage & disease

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21 Epithelial barriers prevent the entry of microbes

22 Movements of phagocytic cells Ameboid movement. Phagocytic cells migrate in and out of blood vessels and throughout the tissues. The process of cellular emigration from capillaries is called diapedesis.

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24 Phagocytosis during innate immunity Stages in phagocytosis A. Phagocyte detects chemicals released by a foreign intruder (e.g. bacteria) B. Phagocyte moves up the concentration gradient towards the intruder C.The phagocyte adheres to the foreign cell and engulfs it in a vacuole by an infolding of the cell membrane. D.Lysosomes (organelles which are rich in digestive enzymes & found in the phagocytes cytoplasm) fuse with the vacuole & release their contents into it leading to killing the bacterium by the enzymes, and the breakdown products are absorbed by the phagocyte.

25 Phagocytosis during innate immunity

26 Phagocytosis during innate immunity

27 Adaptive Immunity

28 Adaptive Immunity Immunity that an organism develops during lifetime. Not genetically determined. May be acquired naturally or artificially. Development of immunity to measles in response to infection or vaccination.

29 Naturally Acquired Immunity I. Obtained in the course of daily life. A. Naturally Acquired Active Immunity: Antigens or pathogens enter body naturally. Body generates an immune response to antigens. Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections).

30 Naturally Acquired Immunity (Continued) I. Obtained in the course of daily life. B. Naturally Acquired Passive Immunity: Antibodies pass from mother to fetus via placenta or breast feeding (colostrum). No immune response to antigens. Immunity is usually short-lived (weeks to months). Protection until child s immune system develops.

31 Artificially Acquired Immunity II. Obtained by receiving a vaccine or immune serum. 1. Active Immunity: Antigens are introduced in vaccines (immunization). Body generates an immune response to antigens. Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid).

32 Vaccination (also called Immunization) The scientific view of immunity => Edward Jenner (1796) Observation => Milkmaids generally get No smallpox Hypothesis => Pus from vaccinia (cowpox) => Protect milkmaids from smallpox Test => Inoculate materials from cowpox pus => Protect a young boy from smallpox (Protective immunity)

33 Eradication of smallpox Edward Jenner

34 Vaccines for common infectious diseases Still no effective vaccines for many infectious microbes, ex. HCV, HIV,..etc

35 Artificially Acquired Immunity (Continued) II. Obtained by receiving a vaccine or immune serum. 2. Passive Immunity: Preformed antibodies (antiserum) are introduced into body by injection. Snake antivenom injection from horses or rabbits. Immunity is short lived (half life three weeks). Host immune system does not respond to antigens.

36 Artificially Acquired Immunity (Continued) Serum: Fluid that remains after blood has clotted and cells have been removed. Antiserum: Serum containing antibodies to a specific antigen(s). Obtained from injecting an animal (horse, rabbit, goat) with antigen (snake venom, botulism or diphtheria toxin). Serology: The study of reactions between antibodies and antigens. Gamma Globulins: Fraction of serum that contains most of the antibodies. Serum Sickness: Disease caused by multiple injections of antiserum. Immune response to foreign proteins. May cause fever, kidney problems, and joint pain. Rare today.

37 Active vs. Passive immunity Active immunity => A host response to a microbe (Ag) => specific and long-term immune defense (memory) Passive immunity => Adoptive transfer of Ab or lymphocytes specific for a microbe (or Ag) => specific, instant but transient immune defense

38 Interaction between innate and & adaptive immunity 1. Innate immunity => Ag presentation (by infected cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

39 Innate vs Adaptive immunity

40 Epitopes: Antigen Regions that Interact with Antibodies

41 Innate vs Adaptive immunity

42 Features of Adaptive immunity

43 Types of adaptive immunity 1. Humoral immunity => Molecules in body fluid, ex. Antibody (Ab) => Key player => B cells => Target extracellular microbes & toxins 2. Cell-mediated immunity => Key player => T cells => regulate other immune cells => Target intracellular microbes, ex. viruses, bacteria For innate immunity, it also includes Humoral & Cellular components for immune defense

44 Cellular Immunity.vs. Antibody Immunity Cellular Immunity Carried out by T-Cells Infected cells are killed by Cytotoxic T Cells. Antibody or Humoral Immunity Carried out by B-cells Antibodies are produced and dumped into blood stream. Antibodies bind to antigens and deactivate them.

45 Humoral Immunity

46 Adaptive Humoral (Antibody- Mediated) Immunity I. Humoral (Antibody-Mediated) Immunity Involves production of antibodies against foreign antigens. Antibodies are produced by a subset of lymphocytes called B cells. B cells that are stimulated will actively secrete antibodies and are called plasma cells. Antibodies are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells. Defense against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells. Also cause certain reactions against transplanted tissue.

