Chapter 21: The Immune System: Innate and Adaptive Body Defenses. M.C. Shamier BSc Shenzhou University

Transcription

1 Chapter 21: The Immune System: Innate and Adaptive Body Defenses M.C. Shamier BSc Shenzhou University

2 Subjects

3 Innate Defenses Innate immunity so not acquired Always prepared Responds quickly Prevents entry and spread of microorganisms First line of defense: intact skin and mucosa Second line of defense: inflammation (phagocytes, other cells and antimicrobial proteins)

4 Adaptive (Specific) Defenses Third line of defense A targeted defense to one particular foreign substance Memory has to be built first: takes more time

5 Part I: Innate Defenses

6 Innate Defenses: Surface Barriers Skin Keratin is resistant to most weak acids and bases and bacterial toxins and enzymes Mucosa (digestive, respiratory, urogenital tract) Acid secretions inhibit bacterial growth Stomach mucosa secretes HCl and protein digesting enzymes killing microorganisms Saliva and lacrimal fluid contain lysozyme, an bacteria destroying enzyme Sticky mucus in digestive and respiratory tract trap many microorganisms

7 Innate Defenses: Cells and Chemicals Phagocytes Macrophages ( big eaters ) (fixed or free) Chronic inflammation Neutrophils (most abundant type of white blood cell) Acute inflammation Opsonization Complement proteins or antibody mark a microorganism to be targeted by a phagocyte

8 Phagocytes

9 Innate Defenses: Cells and Chemicals Natural Killer (NK T-lymphocytes) Kill cancer and virus-infected body cells Detect a lack of self cell-surface regocnition molecules Kill by cytotoxicity (not phagocytosis) Enhancers of inflammation

10 Inflammation: Tissue Response to Injury

11 Signs of Inflammation The four cardinal signs: Redness, heat, swelling, pain Or as traditionally learned in medical school: Rubor (redness), Calor (heat), Tumor (swelling), Dolor (pain)and Functio Laesa (loss of function)

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13 Vasodilation and Increased Vascular Permeability Toll-like receptor (TLR) (found on macrophages) Recognizes microbes Triggers the release of cytokines Cyt=cell, kines kinetics=movement Mast cells release histamine (important in allergy) Other cells: stressed tissue cells, phagocytes, lymphocytes, basophils Chemicals: histamine, cytokines, kinins, prostaglandins, leukotrienes, complement

14 Vasodilation and Increased Vascular Permeability Vasodilation These chemicals cause arteries in the injured area to dilate (increase of diameter) More bloodflow in the area: hyperemia (blood congestion) Causes heat and redness Increased Vascular Permeability Also an effect of the inflammatory chemicals Fluid and clotting factors seep from the blood into tissue Causes swelling (edema) The swelling increases pressure on nerves Causes pain

15 Vasodilation and Increased Vascular Permeability Edema Increased pressure Foreign material into lymphatic vessels to lymph nodes Clotting Isolates injured area and prevents spread of harmful agents Beta-Defensins Broad-spectrum antimicrobial chemicals present in mucosal cells, increased secretion in inflamed tissue

16 Phagocyte Mobilization

17 Antimicrobial Proteins Interferons (IFN) Viruses are cell parasites Some infected cells can secrete interferons to help protect cells that have not yet been infected Interfere with viral replication Not virus-specific Also activate macrophages and mobilize NK cells IFN-α is secreted by most leukocytes IFN-β is secreted by fibroblasts IFN-γ is secreted by lymphocytes

18 Interferons

19 Antimicrobial Proteins Complement system Complements the effectiveness of both innate and adaptive defenses Group of plasma proteins (C1-C9, B, D, P, regulatory proteins) Three pathways Opsonization to enhance phagocytosis Enhancing inflammation Cell lysis with a membrane attack complex (MAC)

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21 Fever In response to infection leukocytes release pyrogens that reset the body s thermostat The temperature setpoint > 37 degrees Celcius Increased metabolic activities in tissue cells speeding up repair Less availability of nutrients for bacteria

