Endeavour College of Natural Health endeavour.edu.au

BIOH122 Human Biological Science 2 Session 9 Immune System 2 Bioscience Department Endeavour College of Natural Health endeavour.edu.au

o Adaptive (Specific) immunity Antigens Self Recognition and MHC Antigen Processing and MHC o Cell mediated immunity Activation of T Cells Activation and Clonal Selection Elimination of Invaders Immunological Surveillance Session Plan o Antibody Mediated Immunity Activation of B cells Clonal selection and Antibody secretion Antigen antibody complex formation Antibodies Complement system Immunological Memory Endeavour College of Natural Health endeavour.edu.au 3

Antigens o Antigens: Antibody generators. o Substances that are recognized as foreign and provoke immune responses are called antigens (Ags) entire microbes, parts of microbes, bacterial toxins, pollen, transplanted organs, incompatible blood cells (whole cells, parts of cells or chemicals) o Characteristics of an antigen: Immunogenicity = ability to provoke immune response Reactivity = ability to react to cells or antibodies it provoked Endeavour College of Natural Health endeavour.edu.au 4

Antigens o Get past the bodies nonspecific defenses antigens are directed to lymphatic tissues enter the bloodstream to be deposited in spleen penetrate the skin and end up in lymph nodes penetrate mucous membranes and lodge in mucosa associated lymphoid tissue Endeavour College of Natural Health endeavour.edu.au 5

Chemical Nature of Antigens / Epitopes o Structure: Large, complex molecules, usually proteins if they have simple repeating subunits they are not usually antigenic (plastics in joint replacements) o Epitope: small part of antigen that triggers the immune response antigenic determinant o Hapten: A smaller substance that can not trigger an immune response unless attached to body protein lipid of poison ivy Endeavour College of Natural Health endeavour.edu.au 6

Antigen Receptors o Antigen Receptors: Present on plasma membranes of lymphocytes that can recognize and respond to a billion different epitopes - even artificially made molecules o Diversity: Genetic recombination of few hundred small gene segments produce a huge variety of antigen receptors o Specificity: Each B or T cell has its own unique set of gene segments that codes its unique antigen receptor in the cell membrane Endeavour College of Natural Health endeavour.edu.au 7

Major Histocompatibility Complex Antigens o Major Histocompatibility Complex (MHC) Antigens: Self antigens, surface markers o They define our cells as self o They also serve as a signal to lymphocytes that antigens/ pathogens are present Glycoproteins located in the plasma membrane of all body cells Also called Human Leukocyte Antigens (HLA) o Two types: MHC class I antigens MHC class II antigens Endeavour College of Natural Health endeavour.edu.au 8

Major Histocompatibility o MHC-I antigens: are built into the cell membrane of all cells except red blood cells Complex Antigens o Function: If a cell is infected with a virus, the MHC-I contains bits of virus marking the cell so T cells recognize that there is a problem in that cell Endeavour College of Natural Health endeavour.edu.au 9

Major Histocompatibility o MHC-II antigens: Appear only on membrane of Antigen Presenting Cells (Dendritic cells, macrophages, B cells) Complex Antigens o Function: If antigen presenting cells ingest foreign proteins, they will display some as part of their MHC-II Endeavour College of Natural Health endeavour.edu.au 10

Pathways of Antigen Processing o Antigen recognition: B and T cells must recognize a foreign antigen before beginning their immune response B cells can bind to antigens in lymph, interstitial fluid, or blood plasma. T cells can only recognize fragments of antigens that have been processed and presented to them as part of a MHC molecule Helper T cells see antigens if part of MHC-II molecules on surface of antigen presenting cell Cytotoxic T cells see antigens if part of MHC-I molecules on surface of body cells Endeavour College of Natural Health endeavour.edu.au 11

