MICR 201 Microbiology for Health Related Sciences

1. MICR 201 Microbiology for Health Related Sciences Microbiology- a clinical approach by Anthony Strelkauskas et al. 2010 Chapter 16: The adaptive immune response

2. Why is this chapter important? • The adaptive immune response is a very powerful system that protects us from a multitude of infectious organisms. • It has the gift of memory, which provides rapidly a more powerful reaction if the same pathogen is seen again. This is the basis for vaccinations. • Without the adaptive immune response we would not survive.

3. Map for chapter 16

4. Introduction: initiation of the adaptive immune response • The adaptive immune response is the second line of defense. • The innate response is a prerequisite for the adaptive immune response. • Alerts and activates the adaptive immune response via cytokines and chemokines. • Presents antigens • Dendritic cells are the most important innate cells for the proper development of an adaptive immune response. This is because: • They take up and process antigens. • They migrate to lymph nodes and present antigens to T cells. • They have enormous surface areas and can interact with many different T cells.

5. Introduction: overview • The adaptive immune response involves lymphocytes which develop from the hematopoietic stem cell in the bone marrow • B-lymphocytes (B cells) • T-lymphocytes (T cells) • It is a response to specific antigens via highly specific antigen receptors • Antibody molecule on B cells • T cell receptor on T cells • It can adapt to any infection. • It has memory. • This confers life-long immunity.

6. Introduction: types of adaptive immune response • The adaptive immune response has two types of response: • Humoral – production of antibodies by B cells • Cellular – strengthening immune cells and killing and regulation of infected cells by T cells

7. Introduction: antigens • Antigen is any molecule that can induce a specific adaptive immune response. • Originally defined as antibody generating agent • There are two types of antigens: • Self • Non-self • During early cell development or maturation lymphocytes are schooled to become tolerant for self antigens. • B cells mature in the bone marrow • T cells mature in the thymus

8. Thymus gland

9. Introduction: lymphatic system • The adaptive response is associated with the lymphatic system. • It patrols (almost ) the entire body. • It involves lymphocytes and lymphoid structures such as lymph nodes.

10. Introduction: lymphatic system The strategic placement of these lymphoid structures makes it possible for the adaptive immune system to deal with potential pathogens from almost any place that is involved in infection.

11. Introduction: lymphoid structures • Strategic lymphoid structures are found in places where pathogens typically enter. • GALT – gut associated lymphoid tissue • Examples include the tonsils, adenoids, appendix, and Peyer’s patches. • BALT – bronchial associated lymphoid tissue • Associated with the respiratory portal of entry • Most available portal of entry • MALT – mucosal associated lymphoid tissue • Associated with mucous membranes • An important portal of entry

12. Peyer’s patches • Peyer’s patches are the most important part of GALT. • They contain M cells (M for microfold). • M cells are antigen collecting cells. • Under M cells are germinal centers • Filled with B cells • Surrounded by T cells

13. M cells and Peyer’s patches

14. Development, differentiation, and maturation of lymphocytes • There are two types of T cell: • Helper T cells (TH) • Cytotoxic (CTL)

15. Development, differentiation, and maturation of lymphocytes • Helper T cells differentiate into subtypes including: • TH1 cells • TH2 cells • TH1 cells activate macrophages to synthesize more antimicrobial factors • TH2 cells instruct B cells to make large amounts antibodies which in turn block pathogens from entering the body and improve phagocytosis

16. Development, differentiation, and maturation of lymphocytes • Cytotoxic T cells kill host cells that have been taken over by specific microbes • Virus infected • Cells infected with intracellular bacteria • Protozoan infected cells • Cytotoxic T cells kill similar to NK cells, they command the target cell to commit suicide. However, they only target specific cells which they recognize with their antigen receptor.

17. Development, differentiation, and maturation of lymphocytes • When B cells and T cells mature, they acquire specific antigen receptors. • The B cell receptor is an immunoglobulin (antibody) molecule. • It has two antigen binding sites. • The T cell receptor is related to immunoglobulins , but • It has only one antigen binding site.