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23 Part II: Adaptive Defenses

24 Adaptive Defenses Is specific Is systemic Has memory Is not always ready, must be primed by an initial exposure to the pathogen

25 Two Types of Adaptive Defense Cellular immunity Cells attacking cells (virus infected, cancer, transplanted) Humoral immunity provided by freely circulating antibodies produced by lymphocytes (plasma B cells) Targets free pathogens mostly

26 Antigens Antigens are molecules recognized by the immune system. The ultimate target of all adaptive immune responses Large, complex molecules not normally present in the body (nonself)

27 Antigens Complete Antigens Immunogenic: stimulate proliferation of specific lymphocytes and antibodies Reactive: ability to react with lymphocytes and antibodies Incomplete Antigens/Haptens Rule: small molecules are not immunogenic Hypersensitivity (allergy) may occur though

28 Antigenic Determinants Only certain parts of antigens are immunogenic: the antigen determinants One antigen can have several antigen determinants and thus activate multiple lymphocyte populations and stimulate the formation of multiple kinds of antibodies This is why large antigens are more likely to be immunogenic and reactive.

29 Antigenic determinants

30 Self-antigens: MHC All our cells bear antigens on their surface Major Histocompatibility Complex genes encode MHC proteins MHC class I protein On all cells of the body, displays a blueprint of all proteins in the cell (and viruses within the cell) Lack of MHC class I targets a cell to Natural Killer cells MHC class II protein On some immune cells, displays antigens from phagocytosed/endocytosed material (bacteria)

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32 Cells of the Adaptive Immune System Antigen Presenting Cells (APC s) B lymphocytes: antibody production T lymphocytes: cell-mediated immunity

33 Lymphocyte Immunocompetence and Self-tolerance Immunocompetence: Ability to recognize and bind to antigen Self-tolerance: Tolerance to self-antigens, to prevent auto-immunity

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35 T-cell Maturation Produced in red bone marrow, then migrate as thymocytes to the thymus Thymus education Positive Selection: T cells must be able to bind to MHC molecules - a requirement for immunogenicity- and to distinguish self and non-self MHC. Negative Selection: T cells must not react strongly with self-antigens.

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38 B-cell Maturation Bone marrow Self-reactive B-cells are eliminated by apoptosis or given a chance to change by receptor editing Self-reactive B-cells that slip through this mechanism go in anergy (are inactivated)

39 Diversity in Antigen Specificity There is a limited number of genes for lymphocyte receptors Somatic recombination is the process responsible for the enormous diversity Shuffling and combination of gene segments

40 Antigen Presenting Cells Role: Phagocytosing antigens and then placing fragments of them on their cell surface presenting the foreign antigens to lymphocytes. Dendritic cells, macrophages, B-cells

41 Humoral Immune Response A B-lymphocyte is activated when the the antigen matching the receptor binds. The receptor-antibody complex is then internalized by endocytosis The B-lymphocyte is stimulated to multiply rapidly, resulting in a family of identical cells Most of these differentiate into plasma cells (the antibody producing cells), short lifespan. A few become long lived memory cells

42 Primary Response After antigen challenge (the first encounter between a lymphocyte and an antigen) there is a lag period of 3-6 days In about 10 days the peak level of antibody is reached

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44 Secondary Response Faster, more prolonged, more effective Within hours a new plasma cell army is generated The antibody concentration (titer) rises within 2-3 days, reaches higher levels, and persists for a longer time The antibodies have a higher affinity

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47 Active and Passive Humoral Activity

48 Vaccines Advantages Their weakened antigens provide functional antigenic determinants that are both immunogenic and reactive. By providing a first meeting with an antigen, encounter with the actual pathogen will induce a secondary immune response They spare us the symptoms and discomfort of the disease that would otherwise occur during the primary immune response.