47 How Do B Cells Produce Antibodies? B cells develop from stem cells in the bone marrow of adults (liver of fetuses). After maturation B cells migrate to lymphoid organs (lymph node or spleen). Clonal Selection: When a B cell encounters an antigen it recognizes, it is stimulated and divides into many clones called plasma cells, which actively secrete antibodies. Each B cell produces antibodies that will recognize only one antigenic determinant.

48 Clonal Selection of B Cells is Caused by Antigenic Stimulation

49 Humoral Immunity (Continued) Clonal Selection Clonal Selection: B cells (and T cells) that encounter stimulating antigen will proliferate into a large group of cells. Why don t we produce antibodies against our own antigens? We have developed tolerance to them. Clonal Deletion: B and T cells that react against self antigens appear to be destroyed during fetal development. Process is poorly understood.

50 Humoral Immunity (Continued) Apoptosis Programmed cell death ( Falling away ). Human body makes 100 million lymphocytes every day. If an equivalent number doesn t die, will develop leukemia. B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains. Many virus infected cells will undergo apoptosis, to help prevent spread of the infection.

51 Antigens Most are proteins or large polysaccharides from a foreign organism. Microbes: Capsules, cell walls, toxins, viral capsids, flagella, etc. Nonmicrobes: Pollen, egg white, red blood cell surface molecules, serum proteins, and surface molecules from transplanted tissue. Lipids and nucleic acids are only antigenic when combined with proteins or polysaccharides. Molecular weight of 10,000 or higher. Hapten: Small foreign molecule that is not antigenic. Must be coupled to a carrier molecule to be antigenic. Once antibodies are formed they will recognize hapten.

52 Epitope: Antigens Small part of an antigen that interacts with an antibody. Any given antigen may have several epitopes. Each epitope is recognized by a different antibody.

53 Epitopes: Antigen Regions that Interact with Antibodies

54 Antibodies Y-shaped protein molecule. Made up of variable and constant regions. Made up of Heavy and Light chains. Produced by B- Lymphocytes Function: Recognize antigens, bind to and deactivate them. Note: Variable region recognizes the anitgens.

55 Antibodies One virus or microbe may have several antigenic determinant sites, to which different antibodies may bind. Each antibody has at least two identical sites that bind antigen: Antigen binding sites. Valence of an antibody: Number of antigen binding sites. Most are bivalent. Affinity: A measure of binding strength. Belong to a group of serum proteins called immunoglobulins (Igs). There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE

56 Classes of Antibodies IgM pentamer released by plasma cells during the primary immune response IgA dimer that helps prevent attachment of pathogens to epithelial cell surfaces IgG monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity IgE monomer that binds to mast cells and basophils, causing histamine release when activated IgD monomer attached to the surface of B cells, important in B cell activation

57 Antibody mechanisms of action Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction All antibodies form an antigen-antibody (immune) complex Defensive mechanisms used by antibodies are: 1. neutralization, 2. agglutination, 3. precipitation, and 4. complement fixation

58 Consequences of Antigen-Antibody Binding 1. Agglutination: Antibodies cause antigens (microbes) to clump together. Enhances phagocytosis Reduces number of infectious units to be dealt with IgM (decavalent) is more effective than IgG (bivalent). Hemagglutination: Agglutination of red blood cells. Used to determine ABO blood types and to detect influenza and measles viruses.

59 Consequences of Antigen-Antibody Binding 2. Opsonization: Antigen (microbe) is covered with antibodies that enhances its ingestion and lysis by phagocytic cells. 3. Neutralization: IgG inactivates viruses by binding to their surface and neutralize toxins by blocking their active sites.

60 Humoral Immunity (Continued) 4. Antibody-dependent cell-mediated cytotoxicity (ADCC): Used to destroy large organisms (e.g.: worms). Target organism is coated with antibodies and bombarded with chemicals from nonspecific immune cells.

61 Humoral Immunity (Continued) 5. Complement Activation: Both IgG and IgM trigger the complement system which results in cell lysis and inflammation.

62 Humoral Immunity (Continued) 6. Disruption of cell by complement/reactive protein attracts phagocytic and other defensive immune system cells

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64 Immunological Memory Antibody Titer: The amount of antibody in the serum. Pattern of Antibody Levels During Infection Primary Response: After initial exposure to antigen, no antibodies are found in serum for several days. A gradual increase in titer, first of IgM and then of IgG is observed. Most B cells become plasma cells, but some B cells become long living memory cells. Gradual decline of antibodies follows.

65 Immunological Memory (Continued) Secondary Response: Subsequent exposure to the same antigen displays a faster and more intense antibody response. Increased antibody response is due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation.