Processing of Exogenous Antigens o Exogenous Antigens: Foreign antigens that are present in fluids outside body cells These include bacteria and bacterial toxins, parasitic worms, inhaled pollen and dust, and viruses that have not yet infected a body cell. o Processed by: Antigen-presenting cells (APCs) and presented together with MHC class II molecules to T cells to alert that intruders are present. Endeavour College of Natural Health endeavour.edu.au 12

Processing of Exogenous Antigens: APC cells with MHCII The steps in the processing and presenting of an exogenous antigen by an antigen-presenting cell: Endeavour College of Natural Health endeavour.edu.au 13

Processing of Endogenous Antigens o Endogenous antigens: Foreign antigens that are present within the body cells include viral proteins or proteins produced by cancer cells o Processed by: Most of the body cells of the body can process endogenous antigens Fragments of endogenous antigen are associated with MHC class I molecules inside the cell. The antigen-mhc-i complex moves to the cell s surface where it alerts T cells Endeavour College of Natural Health endeavour.edu.au 14

Processing of Endogenous Antigens: Most Body cells with MHCI The steps in the processing and presenting of an endogenous antigen by an infected body cell Endeavour College of Natural Health endeavour.edu.au 15

Cytokines o Cytokines: Small protein hormones secreted by lymphocytes and antigen presenting cells, fibroblasts, endothelial cells, monocytes, hepatocytes, and kidney cells o Functions: o stimulate or inhibit many normal cell functions, such as cell growth and differentiation. o Are essential in the immune responses of T and B cells through the process of co-stimulation Endeavour College of Natural Health endeavour.edu.au 16

Cytokines Endeavour College of Natural Health endeavour.edu.au 17

Activation of T Cells: Summary o There are two types of T Cells. Helper T cells & Cytotoxic T cells o A T cell is activated when it receives two signals. o First signal: Antigen recognition by a T-cell receptor (TCR) T-cell receptors (TCRs): recognize and bind to specific foreign antigen fragments that are presented in antigen MHC complexes o Second signal: Costimulation by costimulators or plasma membrane molecules Costimulators: cytokines such as interleukin-2 (IL-2) Endeavour College of Natural Health endeavour.edu.au 18

Activation of Helper T Cells o Activation: The helper T cell becomes activated through Antigen recognition: TCRs on Helper T cells bind to foreign antigen fragment associated with MHC-II at the surface of an APC with the help of CD4 proteins Costimulation: by interleukin-2 Endeavour College of Natural Health endeavour.edu.au 19

Clonal Selection of Helper T Cells o Clonal Selection: activated helper T cell undergoes clonal selection to form a clone of helper T cells: Active helper T cells: secrete cytokines including interleukin-2 (IL-2), Memory helper T cells: Available for swift response if a second exposure should occur o Interleukin-2 (IL-2): act as a costimulator for resting helper T cells or cytotoxic T cells, and it enhances activation and proliferation of T cells, B cells, and natural killer cells. Endeavour College of Natural Health endeavour.edu.au 20

Activation and Clonal Selection of Helper T Cells Endeavour College of Natural Health endeavour.edu.au 21

Activation of Cytotoxic T Cells o Activation: The Cytotoxic T cell becomes activated through Antigen recognition: TCRs on a Cytotoxic T Cell binds to the foreign antigen fragment part of MHC-I on the surface of body cells infected by microbes, some tumor cells, and cells of a tissue transplant Costimulation: By IL-2 and other cytokines from helper T cell Endeavour College of Natural Health endeavour.edu.au 22

Clonal Selection Cytotoxic T Cells o Clonal Selection: activated cytotoxic T cell undergoes clonal selection to form a clone of cytoxic T cells: Active Cytotoxic T cells: attack other body cells that have been infected with the antigen Memory Cytotoxic T cells: Available for swift response if a second exposure should occur Endeavour College of Natural Health endeavour.edu.au 23

Activation and Clonal Selection of Cytotoxic T Cells Endeavour College of Natural Health endeavour.edu.au 24