18. The antigen receptor of lymphocytes B cell T cell

19. Clonal selection of lymphocytes • Once lymphocytes passed schooling and are found not to react with self they are released into the bloodstream and they continuously circulate the lymphatic system. • If an antigen is encountered and fits to the antigen receptor on the lymphocyte, the lymphocyte is activated. • It begins to divide and proliferate. • It forms a clone of cells specific for one antigen. • Lymphocytes that never encounter antigen eventually die.

20. Clonal selection of lymphocytes

21. Proliferation and differentiation of lymphocytes into effector cells • Once signaled, lymphocytes stop migrating and become activated. • They become larger and multiply. • They multiply fourfold every 24 hours for 3-5 days. • They differentiate into effector cells • B cells become Plasma cells that are antibody factories. • T cells become armed effector cells that put out a huge amount of cytokines (TH) or kill the target cells (CTL) • Some will differentiate into memory cells that are able to quickly become effector cells upon re-stimulation

22. Co-stimulatory signals are required for lymphocyte activation • The consequences of lymphocyte activation are dramatic. • As a safeguard, antigen that binds to the antigen receptor is not enough to trigger a full adaptive response. • Other danger signals must be present, called co-stimulatory signals: • Pro-inflammatory cytokines • Other cell surface molecules expressed only under stress • TLR binding. • Once the infection is cleared lymphocytes are no longer stimulated and will die by apoptosis • Lymphocytes never activated also die by “neglect”, or also entering the apoptotic pathway.

23. Antigen presentation to T cells • B cells recognize native antigens. • T cells cannot detect native antigen. They can see antigen only after it has been processed (degraded, taken apart) into short amino acid stretches and placed onto a specialized molecule, the major histocompatibility complex (MHC). • There are two types of MHC: • Class I is found on all cells. • Class II is found only on specialized antigen presenting cells • Monocytes/macrophages, dendritic cell, B cells

24. TH CTL Antigen presentation: delivery • Antigens are delivered by the MHC in different ways: • Class I molecules associate with cytoplasmic or endogenous antigens. • They present to cytotoxic T cells. • These antigens are derived from microbes replicating in the host cell. • Class II molecules associate with antigens from phagocytic cell vesicles or exogenous. • They present to helper T cells. • These antigens are degradation products from the phagolysosome. MHC I MHC II

25. Antigen presentation: T cells • T cell receptors must recognize both the antigen and the MHC. • This is referred to as the antigen-MHC complex. • Additional molecules are required to make sure that the right T cell acts on the right target cell • T helper cells should only act on immune cells that need help to deal with the invading microbe • Cytotoxic T cells should only kill infected cells that have been taken over by the microbe. • To guarantee this there are additional molecules involved in the formation of the antigen-MHC complex. • CD 4 on T helper cells binds to MHC class II • CD8 on cytotoxic T cells binds to MHC class I

26. MHC I/II and CD 8/4 interaction TH CTL Induce apoptosis INFg Cytotoxic granules Cytokines Any nucleated cell Ag presenting cell Note: antigen and antigen receptor are omitted.

27. Effector T cells

28. T cells respond to superantigens • T cells can respond to superantigens. • These are distinct classes of antigens produced by many pathogens. • Superantigens do not need to be bound to the MHC to be recognized. • They can bind to the outside of MHC molecules. • They cause massive overproduction of cytokines. • They cause systemic toxicity and suppression of the adaptive response. • Example: toxic shock syndrome toxin

29. Toxic shock syndrome • First described in menstruating women using certain types of tampons • High fever, rash, skin peeling in palms, shock, multiple organ failure • Staphylococcus TSST production triggered in high absorbency tampons • TSST resorption through vaginal mucosa

30. T helper cells____________. • bind to antigen presented on MHC I. • express CD8. • Release INFg to stimulate macrophages. • All of the above is correct. • None of the above is correct.

31. NK cell and CTL are alike in all of the following except_______. • that they both induce apoptosis in the target cell. • that they release cytotoxic granules. • they recognize only specific infected cells. • that they can kill more than one cell. • All of the above are correct.

32. The humoral B cell response • The humoral response is carried out by B lymphocytes. • It involves the production of the antibody. • In most cases, activation of B cells requires help from T cells. • Some B cells proliferate and differentiate into plasma cells. • Plasma cells produce massive amounts of antibody. • Some B cells become memory cells.