66 Antibody Response After Exposure to Antigen

67 Cellular Immunity

68 Specific Immune Response II. Cell Mediated Immunity Involves specialized set of lymphocytes called T cells that recognize foreign antigens on the surface of cells, organisms, or tissues: Helper T cells Cytotoxic T cells T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc.

69 Importance of Cellular Response T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells (exogenous antigens) T cells are also recognize and target intracellular antigens like: Cells infected with viruses, bacteria, or intracellular parasites Abnormal or cancerous cells Cells of infused or transplanted foreign tissue

70 Cell Mediated Immunity Requires constant presence of antigen to remain effective. Unlike humoral immunity, cell mediated immunity is not transferred to the fetus. Cytokines: Chemical messengers of immune cells. Over 100 have been identified. Stimulate and/or regulate immune responses. Interleukins: Communication between WBCs. Interferons: Protect against viral infections. Chemokines: Attract WBCs to infected areas.

71 Antigen Recognition and MHC Restriction Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must simultaneously recognize: Nonself (the antigen) Self (a MHC protein of a body cell)

72 MAJOR HISTOCOMPATIBILITY COMPLEX The Major Histocompatibility Complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and "antigen presentation". The MHC molecules control the immune response through recognition of "self" and "nonself" and, consequently, serve as targets in transplantation rejection.

73 MAJOR HISTOCOMPATIBILITY COMPLEX The Class I and Class II MHC molecules belong to a group of molecules known as the Immunoglobulin Supergene Family, which includes immunoglobulins Both types of MHC proteins are important to T cell activation

74 Class I MHC Proteins Class I MHC proteins Always recognized by CD8 cytotoxic T cells (CTL) Display peptides from endogenous antigens Endogenous antigens are: Degraded by proteases and enter the endoplasmic reticulum Loaded onto class I MHC molecules Displayed on the cell surface in association with a class I MHC molecule

75 Class II MHC Proteins Class II MHC proteins are found only on mature B cells, some T cells, and antigenpresenting cells Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 T helper cells (Th-cells).

76 MHC Proteins and antigen recognition

77 T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces

78 Cell Mediated Immunity Immune responsive cells can be divided into five groups based on the presence of specific surface components and function into: 1. lymphocytes (B-cells, and T-cells). 2. Accessory cells (Macrophages and other antigenpresenting cells), 3. Killer cells (NK and K cells), and 4. Mast cells.

79 B-lymphocytes Surface components Surface immunoglobulin (Ag recognition) Immunoglobulin Fc receptor Class II Major Histocompatability Complex (MHC) molecule (Ag presentation) Function Direct antigen recognition Differentiation into antibody-producing plasma cells Antigen presentation within Class II MHC

80 T-lymphocytes Surface components CD3 molecule Function T-cell receptor (TCR, Ag recognition) Involved in both humoral and cellmediated responses

81 T-lymphocytes T cells are key cellular component of immunity. T cells have an antigen receptor that recognizes and reacts to a specific antigen (T cell receptor). T cell receptor only recognize antigens combined with major histocompatability (MHC) proteins on the surface of cells. MHC Class I: Found on all cells. MHC Class II: Found on phagocytes. Clonal selection increases number of T cells.

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83 Major Types of T Cells Surface components CD4 molecule Function Helper T-cells (TH) Recognizes antigen presented within Class II MHC Promotes differentiation of B-cells and cytotoxic T-cells Activates macrophages Stimulate B cells to produce antibodies.

84 Central Role of Helper T Cells

85 Suppressor T-cells (TS) Surface components CD8 molecule Function Downregulates the activities of other cells

86 Cytotoxic T-cells (CTL) Surface components CD8 molecule Function Recognizes antigen presented within Class I MHC Release protein called perforin which forms a pore in target cell, causing lysis of infected cells. Undergo apoptosis when stimulating antigen is gone.

87 Cytotoxic T Cells Lyse Infected Cells

88 Types of T cells (Continued) Delayed Hypersensitivity T (TD) Cells: Mostly T helper and a few cytotoxic T cells that are involved in some allergic reactions (poison ivy) and rejection of transplanted tissue. T Suppressor (Ts) Cells: May shut down immune response.

89 Nonspecific Cellular Components Natural Killer (NK) Cells: Lymphocytes that destroy virus infected and tumor cells. Not specific. Don t require antigen stimulation. Not phagocytic, but must contact cell in order to lyse it. Surface components Variable Function Direct cell killing Kills variety of target cells (e.g. tumor cells, virusinfected cells, transplanted cells)

90 Nonspecific Cellular Components Polymorphonuclear cells (PMNs) Surface components Immunoglobulin Fc receptor Complement component C3b receptor Function Bind Fc portion of immunoglobulin (enhances phagocytosis) Bind complement component C3b (enhances phagocytosis)

