Adaptive Immunity. PowerPoint Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University C H A P T E R

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1 PowerPoint Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University C H A P T E R 16 Adaptive Immunity

2 The Body s First Line of Defense Innate Immunity The Role of Skin in Innate Immunity The Role of Mucous Membranes in Innate Immunity The Role of the Lacrimal Apparatus in Innate Immunity The Role of Normal Microbiota in Innate Immunity Other First-Line Defenses Innate Immunity = Present at birth prior to contact with infectious agents Rapid-works against many The Body s Second Line of Defense - Innate Immunity Defense Components of Blood Phagocytosis Nonphagocytic Killing Nonspecific Chemical Defenses Against Pathogens Inflammation Fever The Body s Third Line of Defense Adaptive Immunity (Chapter 16) Slower - specific

3 The Body s Third Line of Defense Adaptive Immunity Slower - specific Adaptive immunity is the body's ability to recognize and defend itself against distinct invaders and their products Five attributes of adaptive immunity Specificity Inducibility Clonality Unresponsiveness to self Memory

4 WBC

5 Overview of Adaptive Immunity Involves activity of lymphocytes Two main types of lymphocytes B lymphocytes (B cells) Arise and Mature in the bone marrow T lymphocytes (T cells) Arise in bone marrow but Mature in the thymus Lymphocyte Red blood cell

6 Two types of adaptive immune responses (historical classification) Antibody immune responses (B cells) aka humoral immunity especially extracellular pathogens and toxins Cell-mediated immune responses (T cells) especially intracellular pathogens e.g. cells infected with viruses Immunological memory Long-lived B and T retain the ability to fight specific pathogens

7 6 Elements of Adaptive Immunity The Tissues and Organs of the Lymphatic System Antigens B Lymphocytes (B Cells) and Antibodies T Lymphocytes (T Cells) Clonal Deletion Immune Response Cytokines

8 The Tissues and Organs of the Lymphatic System Composed of lymphatic vessels, lymph, lymphatic cells, tissues, and organs Major Function: Screen the tissues of the body for foreign antigens Lymphatic vessels (One-way system that conducts lymph from tissues and returns it to the circulatory system) Lymph (colorless, watery Liquid with similar composition to blood plasma - arises from fluid leaked from blood vessels into surrounding tissues)

9 Figure 16.2 The lymphatic system. Blood capillary From heart Tissue cell Tonsils Cervical lymph node Intercellular fluid Lymphatic ducts Thymus gland Lymph to heart via lymphatic vessels Gap in wall Axillary lymph node Heart Breast lymphatics Spleen Valve Abdominal lymph node To heart Lymphatic capillary Intestines Peyer s patches in intestinal wall Appendix Part of mucosaassociated lymphoid tissue (MALT) Cortex Afferent lymphatic vessel Medulla Red bone marrow Inguinal lymph node Lymphatic vessel Vein Valve (prevents backflow) Artery Lymphatic nodule Efferent lymphatic vessel Capsule Primary follicle

10 Figure 16.2 The lymphatic system. Blood capillary From heart Tissue cell Intercellular fluid Carry toxins/pathogens to lymphocytes Lymph to heart via lymphatic vessels Flows in one direction towards the heart Gap in wall To heart Valve Lymphatic capillary On the way flows through 1000 lymph nodes Afferent lymphatic vessel Cortex Medulla Valve (prevents backflow) Vein Artery lymph node Lymphatic nodule Efferent lymphatic vessel Capsule Primary follicle

11 Figure 16.2 The lymphatic system. Cortex outer portion contains primary follicles site of clones of B cells proliferate Many afferent (inbound) One/two efferent (outbound) Think Traffic Bottle-Neck due to closedown of lanes Cortex Afferent lymphatic vessel Medulla Facilitates interaction between immune cells and immune cells and material in lymph Vein Valve (prevents backflow) Artery Lymphatic nodule Primary follicle Contain B cells lymph node Efferent lymphatic vessel Capsule Lymphocytes arise and mature in primary lymphoid organs primary lymphoid organs Bone marrow B Thymus - T Mature Lymphocytes go to secondary lymphoid organs lymph node, spleen, tonsils and MALT (mucosa associated lymphoid tissue)