Elimination of Invaders o Cytotoxic T cells: Act as soldiers in cell mediated response o Migration: Cytotoxic T cells leave secondary lymphatic organs and tissues, migrate to site of infection, tumour formation, or transplanted tissues o Cytotoxic T cells recognize and attach to target cells. o Endeavour College of Natural Health endeavour.edu.au 25

Elimination of Invaders o Attack: Cytotoxic T cells kill infected target cells by: 1. Releasing Granzymes: Protein-digesting enzymes that trigger apoptosis. 2. Releasing proteins from their granules Perforin: creates channels in the plasma membrane of a target cell causes cell lysis. Granulysin: Enters through the channels and destroys the microbes by creating holes in their plasma membranes 3. Secreting Lymphotoxin that activates enzymes in the target cell causing its DNA to fragment 4. Secrete gamma-interferon to activate phagocytic cells Endeavour College of Natural Health endeavour.edu.au 26

Elimination of Invaders When the cytotoxic T cell detaches from a target cell, it can destroy another cell. Endeavour College of Natural Health endeavour.edu.au 27

Immunological Surveillance o Tumor antigen: Surface molecules displayed by Cancerous cells o Immunological surveillance: Immune system finds, recognizes and destroys cells with tumour antigens Carried out by cytotoxic T cells, macrophages and Natural Killer cells most effective in finding tumours caused by viruses o Transplant patients taking immunosuppressive drugs suffer most from viral-induced cancers Endeavour College of Natural Health endeavour.edu.au 28

Graft Rejection o The immune system can recognize proteins in transplanted organs as foreign and mount a graft rejection. o After an organ transplant, the immune system has both cell-mediated and antibody-mediated immune responses = graft rejection o Close match of histocompatibility complex antigens has weaker graft rejection response o immunosuppressive drugs (cyclosporine) inhibits secretion of interleukin-2 by helper T cells little effect on B cells so maintains some resistance Endeavour College of Natural Health endeavour.edu.au 29

Antibody-Mediated Immunity Endeavour College of Natural Health endeavour.edu.au 30

Antibody mediated immunity Activation of B cells Clonal selection and Antibody secretion Antigen antibody complex formation Antibodies Complement system Immunological Memory o Self recognition and self tolerance o Immunological Pathologies o Aging, stress and the immune system Endeavour College of Natural Health endeavour.edu.au 31

Antibodies o Antibody: A protein that can combine specifically with the antigenic determinant on the antigen that triggered its production. o Five principal classes: IgG, IgA, IgM, IgD, and IgE Based on chemistry and structure, each with specific biological roles. Endeavour College of Natural Health endeavour.edu.au 32

Antibody Structure Endeavour College of Natural Health endeavour.edu.au 33

Antibody Structure o Chemical structure: Globulins glycoproteins called immunoglobulins o 4 polypeptide chains - 2 heavy and 2 light chains Mid region: hinged lets it assume a T or Y shape Tips are the variable regions: form the antigen binding sites Rest is the constant region: 5 different classes based on constant region IgG, IgA, IgM, IgD and IgE Endeavour College of Natural Health endeavour.edu.au 34

Antibody Classes and Function Endeavour College of Natural Health endeavour.edu.au 35

Antibody-Mediated Immunity o Antibody-mediated (humoral) immunity (AMI): refers to destruction of antigens by antibodies. B cells transform into plasma cells, Plasma cells synthesize and secrete specific proteins called antibodies works mainly against antigens dissolved in body fluids (humours) and extracellular pathogens, primarily bacteria, that multiply in body fluids but rarely enter body cells. o Specificity: Millions of different B cells, each capable of responding to a specific antigen Endeavour College of Natural Health endeavour.edu.au 36

Antibody-Mediated Immunity Major steps in antibody-mediated immune response: o Activation of B cells o Clonal selection and Antibody secretion o Antigen antibody complex formation Endeavour College of Natural Health endeavour.edu.au 37

