Chapter 1 part 1. Slides 1-34

1. Chapter 1 part 1. Slides 1-34

2. Chapter 1 Basic Concepts In Immunology This chapter introduces the cellular and molecular players of the immune system (based mainly on our understanding of the immune systems of mice and humans) • Components of the immune system (organs, cells, molecules) • Principles of innate and adaptive immunity • Recognition and effector mechanism This chapter is a summary of immunology. It provides the framework upon which the remainder of the course is built. If you do not have a solid understanding of this chapter, you will have significant difficulty following the subsequent chapters.

3. In 1796 Edward Jenner infects a boy with cow pox to protect against small pox (before germ theory of disease)vacca=cow

5. Mid-late 1800s Robert Koch showed that microorganism cause infectious diseases and that different organisms cause different diseases Louis Pasteur first showed how vaccines could be made to a variety of bacterial and viral pathogens. 4 broad categories of pathogens (disease causing organisms): viruses, bacteria, fungi, and “parasites” (eukaryotes including protozoans and worms) Emil Von BehringandShibasaburo Kitasato found, in the blood of immune individuals, a substance that bound to the bacteria to which they were immune. Called the substance ANTIBODY

6. Specific immunity can be induced by a variety of substances. Things that are targets of adaptive immunity are called ANTIGENS* *Things that induce an adaptive immune response are immunogens Adaptive Immunity: Specific Immune Response (e.g., antibody) against a particular microorganism is an adaptive immune response. That is, it occurs during one’s lifetime as an adaptation to the presence of that particular organism. (usually, specific means the ability to distinguish one organism from another) An adaptive immune response might provide lifelong protective immunity to a given pathogen. These are central principles of adaptive immunity Antigen-specific responses are mediated by lymphocytes

7. Innate immunity is the immunity that is immediately available without having to adapt to the specific pathogen that is present. It is not specific to a particular organism such that identical responses can protect against several organisms. Innate immunity is germline encode (evolved on an evolutionary time scale). Innate immunity is mediated by phagocytes (cell that ingest bacteria or other particulate matter) such as macrophages and neutrophils. It is also mediated by chemical compounds and physical barriers that will be described later.

8. Together, innate and adaptive immunity prevent most infectious diseases (no symptoms from exposure to the microorganisms) or cure infections This course mostly deals with adaptive immunity. However, you must understand innate immunity and how adaptive immunity works together with innate immunity to prevent or cure infections.

9. Cellular components of the immune system Adaptive immunity is mediated primarily by lymphocytes Innate immunity largely involves granulocytes and macrophages • The Main players • B cells • T cells • Neutrophils • Macrophages • Dendritic cells Lymphocytes

10. Most cellular components of the immune system originate in the bone marrow and circulate through blood tissues lymphoid organs lymphatic system [lymphoid organs and specialized vessels (lymphatics) used primarily by the immune system]

11. progenitors   Innate immunity largely involves granulocytes and macrophages (although macrophages can influence adaptive immunity)           Adaptive immunity is mediated primarily by B and T lymphocytes        other cells are regulatory or involved with both adaptive and innate immunity and/or are precursors of another cell type    

12. Cells of the myeloid lineage or PMN

13. B cell B cells and T cells look alike but have important differences T cell Mature lymphocytes have antigen-specific receptors [antibody on B cells and T cell receptor (TCR) on T cells]

14. B cells have antibody on their surface as an antigen receptor Plasma cells (effector B cells) secrete antibody antibody (ab) = immunoglobulin (Ig)immunoglobulin = antibody B cell antigen receptor (BCR) = B cell receptor = B cell surface antibody = Membrane immunoglobulin (mIg) (a transmembrane protein) Soluble antibody is sIg (not BCR because it is not on a B cell) Generally, if one does not specify BCR, they probably mean soluble antibody All BCRs are antibodies but not all antibodies are BCRs

15. Three Major types of T lymphocytes Cytotoxic T lymphocyte (CTL) kill infected host cells (a.k.a.* cytotoxic T cells or killer T cell) TH1 cells activate macrophages (a.k.a. inflammatory T cells) TH2 cells activate B cells (a.k.a. T helpers or helper T cells) Although T cells are key players in adaptive immunity and have antigen-specific receptors, T cell do not secrete their antigen-specific receptor and do not directly kill or damage pathogens. In fact, T cell’s antigen receptor does not bind to pathogenic organisms (so, how can they have antigen-specific receptors that protect against specific pathogens?). *a.k.a.; also known as

16. antigen on surface presenting cells (APC) TCR T cell APC The T cell antigen-binding molecule is called the T cell antigen receptor or the TCell Receptor (TCR). It is found only on T cells (no soluble form) Antibodies bind native antigens (antigens as they are found in nature). The TCR does not bind native antigen. The TCR binds antigens taken-up, processed* and presented to it on the surface of other cells. There is always cell-cell contact between the T lymphocyte and the hostantigen presenting cell (APC) signaling *processing is the degradation of the antigen; details of this process should become clear later

17. TCR  BCR TCR Ig TCRantibody (Ab) Ig=AbAll BCRs are Igs but not all Igs are BCRs

18. Natural killer (NK) cells are lymphocytes that can kill host cells (e.g., virus infected cells) without making their own antigen-specific receptor (do not require ab or TCR and are part of innate immunity) Once referred to as large grauular lymphocytes or LGLs

19. The distribution of lymphoid tissues Lymphoid organs contain lymphocytes and non-lymphoid cells such as macrophages and dendritic cells (and epithelial cells) Lymphoid organs are important for the generation and maturation of lymphocytes, the initiation of immune responses and the perpetuation of immune responses