12 Figure 16.2 The lymphatic system. Tonsils Spleen Similar in structure to lymph node but Filters blood Cervical lymph node Lymphatic ducts Thymus gland Axillary lymph node Heart Breast lymphatics tonsils and MALT (mucosa associated lymphoid tissue) Lack tough outer capsules of lymph nodes but function in similar manner MALT contains most of the body s lymphocytes Red bone marrow Abdominal lymph node Intestines Peyer s patches in intestinal wall Appendix Inguinal lymph node Lymphatic vessel Part of mucosaassociated lymphoid tissue (MALT)

13 Elements of Adaptive Immunity Antigens (biochemical shapes) e.g. lipid A or other toxins Properties of antigens Molecules the body recognizes as foreign and worthy of attack Recognized by three-dimensional regions called epitopes on antigens Large, complex foreign macromolecules make the best antigens Include various bacterial components as well as proteins of viruses, fungi, and protozoa Food and dust can also contain antigenic particles Penicillin?

14 Figure 16.3a Antigens, molecules that provoke a specific immune response. Epitopes (antigenic determinants) Nucleus Cytoplasmic membrane Antigen Cytoplasm Epitopes (antigenic determinants)

15 Figure 16.3b-d Antigens, molecules that provoke a specific immune response. Extracellular microbes Endogenous antigens Autoantigens (normal cell antigens) Intracellular virus Exogenous antigens Virally infected cell Normal (uninfected) cell Exogenous antigens Endogenous antigens Autoantigens Self tolerance Immune cells which treat autoantigens as foreign are eliminated

16 6 Elements of Adaptive Immunity The Tissues and Organs of the Lymphatic System Antigens B Lymphocytes (B Cells) and Antibodies T Lymphocytes (T Cells) Clonal Deletion Immune Response Cytokines

17 Elements of Adaptive Immunity B Lymphocytes (B Cells) and Antibodies Found primarily in the spleen, lymph nodes, and MALT Small percentage of B cells circulate in the blood Major function is the secretion of antibodies Each of the antibody act against a specific antigen How do you get the specificity? From B cell receptor

18 Elements of Adaptive Immunity B Lymphocytes (B Cells) and Antibodies Specificity of the B cell receptor (BCR) Each B lymphocyte has multiple copies of the B cell receptor Each B cell generates a single BCR Two variable regions of the BCR form the antigen-binding sites Each BCR recognizes only one epitope The entire repertoire of an individual's BCRs is capable of recognizing millions of different epitopes

19 Figure 16.4 B cell receptor (BCR). Exact binding between ABS and epitope is responsible for specificity of an antibody immune response Heavy chain Light chain Epitope Antigenbinding sites Variable region Variable region Disulfide bond 500,000 identical copies on surface of B lymphocytes Cytoplasmic membrane of B lymphocyte Transmembrane portion of BCR 10 9 to B lymphocytes Cytoplasm

20 Figure 16.5 Basic antibody structure. Antibodies are immunoglobulins similar to BCRs Have antigen-binding sites and antigen specificity identical to the BCR of the activated B cell Arm (F ab ) Light chain Arm (F ab ) Antigen-binding sites Variable region of heavy chain Variable region of light chain Hinge Hinge Constant region of light chain Constant region of heavy chain Stem (F c ) Stem (F c ) 5 types Heavy chains

21 Pathogenic antigen Activated B cell is called Plasma cell and makes BCR like antibodies into blood or lymph BCR BCR antibodies Similar in structure but one is attached the other is free

22 Elements of Adaptive Immunity Antibody function Antigen-binding sites are complementary to epitopes Antibodies function in several ways mediated by stem epitope Activation of complement and inflammation Neutralization Opsonization Killing by oxidation Agglutination Antibody-dependent cellular cytotoxicity (ADCC) Stem part