49 Vaccines Shortcomings Cellular immunity is not activated Rarely vaccines cause the diseases they are trying to prevent because the virus is not weakened enough

50 Antibodies (Immunoglobins - Ig s) Proteins secreted by plasma (B) cells, capable of specifically binding an antigen Basic Structure An Y/T shaped molecule consisting of two heavy chains and two light chains The chains have a variable and a constant region. V-region determines antigenic specificity C-region determines antibody class Every single (monomeric) antibody has 2 antigen-binding sites.

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52 Antibody Classes

53 Antibody Classes

54 Antibody Diversity (Isotype Switching) The production of different classes of antibodies with the same antigen-specificity IgM is a sign of acute infection or active disease.

55 Antibody Action Antibodies cannot destroy antigens, but inactivate and tag them for destruction Neutralization: blocking specific sites on viruses/bacterial endotoxins with loss of their toxic effects. Agglutination: one antibody can bind multiple antigens, agglutinating foreign cells Precipitation: cross-linking soluble antigens to nonsoluble easy phagocytic targets Complement: chief defense against cellular antigens, using cell lysis or opsonization

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57 Monoclonal Antibodies for Research and Therapy

58 Rituximab Monoclonal antibody against the antigen CD20, which is characteristic of B lymphocytes Multiple Myeloma is plasma (B) cell cancer Rituximab selectively attacks B cells

59 Immunohistochemistry Antibodies, linked to substances that leave colored stains are used to visualize cells bearing a specific antigen in tissue.

60 Cell-Mediated Immune Response Antibodies are useless against microorganisms that hide and multiply within our cells This is where the cellular immune response comes in, for which T-lymphocytes are responsible. Two major populations of T-cells: T helper cells (CD4+ ) Cytotoxic T cells (CD8+) Smaller populations: Regulatory T cells (FoxP3+) Memory T cells

61 Cell-Mediated Immune Response T cells cannot react to free antigens or natural antigens They only recognized processed fragments of antigens presented on body cells by MHC-molecules

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63 Antigen Presentation to T cells Double recognition Recognition of non-self: the antigen Recognition of self: an MHC protein MHC class I activates (CD8) cytotoxic T cells Display peptides generated from degradation of proteins within the cell (a blueprint of the cell s interior) MHC class II activates (CD4) T helper cells Display peptides generated from degradation after phagocytosis/endocytosis of extracellular (foreign) proteins.

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66 MHC class I Present on all body cells vs. MHC class II Found on APC s (dendritic cells, macrophages, B cells) Presentation of endogenous (and viral) proteins Activate CD8 cytotoxic T cells Presentation of exogenous proteins Activate CD4 T helper cells.

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68 T cell Activation 1. Antigen Binding 2. Co-stimulation

69 T cell Activation: 1. Antigen Binding The T cell receptor (TCR) binds to an antigen-mhc complex on the surface of an antigen presenting cell (APC). MHC-restriction: CD4 cells require MHC class II CD8 cells require MHC class I

70 T cell Activation: 2. Co-stimulation The T cell must also bind to other surface receptors on the APC: co-stimulatory molecules. B7 (=CD80) binding to CD28 Co-stimulation triggers release of cytokine chemicals that lead to T cell differentiation and proliferation Lack of co-stimulation leads to anergy: unresponsiveness

71 T cell Activation Next The T cell enlarges Proliferates to form a clone Primary response peaks within a week Between 7 and 30 days: T cells decrease in number by apoptosis T cells are potential hazards Produce huge amounts of inflammatory cytokines Infection driven hyperplasia: may promote malignancy (cancer) in chronically inflamed tissue. Memory T cells persist, perhaps for life.

72 Cytokines The chemical messengers involved in cellular immunity Influence development, differentiation and immune responses Interferons (IFN s) and interleukins (IL s)

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74 T effector cells: Helper T cells Expresses the CD4 antigen Central role in adaptive immunity, both cellular and humoral Activate and induce proliferation of T and B cells Th1 is associated with cellular immunity Th2 is associated with humoral immunity

75 Th2 Most antigens are T cell-dependent, meaning that stimulatory signals from T cells is required for a strong and long lasting humoral immune response. The T helper 2 cell secretes IL-4 to do this

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77 Th1 T helper 1 cells cause dendritic cells (APC s) to express co-stimulatory molecules required for T cell activation. The type of T cell activated is the (CD8) cytotoxic T cell. Also, the T helper 1 cell secretes inflammatory cytokines activating the innate immune system.

