Lesson 9 Adaptive Immunity

1. Lesson 9Adaptive Immunity July 16, 2014

2. Immunity • Innate immunity: defenses against any pathogen • Adaptive immunity: induced resistance to a specific pathogen • Humoral • Cell-mediated

3. Figure 17.20 The dual nature of the adaptive immune system. Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune system Control of freely circulating pathogens Control of intracellular pathogens Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite. Extracellular antigens A B cell binds to the antigen for which it is specific. A T-dependent B cell requires cooperation with a T helper (TH) cell. A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors). T cell Cytokines activate T helper (TH) cell. Cytokines activate macrophage. Cytokines Cytokines B cell Cytokines from the TH cell transform B cells into antibody-producing plasma cells. Activation of macrophage (enhanced phagocytic activity). The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells. TH cell The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell. Cytotoxic T lymphocyte Plasma cell Plasma cells proliferate and produce antibodies against the antigen. Memory cell Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. Lysed target cell

4. Dual Nature of Adaptive Immunity • Main components of Adaptive Immunity are T cells and B cells • The liver serves as the source of both T and B cells early in development and in bone marrow in adulthood • T cells develop in thymus in adults • B cells develop in the red bone marrow in adults

5. Figure 17.8 Differentiation of T cells and B cells. Stem cells develop in bone marrow or in fetal liver Stem cell (diverges into two cell lines) Red bone marrow of adults Thymus Differentiate to B cells in adult red bone marrow Differentiate to T cells in thymus B cell T cell Migrate to lymphoid tissue such as spleen, but especially lymph nodes

6. Dual Nature of Adaptive Immunity • Humoral immunity • Due to antibodies • B cells mature in the bone marrow • Name derived from chickens: bursa of Fabricius • Bursa is an organ found in chickens that when removed results in the abrogation in antibody production

7. Dual Nature of Adaptive Immunity • Cellular immunity • Due to T cells • T cells mature in the thymus • Stimulate the production macrophages • Activate B-cells into becoming plasma cells • Activate cytotoxic T-lymphocytes

8. The Nature of Antigens • Antigen (Ag): a substance that causes the body to produce specific antibodies • Microbial cell wall components, proteins, capsules, flagella, toxins, viral coats • Non-microbial agents such as blood cell surface molecules can serve as antigens • Organ rejection • Antibodies (Ab) interact with epitopes, or antigenic determinants which are specific regions on the antigen • Hapten: antigens that are too small to stimulate a immune response. Require carrier molecules

9. Figure 17.1 Epitopes (antigenic determinants). Antibody A Epitopes (antigenic determinants) on antigen Antigens:componentsof cell wall Binding sites Bacterial cell Antibody B

10. Figure 17.2 Haptens. Hapten-carrier conjugate Hapten molecules Carrier molecule

11. The Nature of Antibodies • Globular proteins called immunoglobulins • Antigen-binding sites are parts of the antibody that binds the epitope • Valence refers to the number of antigen binding sites on an antibody • Two binding sites are bivalent (most common) • One binding site is monovalent

12. Figure 17.3ab The structure of a typical antibody molecule. Antigen-binding site Heavy chain Light chain Fc (stem) region Hinge region Antibody molecule Epitope (antigenic determinant) Antigen Antigen- binding site Enlarged antigen-binding site bound to an epitope

13. IgG Antibodies • Monomer • 80% of serum antibodies • Fix complement • In blood, lymph, and intestine • Cross placenta (passive immunity) • Enhance phagocytosis; neutralize toxins and viruses; protect fetus and newborn • Half-life = 23 days

14. IgM Antibodies Disulfide Bond • Pentamer • 5–10% of serum antibodies • Fix complement • In blood, in lymph, and on B cells • Agglutinate microbes; first Ab produced in response to infection • Half-life = 5 days J-Chain

15. IgA Antibodies J-Chain • Dimer • 10–15% of serum antibodies • In secretions • Mucosal protection • Secretory Component protects Ab from degradation • Half-life = 6 days Secretory Component

16. IgD Antibodies • Monomer • 0.2% of serum antibodies • In blood, in lymph, and on B cells • On B cells, initiate immune response • Half-life = 3 days

17. IgE Antibodies • Monomer • 0.002% of serum antibodies • On mast cells, on basophils, and in blood • Allergic reactions; lysis of parasitic worms • Attracts complement and phagocyticcells • Half-life = 2 days

18. Activation of B Cells • B-cells, when activated, become either plasma cells (Ab producers) or memory cells (responsible for enhanced secondary response) • B-cells are capable of producing multiple Abs (IgM, IgG, IgA) with the same antigenic determinants (class switching) • Major histocompatibility complex (MHC) expressedon mammalian cells are responsible for antigenic determinants • Molecules containing glycoproteins • Found on Antigen-presenting cells (APC) and lymphocytes • Presents antigen on the surface of the B cell ANIMATION Antigen Processing and Presentation: Overview