23 Figure 16.6 Six functions of antibodies. Adhesin proteins Bacterium Soluble becomes insoluble Toxin Virus Neutralization Agglutination NK lymphocyte Opsonization F c receptor protein Pseudopod of phagocyte F c receptor protein Perforin allows granzyme to enter, triggers apoptosis and lysis Antibody-dependent cellular cytotoxicity (ADCC) Bacteria die Oxidation

24 Figure 16.6 Five functions of antibodies. Neutralization Agglutination 4. Adhesin proteins Bacterium IgA Toxin Opsonization Virus - changing the surface of an antigen to enhance phagocytosis Opsonins coat Pathogens and stimulate phagocytosis IgG F c receptor protein Oxidation Pseudopod of phagocyte Neutrophils and macrophages NK lymphocyte F c receptor protein Perforin allows granzyme to enter, triggers apoptosis and lysis Antibody-dependent cellular cytotoxicity (ADCC) Bacteria die

25 Classical pathway Antigen Alternative pathway C3b Endotoxin and glycoproteins Lectin pathway Mannose Lectins Antibody C3b Factors B, D, and P Complement proteins 1, 2, 4 Complement cascade Activation (C3 C3a + C3b) Opsonization Inflammation C5 convertases C5 C5a + C5b Inflammation Membrane attack complex and cell lysis

26 1. Activate complement Figure 15.9 The classical pathway and complement cascade. H 2 O H 2 O H 2 O Pathogen Membrane attack complex C9 C9 C9 C9 C9 C9 C9 C9 C9 C9 C8 C7 C5b C6 Cytoplasmic membrane H 2 O IgM/IgE 1 C1 becomes an active enzyme when it binds to antibody-antigen complexes. Enzymatic C1 Antigen Antibody Causes chemotaxis of phagocytes and triggers inflammation Causes inflammation C5a C5b 6 5 C5b combines with C6, C7, C8, and several molecules of C9 to form a membrane attack complex (MAC). A MAC drills a circular hole in the pathogen s cytoplasmic membrane, leading to lysis of the cell. This enzyme cleaves C5 into C5a and C5b. 2 Enzyme C1 splits molecules of C2 and of C4. 3 Fragments of C2 and C4 combine to form a second enzyme that splits C3 into C3a and C3b. 4 C3b combines with the remaining fragments of C2 and C4 to form a third enzyme. Causes chemotaxis of phagocytes and triggers inflammation Acts as opsonin

27 Figure 16.5 Basic antibody structure. Antibodies are immunoglobulins similar to BCRs Have antigen-binding sites and antigen specificity identical to the BCR of the activated B cell Arm (F ab ) Light chain Arm (F ab ) Antigen-binding sites Variable region of heavy chain Variable region of light chain Hinge Hinge Constant region of light chain Constant region of heavy chain Stem (F c ) Stem (F c ) 5 types Heavy chains

28 Elements of Adaptive Immunity B Lymphocytes (B Cells) and Antibodies Classes of antibodies IgM first antibody produced pentamer best for complement activation Class switching IgM to IgG IgG most common 80%- and longest-lasting antibody only ab to cross placenta and protect developing child IgA associated with body secretions mono/dimers tears/saliva/milk IgE involved in response to parasitic infections and allergies IgD exact function is not known not secreted but membrane bound

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30 6 Elements of Adaptive Immunity The Tissues and Organs of the Lymphatic System Antigens B Lymphocytes (B Cells) and Antibodies T Lymphocytes (T Cells) Clonal Deletion Immune Response Cytokines

31 Elements of Adaptive Immunity T Lymphocytes (T Cells) 70-85% of all lymphocytes in blood Produced in the red bone marrow and mature in the thymus Circulate in the lymph and blood Migrate to the lymph nodes, spleen, and Peyer's patches Have T cell receptors (TCRs) on their cytoplasmic membrane

32 Figure 16.7 A T cell receptor (TCR). Variable regions Constant regions Recognizes MHC + antigen Antigen-binding site Carbohydrate Cytoplasmic membrane of T cell T cell receptor (TCR) Cytoplasm