Activation of B Cells o Stimulation: B cells sit still in lymph nodes, spleen or mucosa-associated lymphatic tissue. Activated when an antigen is presented to them. response is more intense if antigen is on an APC o Antigen binding: During activation of a B cell, an antigen binds to B cell antigen receptors on the cell surface. B cell antigen receptors are chemically & structurally similar to the antibodies that will eventually be secreted by their progeny. Endeavour College of Natural Health endeavour.edu.au 39

Activation of B Cells o Antigen processing: Antigen is taken into the B cell, broken down into peptide fragments and combined with the MHC-II self-antigen, and moved to the B cell surface. o Co-stimulation: Helper T cells recognize the antigen- MHC-II combination and produce interleukin-2 and other cytokines that function as costimulators to activate B cells. Endeavour College of Natural Health endeavour.edu.au 40

Clonal Selection and antibody secretion o Clonal selection: Once activated, clones of B cells are produced. o Rapid cell division and differentiation occurs to form Long-lived memory B cells: quickly proliferate and differentiate into more plasma cells and memory B cells against the same antigen if re-attacks. Plasma cells: produce and secrete antibody at 2000 molecules/sec for 4-5 days o Antibody enters the circulation to attack the antigen. Endeavour College of Natural Health endeavour.edu.au 41

Activation and clonal selection of B cells Note: This process shows B Cell activation through direct binding of BCR with antigen. B Cells can also be activated through BCR binding of antigen from an Antigen Presenting Cell (as shown in Figure 22.13) Endeavour College of Natural Health endeavour.edu.au 42

Antigen antibody complex formation o Antibodies produced by a clone of plasma cells enter the circulation in lymph and blood. o Combine with the specific antigen to form antigen antibody complexes with the antigen that initiated their production. Endeavour College of Natural Health endeavour.edu.au 43

Antibody Actions o Neutralize antigens: by blocking the effects of toxins or preventing its attachment to body cells o Immobilize bacteria: by attacking cilia/flagella o Agglutinate and precipitate antigens: by cross-linking them causing clumping and precipitation o Complement activation: Antigen antibody complexes initiate the complement system o Enhancing phagocytosis: through precipitation, complement activation or opsonization (coating with a special substance) Endeavour College of Natural Health endeavour.edu.au 44

Complement System o Complement system is made up of over 30 inactive proteins and must be activated. o Activation by: The classical pathway: stimulated through antigenantibody complex The alternative pathway: through lipid carbohydrate complexes on the surface of microbes The lectin pathway: through lectins produced by liver in response to chemicals secreted by macrophages Endeavour College of Natural Health endeavour.edu.au 45

The Complement System o Inflammation, o Phagocytosis o Cell lysis Endeavour College of Natural Health endeavour.edu.au 46

Immunological Memory o Immunological Memory achieved due to: the presence of long-lasting antibodies and very long-lived lymphocytes that arise during clonal selection of antigen-stimulated B cells and T cells (decades) o Provides the basis for acquired immunity including immunization by vaccination against certain diseases Endeavour College of Natural Health endeavour.edu.au 47

Immunological Memory o Primary response: a slow rise in the antibody titre (amount of antibody in serum) after an initial contact with an antigen, followed by a gradual decline with the recovery from an infection. Memory cells are formed that may remain for decades Endeavour College of Natural Health endeavour.edu.au 48

Immunological Memory o The secondary response: rapid proliferation of memory cells when the same antigen re-attack results in a far greater antibody titre (mainly of IgG) than during a primary response. provides protection should the same microbe enter the body again. Quicker recognition and intense and removal occursnot even sick. Endeavour College of Natural Health endeavour.edu.au 49

Immunological Memory Production of antibodies following exposure to antigen. Primary (first exposure) and secondary (second exposure) responses. Note: IgG are produced in large amounts in 2 O exposure through process called Class Switching Endeavour College of Natural Health endeavour.edu.au 50