19. T-dependent antigens • Ag presented with (self) MHC to TH cell • Distinguishes (self) from antigen to prevent antibody production against host cells • Lupus, Type I diabetes, and rheumatoid arthritis • TH cell produces cytokines that activate the B cell • T-independent antigens • Antigens stimulate B cells directly to make Abs • Antigens are characterized by repeating subunits that bind multiple B cell receptors • Polysaccharides • Lipopolysaccharides

20. Figure 17.4 Activation of B cells to produce antibodies. Extracellularantigens MHC class II with Ag fragment displayed on surface MHC class II with Ag fragment Antibodies Ag fragment B cell B cell Immunoglobulin receptorscoatingB cell surface Plasma cell TH cell B cell Cytokines Immunoglobulin receptors on B cell surface recognize and attach to antigen, which is then internalized and processed. Within the B cell a fragment of the antigen combines with MHC class II. MHC class II–antigen-fragment complex is displayed on B cell surface. Receptor on the T helper cell (TH) recognizes complex of MHC class II and antigen fragment and is activated— producing cytokines, which activate the B cell. The TH cell has been previously activated by an antigen displayed on a dendritic cell (see Figure 17.10). B cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells.

21. Figure 17.6 T-independent antigens. Polysaccharide (T-independent antigen) Epitopes B cell receptors

22. Clonal Selection ANIMATION Humoral Immunity: Clonal Selection and Expansion

23. Figure 17.5 Clonal selection and differentiation of B cells. Stem cell Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen. Antigen B cell III complexes with its specific antigen and proliferates. B cells II I III IV Memory cells Some B cells proliferate into long-lived memory cells, which at a later date can be stimulated to become antibody-producing plasma cells. See Figure 17.17. Other B cells proliferate into antibody-producing plasma cells. Plasma cells Plasma cells secrete antibodies into circulation. Antigens in circulation now attached to circulating antibodies Cardiovascular system

24. Activation of B Cells • Clonal deletion eliminates harmful B cells • MHC molecules that contain self-antigens • Process in which the immune system does not attack an antigen is called immune tolerance • Gestational immune tolerance protects a baby from the immune system of the parent • Produces cytokines to inhibit immune system detection (neurokinin B) • Do not contain receptors that bind cytotoxicTcells

25. Antigen-Antibody Binding • Affinity—is the strength of a bond b/w antigen and antibody • Antibodies recognize the shape of an antigen • Better the fit b/w the antigen’s shape and Ab the stronger the affinity • Abs are highly specific (discern minor differences in antigens)

26. Results of Antigen–Antibody Binding • Agglutination • Opsonization • Activation of complement • Antibody-dependent cell-mediated cytotoxicity • Neutralization ANIMATION Humoral Immunity: Antibody Function

27. Figure 17.7 The results of antigen–antibody binding. PROCTECTIVE MECHANISM OF BINDING ANTIBODIES TO ANTIGENS Agglutination (see also Figure 18.5) Activation of complement (see also Figure 16.9) Causes inflammation and cell lysis Reduces number of infectious units to be dealt with Complement Bacteria Lysis Bacterium Antibody-dependent cell-mediated cytotoxicity (see also Figure 17.16) Opsonization (see also Figure 16.9) Coating antigen with antibody enhances phagocytosis Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells Phagocyte Eosinophil Epitopes Large target cell (parasite) Neutralization (see also Figure 18.9) Perforin and lytic enzymes Blocks adhesion of bacteria and viruses to mucosa Blocks attachment of toxin Virus Toxin Bacterium

28. T Cells and Cellular Immunity • T cells are derived from stem cells of bone marrow • These stem cells migrate to the thymus where they mature into T cells • Thymic selection eliminates many immature T cells • Similar to clonal deletion of B cells. Weed out cells that would otherwise attack “self” • Mainly responsible for clearance of intracellular bacteria

29. Table 17.2 Principal Cells That Function in Cell-Mediated Immunity

30. T Cells and Cellular Immunity • T cells require antigen-presenting cells (APCs) to become activated • T cells respond to Ag by T-cell receptors (TCRs) • Similar to antibodies on the surface of B cells • Pathogens entering the gastrointestinal or respiratory tracts pass through: • M (microfold) cells over • Peyer’s patches (secondary lymphoid organs), which contain APCs • T cells are characterized by glycoproteins on surface • CD4—bind to MHC II molecules (found on lymphocytes) • CD8—bind to MHC I molecules (present on all nucleated cells)

31. (a) M cell on Peyer’s patch. Note the tips of the closely packed microvilli on the surrounding epithelial cells. (b) M cells facilitate contact between the antigens passing through the intestinal tract and cells of the body’s immune system. Figure 17.9 M cells. Microvilli on epithelial cell Antigen M cell TH cell Pocket B cells Macrophage Epithelial cell