33 Elements of Adaptive Immunity T Lymphocytes Specificity of the T cell receptor (TCR) TCRs do not recognize epitopes directly TCRs only bind epitopes associated with an MHC protein T cells act primarily against cells that harbor intracellular pathogens Some T cells act against body cells that produce abnormal cell-surface proteins like in cancer Do not secrete Igs but act directly against cells therefore called cellmediated immune response

34 Elements of Adaptive Immunity T Lymphocytes Types of T lymphocytes Based on surface glycoproteins and characteristic functions, three types Cytotoxic T lymphocyte (Tc or CD8) Directly kills other cells Helper T lymphocyte (Th or CD4) produces cytokines AIDS binds CD4 Helps regulate B cells and cytotoxic T cells Includes type 1 and type 2 helper T cells (distinguished by what they secrete and what is on their surface) Regulatory T lymphocyte (Tr or CD4/CD25) produces cytokines - prevents autoimmune diseases Represses adaptive immune responses

35 6 Elements of Adaptive Immunity The Tissues and Organs of the Lymphatic System Antigens B Lymphocytes (B Cells) and Antibodies T Lymphocytes (T Cells) Clonal Deletion Immune Response Cytokines

36 Elements of Adaptive Immunity Clonal Deletion elimination of a cell kills its offsprings (clones) Vital that immune responses not be directed against autoantigens Immune system must be tolerant of self impaired leads to autoimmune disease Body eliminates self-reactive lymphocytes Lymphocytes that react to autoantigens undergo apoptosis

37 Figure 16.8 Clonal deletion of T cells. Thymus cells express all proteins in a body Thymus Thymus cells 2 MHC TCRs with differently shaped binding sites Epitope 1 3 Recognize MHC? Stem cell (in red bone marrow) T cells Thymus cells End result is those which recognize MHC but do not recognize autoantigens survive Others eliminated No Yes Receive survival signal Apoptosis 4 Recognize MHC-autoantigen? No Yes Few Most Apoptosis Repertoire of immature Tc cells Regulatory T cell (Tr)

38 Figure 16.9 Clonal deletion of B cells. Stem cell (in red bone marrow) 1 B cells 2 Cell with autoantigens BCRs with 3 differently shaped binding sites 4 Cell with autoantigens Apoptosis Blood vessel To spleen

39 6 Elements of Adaptive Immunity The Tissues and Organs of the Lymphatic System Antigens B Lymphocytes (B Cells) and Antibodies T Lymphocytes (T Cells) Clonal Deletion Immune Response Cytokines

40 Elements of Adaptive Immunity Immune Response Cytokines Soluble regulatory proteins that act as intercellular signals secreted by various leukocytes and form network Interleukins (ILs) Signal among leukocytes Interferons (IFNs) Antiviral proteins that may act as cytokines Growth factors Proteins that stimulate stem cells to divide Tumor necrosis factor (TNF) Secreted by macrophages and T cells to kill tumor cells and regulate immune responses and inflammation Chemokines Chemotactic cytokines that signal leukocytes to move

41 Preparation for an Adaptive Immune Response The Roles of the Major Histocompatibility Complex and Antigen- Presenting Cells Group of antigens first identified in graft patients Important in determining compatibility of tissues for tissue grafting Major histocompatibility antigens are glycoproteins found in the membranes of most cells of vertebrate animals Hold and position antigenic determinants for presentation to T cells

42 Figure The two classes of major histocompatibility complex (MHC) proteins. Antigen-binding sites (grooves) Class II MHC on B cell or other antigen-presenting cell (APC) Class I MHC on every nucleated cell B cells, macrophages, dendritic cells Cytoplasmic membrane Cytoplasm

43 Figure Dendritic cells. Dendrites

44 Preparation for an Adaptive Immune Response Antigen Processing Antigens processed for MHC proteins to display epitopes Different processes for 1) endogenous and 2) exogenous antigens

45 Figure The processing of T-dependent endogenous antigens. by all cells 1 Polypeptide is catabolized. MHC I protein in membrane of endoplasmic reticulum Epitopes MHC I protein epitope complex 2 Lumen of endoplasmic reticulum Epitopes are loaded onto complementary MHC I proteins in the ER. 3 Golgi bodies package MHC I protein epitope complexes into vesicles. 4 Vesicles fuse with cytoplasmic membrane. MHC I protein epitope complexes on cell surface Cytoplasmic membrane 5 MHC I protein epitope complexes are displayed on cytoplasmic membranes of all nucleated cells.