Immunological Memory Endeavour College of Natural Health endeavour.edu.au 51

Self recognition and self tolerance o Mature T and B Cells must recognise but not react to self. This is defined by their responses to MHC proteins. o Process happens in bone Marrow (B Cells) and Thymus (T Cells) o It occurs through positive and negative selection o Self-recognition: T cells ability to recognize self major histocompatibility complex (MHC) proteins. o Self-tolerance: T cells lacking reactivity to peptide fragments from self proteins. o T cells mature in thymus those that can t recognize self, or react to it are destroyed or neglected only 1 in 100 emerges as an immunocompetent T cell Endeavour College of Natural Health endeavour.edu.au 52

Immunological Pathologies Endeavour College of Natural Health endeavour.edu.au 53

Hypersensitivity Reactions o Hypersensitivity: A person s over reactivity to a substance that is tolerated by most others. o Four basic types of hypersensitivity reactions: Type I (anaphylaxis) reactions Type II (cytotoxic) reactions Type III (immune complex) reactions Type IV (cell-mediated) reactions or delayed hypersensitivity reactions Endeavour College of Natural Health endeavour.edu.au 54

Autoimmune Disease o In an autoimmune disease the immune system fails to display selftolerance and attacks the person s own tissue. Due to T or B Cells being produced that are not self tolerant. Due to Cytoxic T or Helper T cells reactivity to self. Due to B Cells Plasma Cells production of Auto-antibodies Systemic lupus erythematosus is a chronic autoimmune, inflammatory disease that affects multiple body systems. Type I Diabetes: Autoimmune destruction of pancreatic cells that produce insulin Rheumatoid arthritis: Autoimmune destruction joints (mostly a IgM autoantibody) Multiple Sclerosis: T Cells bind to parts of the myelin sheath of nerve axons. Endeavour College of Natural Health endeavour.edu.au 55

Immunological Pathologies o Cancer of the Immune system Lymphomas are cancers of the lymphatic organs especially the lymph nodes. The two main types are: Hodgkin s disease and non-hodgkin s lymphoma. o Infections of the immune system Infectious mononucleosis (Glandular fever) is a contagious disease primarily affecting lymphatic tissue throughout the body but also affecting the blood. It is caused by the Epstein-Barr virus which multiplies in B cells. Human Immunodeficiency Virus (HIV) primarily infects helper T cells (also macrophages, and dendritic cells) Endeavour College of Natural Health endeavour.edu.au 56

Stress, Aging and the Immune System Endeavour College of Natural Health endeavour.edu.au 57

Stress and Immunity Stress affects habit, lifestyle and health: o Under stress, people are less likely to eat well or exercise regularly, two habits that enhance immunity. o Cortisol, a hormone secreted by the adrenal cortex in association with the stress response, inhibits immune system activity. o Feelings, moods, and beliefs also influence the level of health and the course of a disease Endeavour College of Natural Health endeavour.edu.au 58

Aging Effects of aging on immune functions: o With aging, the immune system functions less effectively T cells less responsive to antigens age-related atrophy of thymus decreased production of thymic hormones B cells less responsive production of antibodies is slowed Produce more auto-antibodies o Individuals become more susceptible to infections and malignancies (decreased T and B cell responses) o Response to vaccines is decreased Endeavour College of Natural Health endeavour.edu.au 59

Readings and Resources o Tortora, GJ & Derrickson, B 2014. Principles of Anatomy and Physiology, 14th edn, Wiley. o Harris, P, Nagy, S & Vardaxis, N 2010, Mosby s Dictionary of Medicine, Nursing and Health Professions, 2nd edn, Mosby Elsevier. o Guyton, AC & Hall, JE 2011, Textbook of Medical Physiology, 12th edn, Saunders Elsevier. o Marieb, EN & Hoehn, K 2010, Human Anatomy and Physiology, 8th edn, Benjamin Cummings Pearson. o Moore, KL, Dalley, AF & Agur, AMR 2010, Clinically Orientated Anatomy, 6th edn, Lippincott, Williams & Wilkins. Endeavour College of Natural Health endeavour.edu.au 60

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