32. T Cell Classification • Certain glycoproteins on the surface of T cells help distinguish classes of T cells • Clusters of Differentiation (CD) • Responsible for the adhesion of T cells to receptors • Cells containing CD4 are called CD4+ cells and cells containing CD8 are called CD8+ cells

33. T Helper Cells • CD4+ or TH cells • TCRs recognize Ags and MHC II on APC • TLRs are a costimulatory signal on APC and TH • TH cells produce cytokines and differentiate into: • TH1cells • TH2 cells • TH17 cells • Memory cells

34. T Helper Cells • TH1 produce IFN-gwhich activates cells related to cell-mediated immunity, macrophages, and Abs • TH2 activate eosinophils and B cells to produce IgE • TH17 stimulate the innate immune system • TF stimulate B cells to produce plasma cells and are involved in class switching ANIMATION Antigen Processing and Presentation: Steps

35. Figure 17.11 Lineage of effector T helper cell classes and pathogens targeted. Antibodies TH1 cells B cell TH2 cells TH17 cells Cell-mediated immunity; control of intracellular pathogens, delayed hypersensitivity reactions (page 535); stimulates macrophages. Recruits neutrophils; provides protection against extracellular bacteria and fungi TH cell IL-17 IFN-g TH17 cells TH1 cells IL-4 TH2 cells Fungi Extracellular bacteria Neutrophil Macrophage Intracellular bacteria and protozoa Mast cell Basophil Eosinophil Important in allergic responses, especially by production of IgE Stimulates activity of eosinophils to control extracellular parasites such as helminths (see ADCC, page 495). Helminth

36. Activation of CD4+ T Helper Cells ANIMATION Cell-Mediated Immunity: Helper T Cells

37. Figure 17.10 Activation of CD4+T helper cells. An APC encounters and ingests a microorganism. The antigen is enzymatically processed into short peptides, which combine with MHC class II molecules and are displayed on the surface of the APC. A receptor (TCR) on the surface of the CD4+T helper cell (TH cell) binds to the MHC–antigen complex. If this includes a Toll-like receptor, the APC is stimulated to secrete a costimulatory molecule. These two signals activate the TH cell, which produces cytokines. TH cell receptor (TCR) The cytokines cause the TH cell (which recognizes a dendritic cell that is producing costimulatory molecules) to become activated. APC (dendritic cell) T helper cell Antigen Complex of MHC class II molecule and antigen fragment Cytokines Antigen fragment (short peptides) Microorganism carrying antigens Costimulatory molecule, (required to activate T cells that have not previously encountered antigen)

38. T Cytotoxic Cells • CD8+or TC cells • Target cells are self-cells carrying endogenous antigens • Activated into cytotoxic T lymphocytes (CTLs) • CTLs recognize Ag + MHC I • Induce apoptosis in target cell • CTL releases perforinand granzymes ANIMATION Cell-Mediated Immunity: Cytotoxic T Cells

39. Figure 17.12 Killing of virus-infected target cell by cytotoxic T lymphocyte. Processed antigen presented with MHC class I T cell receptors Infected target cell is lysed MHC class I Processed antigen CTL Virus-infected cell (example of endogenous antigen) Virus-infected cell Cytotoxic T lymphocyte (CTL) A normal cell will not trigger a response by a cytotoxic T lymphocyte (CTL), but a virus-infected cell (shown here) or a cancer cell produces abnormal endogenous antigens. The abnormal antigen is presented on the cell surface in association with MHC class I molecules. CD8+T cells with receptors for the antigen are transformed into CTLs. The CTL induces destruction of the virus-infected cell by apoptosis.

40. Figure 17.13 Apoptosis.

41. T Regulatory Cells • Tregcells • CD4 and CD25 on surface • Suppress T cells against self

42. Antigen-Presenting Cells • Digest antigen via phagocytosis • Ag fragments on APC surface with MHC • B cells • Dendritic cells • Activated macrophages ANIMATION Antigen Processing and Presentation: MHC

43. Figure 17.14 A dendritic cell.

44. Figure 17.15 Activated macrophages. Activated macrophages Resting (inactive) macrophage

45. Natural Killer (NK) Cells • Granular leukocytes destroy cells that don’t express MHC I • Kill virus-infected and tumor cells • Attack parasites

46. ADCC • Antibody-dependent cell-mediated cytotoxicity

47. Figure 17.16 Antibody-dependent cell-mediated cytotoxicity (ADCC). KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Large parasite Epitope Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally. Eosinophils Fluke (b) Eosinophils adhering to the larval stage of a parasitic fluke

48. Figure 17.16a Antibody-dependent cell-mediated cytotoxicity (ADCC). KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Epitope Large parasite Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally.

49. Figure 17.16b Antibody-dependent cell-mediated cytotoxicity (ADCC). Eosinophils Fluke Eosinophils adhering to the larval stage of a parasitic fluke.

50. Cytokines • Chemical messengers • Overproduction leads to cytokine storm