46 Figure The processing of T-dependent exogenous antigens by APCs mostly dendritic cells Phagocytosis by APC Exogenous pathogen with antigens MHC II protein epitope complex 1 MHC II protein in membrane of vesicle Epitopes in phagolysosome 2 Vesicles fuse and epitopes bind to complementary MHC II molecules. 3 Vesicle fuses with cytoplasmic membrane. MHC II protein epitope complexes on cell surface Cytoplasmic membrane 4 MHC II protein epitope complexes are displayed on cytoplasmic membranes of antigenpresenting cell.

47 Cell-Mediated Immune Responses Activation of Cytotoxic T Cell Clones and Their Functions Adaptive immune responses initiated in lymphoid organs Steps involved in activation of cytotoxic T cells Antigen presentation Helper T cell differentiation Clonal expansion Self-stimulation

48 Figure 16.15a A cell-mediated immune response. Active cytotoxic T (Tc) cell TCR CD8 Viral epitope MHC I protein Virally infected cell Intracellular virus

49 Figure Activation of a clone of cytotoxic T (Tc) cells. 1 Antigen presentation Within lymph node Dendritic cell MHC I MHC II Epitope TCR DC MHC I CD8 Epitope TCR 2 Th cell Th differentiation Th1 cell Self-stimulation IL-2R IL-2 IL-2 IL-12 Active Tc cells IL-2 4 Inactive Tc cell IL-2 receptor (IL-2R) 3 Tc cell Immunological synapse Clonal expansion Memory T cell An enhanced cell mediated immune response upon subsequent exposure to the same antigen is called a memory response IL-2R Active Tc cells IL-2

50 Figure A T-dependent antibody immune response. Repertoire of Th cells (CD4 cells) Th cell Majority of response slow And has memory TCRs 1 CD4 APC presents antigen to Th cells for Th activation and cloning. APC TCR Epitope MHC II APC CD4 CD28 CD80 (or CD86) Th cell clones IL-4 2 Th cell differentiates into Th2 cell. CCR3 CCR4 Th2 cell MHC II proteins Th2 cell Th2 cell TCR Epitope CD4 CD40L Repertoire of B cells IL-4 MHC II B cell CD40 3 Th2 cell activates B cell. Clone of plasma cells 4 Antibodies Memory B cells

51 Figure 16.15b-c A cell-mediated immune response. 2 modes in which Tc kills perforin granzyme or CD95 cytotoxic pathway. Tc cell Perforin Granzyme Tc cell Inactive apoptotic enzymes Perforin complex (pore) Granzymes activate apoptotic enzymes Active enzymes induce apoptosis Inactive apoptotic enzymes CD95L CD95 Enzymatic portion of CD95 becomes active Active enzymes induceapoptosis Virally infected cell Virally infected cell

52 Figure T-independent antigen by a B cell. Polysaccharide with repeating subunits BCRs B cell Fast but no memory Plasma cells Antibodies

53 Figure A plasma cell. double the size and filled with ER Golgi body Nucleus Rough endoplasmic reticulum

54 Figure The production of primary and secondary antibody immune responses. Secondary response = faster, greater and different antibody profile Because of memory B cells

55 Types of Acquired Immunity Specific immunity acquired during an individual's life Two types Naturally acquired (active or passive) Response against antigens encountered in daily life Active infections Passive (womb) IgG cross placenta (newborn) IgA in breast milk Artificially acquired (active or passive) Response to antigens introduced via a vaccine Active antigens in vaccine Passive antibodies/antisera or antitoxins from others Active = slow but have memory Passive = fast but no memory