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79 T effector cells: Cytotoxic T cells Expresses the CD8 antigen The only T cells that can directly attack other cells Targets: virus-infected cells, or other intracellular pathogens, cancer cells, foreign cells (transplantation). Binds to the complex of MHC-I with a non-self antigen Attack by releasing perforins and granzymes or by binding to a Fas receptor to induce apoptosis

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82 T effector cells: Natural Killer cells Are similar in function to CD8 cytotoxic T cells However, cytotoxic cells are antigen specific whereas NK cells target cells that do not express MHC class I molecules.

83 T effector cells: Regulatory T cells Dampen the immune response Suppress self-reactive lymphocytes Inhibitory cytokines: IL-10, TGF-β

84 Part III: Homeostatic Imbalances: -Immunodeficiency -Auto-immunity -Hypersensitivity

85 Homeostatic Imbalances Immune function Too weak: infections Too strong: self-damage

86 Immunodeficiency Congenital or acquired condition causing immune cells, phagocytes or complement to behave abnormally Congenital Deficiency of ADA (adenosine deaminase) leads to accumulation of metabolites lethal to lymphocytes, resulting in no T or B cells. Agammaglobulinemia is a block in B cell development, leading to absence of plasma cells and no production of antibodies.

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88 Immunodeficiency Acquired Hodgkin s disease: B cell cancer leads to immune deficiency by depressing lymph node cells Drugs can have an immunosuppressive effect (chemotherapy, corticosteroids) Acquired Immune Deficiency Syndrom (AIDS): HIV virus infects CD4 (T helper) cells, eventually depleting them. Remember that T helper cells are essential in activating humoral as well as cellular-mediated defenses.

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90 AIDS

91 The immunocompromised Frequent opportunistic infections by bacteria, viruses, fungi and parasites that are normally controlled by the immune system. Pulmonary infections Gastrointestinal infections Neurological infections Higher risk of malignancies

92 Autoimmune Diseases When the immune system loses the ability to distinguish between self and non-self. Antibodies and cytotoxic T-cells destroy own tissue Multiple Sclerosis: myelin of nerves is destroyed impairing conduction of electrical signals Type 1 Diabetes Mellitus: pancreatic beta cells are destroyed, resulting in a deficit of insulin Rheumatoid Arthritis: systemic damage to joints

93 Autoimmune Diseases How? Self-reactive lymphocytes are normally eradicated in bone marrow (B cells) or in the thymus (T cells). Antibodies made against foreign antigens may also recognize self-antigens if they have a high resemblance. New self-antigens may appear By gene mutations leading to new proteins Changes in the structure of self-antigens Release of antigens that are normally hidden behind barriers so there was no need to build up tolerance before.

94 Hypersensitivity The immune system causes tissue damage fighting off a percieved threat that would otherwise be harmless. Type I: Allergy (immediate) Type II: Cytotoxic / antibody Type III: Immune Complex Disease Type IV: Delayed Type

95 Hypersensitivity Type I hypersensitivity: Allergy (immediate)

96 Hypersensitivity Type II hypersensitivity: Cytoxic / Antibody Transplant rejection Antibodies bind and stimulate phagocytosis and complement mediated lysis Type III hypersensitivity: Immune-complex Disease Antigens are widely distributed and form insoluble antibody-antigen complexes The complexes become trapped in tissue and induce inflammation and tissue damage

97 Hypersensitivity Type IV hypersensitivity: Delayed Type The reaction elicited by antigen occurs relatively slowly (hence the name "delayed hypersensitivity"). The hypersensitivity is mediated via T-cells and macrophages. Eczema is an important example

98 End of Chapter 21