91 Nonspecific Cellular Components Macrophages Surface components Variable Immunoglobulin Fc receptor Complement component C3b receptor Class II MHC molecule Function Bind Fc portion of immunoglobulin (enhances phagocytosis) Bind complement component C3b (enhances phagocytosis) Antigen presentation within Class II MHC Secrete IL-1 (macrokine) promoting T-cell differentiation and proliferation Can be "activated" by T-cell lymphokines

92 Nonspecific Cellular Components Dendritic cells Surface components Class II MHC molecule Function Antigen presentation within Class II MHC

93 Nonspecific Cellular Components Mast cells Surface components High affinity IgE Fc receptors Function Bind IgE and initiate allergic responses by release of histamine

94 Relationship Between Cell-Mediated and Humoral Immunity 1. Antibody Production T-Dependent Antigens: Antibody production requires assistance from T helper cells. A macrophage cells ingest antigen and presents it to T H cell. T H cell stimulates B cells specific for antigen to become plasma cells. Antigens are mainly proteins on viruses, bacteria, foreign red blood cells, and hapten-carrier molecules. T-Independent Antigens: Antibody production does not require assistance from T cells. Antigens are mainly polysaccharides or lipopolysaccharides with repeating subunits (bacterial capsules). Weaker immune response than for T-dependent antigens.

95 Humoral Response to T Dependent Antigens

96 The Pathway of Specific Immune Response Step 1 Pathogens eaten by Macrophage Step 2 Displays portion of Pathogen on surface Pathogens Step 3 Helper-T cell recognizes Pathogen

97 Activates Cytotoxic Activates B- Cell T- Cell Memory T-Cell Memory B-Cell Kills Infected Cells Antibodies

98 Immune Response Explained 1. Antigen infects cells. 2. Macrophage ingests antigen and displays portion on its surface. 3. Helper T- Cell recognizes antigen on the surface of the macrophage and becomes active. 4. Active Helper T-Cell activates Cytotoxic T-Cells and B-Cells. 5. Cytotoxic T-Cells divide into Active Cytotoxic T-cells and Memory T Cells. 6. Active Cytotoxic T-Cells kill infected cells. 7. At the same time, B-Cells divide into Plasma Cells and Memory B- Cells. 8. Plasma cells produce antibodies that deactivate pathogen. 9. Memory T and Memory B cells remain in the body to speed up the response if the same antigen reappears. 10. Supressor T-Cells stop the immune response when all antigens have been destroyed.

99 Immune Response Summary Antigen Displays copy of antigen on surface of cell Macrophage Cellular Immunity Active Cytotoxic T-Cell Helper T - Cell Antibody Immunity Active B - Cell Kills Infected Cells Memory T- Cell Plasma Cell Memory B-Cell Antibodies Deactivates Antigens

100 Overview of the Immune Response

101 Primary.vs. Secondary Immune Response Primary Immune Response This is a response to an invader the First time the invader infects the body. No measurable immune response for first few days. Next days antibody production grows steadily Secondary Immune Response A more rapid response to an invader the 2 nd time it invades the body. Antibody production increases dramatically and in a much shorter time period..

102 Primary.vs. Secondary Immune Response

103 SUMMARY 1. Protective immunity against microbes is mediated by the early response of innate immunity and the later response of adaptive immunity. 2. Innate immune responses are initiated by recognition of common microbial structures by - Provide the first line of host defense - Activate and regulate the adaptive immunity 3. Adaptive immune responses are initiated by recognition of foreign antigens by specific lymphocytes. - Provide more potent, specific (Ag), & broad protection - Develop immune memory for next exposure - Feedback regulate innate immunity

104 Failure of the immune system Ineffective response -Immunodeficiency Overactive response -Hypersensitivity Auto-reactive response -Autoimmunity

105 Autoimmune Disease Autoimmune diseases are diseases where the immune system begins to attack itself. Ex: Rheumatoid Arthritis crippling disease of the joints. Lupus disease of blood and organs. Multiple Sclerosis disease of nervous system Cause(s): unknown Cures/Treatments: No known cures. Usually treated with drugs.

106 Allergies Allergy - An exaggerated response by the immune system to an allergen. Allergen: a normally harmless substance that causes an allergic reaction. ex: dust, pollen, mould, food, insect stings Types of Allergic reactions There are two types of allergic reactions. a. Immediate occurs within seconds and normally lasts for about 30 mins. b. Delayed takes longer to react and can last for a much longer time.

107 What happens during an allergic reaction? During an allergic reaction antibodies cause histamines to be released from certain cells. Histamines cause: a. Swelling of tissues b. Release of fluids (runny noses and eyes) c. muscle spasms (some cases) Anaphylaxis or anaphylactic shock: This is the sudden and severe allergic reaction to a substance that can cause death. Treatments for Allergies 1.Avoidance of material especially food. 2.Epinephrine epi pen 3.Antihistamines -- benadryl