33. The humoral response: antibodies • Antibodies are found in the blood and in extracellular spaces. • They contribute to the adaptive response in three ways: • Neutralization • Neutralizes toxins and viruses • Prevents bacterial attachment • Opsonization • Facilitates uptake of pathogens by phagocytic cells • Complement • Activates the classical pathway

34. The humoral response:Antibody production

35. The antibody molecule • Antibodies are also called immunoglobulins (Ig). • All Ig molecules have a Y shape. • They are composed of 4 polypeptide chains. • Two light chains • Two heavy chains • The 4 amino terminal ends make up the antigen-binding site. • Remainders of the heavy chains make up the constant region that interacts with host cells • E.g. phagocytes

36. The antibody molecule

37. The antibody molecule: antigen binding • Is based on contacts between the antigen and binding site. • Depends on the size and shape of the antigen. • Binding is along the side of large antigens. • Antibody binding involves hydrophobic and electrostatic forces but is never covalent. • Antibodies are generally made against epitopes. • Epitopes are small surface regions of antigens.

38. Antibody (immunoglobulin) isotypes • There are 5 isotypes: • IgG • IgM • IgA • IgD • IgE • They differ in the type of the constant region. • A B cell always makes IgM isotype first and then switches to other isotypes with the help of cytokines that have been released by T helper cells. The antigen binding site remains the same.

39. Antibody isotypes

40. Antibody isotypes • The constant region of any immunoglobulin has three main functions: • Recognition by specialized receptors on phagocytic cells (IgG) • Forming antigen-antibody complexes that initiate classical complement pathway (IgM, IgG) • Delivering antibody to tissues and secretions (IgG, IgA)

41. IgM • IgM is the first antibody to be produced. • IgM can be in a pentamer structure. • This has ten binding sites and great binding strength. • It is usually found in blood. • It is an excellent activator of the complement system. • It is the primary response to bloodborne pathogens. • It is also found in pleural spaces. • This protects against environmental pathogens.

42. IgG • IgG is smaller than IgM and can easily diffuse out of the blood. • The principle isotype of IgG is found in the blood and extracellular fluid. • It is very effective for opsonization and complement activation. • It can cross the placenta and protect the unborn embryo and fetus. • IgG in a sick newborn does not prove infection! • Maternal IgG lasts for about 6 - 9 months.

43. IgA • IgA is the principle antibody in secretions. • It is found in the respiratory and digestive tracts. • It is present in colostrum and milk and protects the newborn. • It is very effective in blocking pathogen attachment to the host and toxin inactivation.

44. Transcytosis of IgA

45. IgE • IgE is found in low levels in the blood and extracellular fluids. • It binds tightly to mast cells just below the skin and mucosa. • It is also found along the blood vessels in connective tissue. • After antigen binding, powerful chemical mediators are released by the mast cell. • They cause coughing, sneezing and vomiting.

46. IgD • IgD is found in very small amounts in the blood. • It is found on the surface of B cells. • It plays a role in B cell maturation.

47. Which of the following antibody isotype & function is mismatched? • IgM & complement activation • IgG & opsonin • IgA & neutralization • IgD & placenta transfer • All are correctly matched.

48. A newborn baby has a rash and organ anomalies. You determine antibody titers against rubella. Which of the following results from the baby’s serum suggests that the baby had an intrauterine infection with rubella? • Moderate titer ++ for IgG. • IgM ++ , IgG +++ • High ++++ titer for IgG • High IgA +++ • High IgD +++

49. Antibody mediated cell activation • Antibodies can also activate the following cells to release their granules filled with bioactive molecules: • NK cells: IgG • Basophils • Mast cells IgE (important for parasitic infections)

50. Activation of mast cells by IgE • A substantial amount of IgE is bound to mast cells. • When bound to antigen, antibody crosslinking causes the immediate release ofhistamine. • This occurs in seconds. • It causes an increase in blood flow – vascular dilation. • It promotes the movement of blood proteins and fluids in tissue. • There is a following influx of neutrophils, macrophages, and lymphocytes.