20. Central lymphoid organs Central (primary) lymphoid organs are the sites for generation and early maturation of B and T lymphocytes (for the generation of antigen receptors but not for the generation of antigen-specific responses) T cells mature in the thymus (T for thymus) B cells mature in the bone marrow B for bursa of Fabricius (a lymphoid organ in birds) [After Hieronymus Fabricius (1537-1619), Italian anatomist] Where do you find T cell progenitors? Ans: All lymphocyte progenitors are found in the bone marrow

21. Peripheral lymphoid organs and other stuff Blood circulation Heart capillaries    Peripheral lymphoid organs  • 1. trap antigens • are the sites for initiation of most immune response • provide signals for recirculation of lymphocytes    *other stuff (not peripheral lymphoid organs)

22. The flow of lymph through lymphatic vessels

23. To thoracic duct Flow of lymph from interstitial spaces

24. Gut associated lymphoid tissue (GALT)(tonsils, adenoids, Peyer’s patches, appendix)

25. Immature B and T cells mature in the central lymphoid organs (bone marrow for B cells and thymus for T cells). Then, they circulate in the blood and through the peripheral lymphoid organs; the circulating lymphocytes are mature naïve lymphocytes. As long as they have not encountered the specific antigen that binds their antigen receptors (BCR or TCR), they are referred to as naïve. Note: by this logic, they must have made their antigen receptor in the absence of antigen. When mature naïve lymphocytes encounter antigen (bind antigen in their antigen receptor), they 1. Stick in the lymph nodes (or other peripheral lymphoid organ)(they stop circulating, i.e., altered trafficking) 2. Proliferate (divide) 3. Differentiate into effector cells (or memory cells): B cell effectors are plasma cells; T cells effectors are effector CTLs, effector TH1 or effector TH2 Steps 2 and 3 are lymphocyte activation

26. Antigens in periphery may be taken up by macrophages and dendritic cells and may be transported to the peripheral lymphoid organs via the lymphatics (afferent lymph) Antigens can also enter the lymphatics (afferent lymph) and move to the draining lymphoid organ where they can be taken-up by macrophages and dendritic cells In the lymphoid organ, antigens can bind to the BCR of antigen-specific B cells and/or be presented (shown) by dendritic cells where they can bind to the TCR of antigen-specific T cell. This results is B or T lymphocyte activation (proliferation and differentiation) B cell activation requires help from activated T cells Effector lymphocytes may stay in the lymphoid organ (TH2 and some plasma cells) or leave via the efferent lymph to go to the site of infection (plasma cell, TH1 and CTL) or, for plasma cells, go to the bone marrow to make antibody (altered trafficking)

27. Principles of innate and adaptive immunity Innate immunity (e.g., macrophages, neutrophils, certain molecules) is the first line of defense. It is fast (usually good-to-go) and usually effective. Adaptive immunity (mediated by B and T cells) can be slow to respond (several days). It is highly effective when the innate immune system cannot fully deal with the threat.

28. (1st) RBC neutrophil lymphocyte monocyte Monocyte macrophage (2nd) Endothelial cells Bacteria may trigger an innate inflammatory response macrophage bacteria Macrophages phagocytize bacteria and release cytokines and/or chemokines (hormones of the immune system) cytokines and chemokines can cause an inflammatory response Complement can also initiate inflammation and act as an opsonin

29. Caused by vasodilatation and movement of cells and/or fluid into the interstitial spaces Ultimately controlled by endothelial cells The Cardinal Signs of Inflammation Redness Swelling Heat Pain Redness Caused by cytokines and other chemical mediators

30. Adaptive immune response begins with the uptake of antigens by immature dendritic cells * mature dendritic cells are (professional) antigen presenting cells (APC) Macropinocytosis by dendritic cells(receptor-mediated and random) Dendritic cells take up antigen to present to T cell. Dendritic cells do not constitute an effective mechanism against pathogens as do macrophages and neutrophils.

31. Innate immunity relies on receptors that recognize common bacterial (and other) molecules. The information on the structure of these receptors is germline encode. Thus, the number of different receptors is limited (<20 known) and these receptors cannot evolve as fast as most pathogens. Pathogens sometimes modify or mask molecule recognized by the germline encoded receptors or inactivate the cells of innate immunity. Virus are generally not recognized by these receptors. Dendritic cells can pick-up stuff randomly (e.g., viruses) and present it to T cells (via a process that “unmasks” hidden antigens: antigen processing) Lymphocytes have overcome the problem of a limited number of germline encoded receptors. Lymphocytes can somatically create 109 to 1016 different antigen receptors (ab or TCR).

32. However, you cannot simultaneously maintain 109-1016 different antibodies at functional levels. This problem is solved byclonal selection(perhaps the most important concept in immunology) As an aside, for now, human have fewer than genes. 25,000 So, how can you make 1,000,000,000+ different antibodies and TCRs?

33. Bone marrow for B cells Thymus for T cells Antigen binding in the bone marrow leads to B cell deletion (death). Strong antigen binding in the thymus leads to T cell deletion periphery clonal expansion Antigen binding in the periphery can lead to activation (other signals are required, too) Clonal Selection The somatic evolution of B and T cells antigen recognition repertoires X X X X

34. 1* (Mature lymphocytes) 3 4 (Immature lymphocytes) 2 The self/nonself discrimination (or tolerance) is “learned” in the soma *Numbers represent the 4 panels in the previous slide 1 and 2 in the central lymphoid organs (thymus or bone marrow); 3 and 4 in the periphery

35. Clonal selection solves the problem of a repertoire that is too large to be fully functional all the times. Clonal selection is the basis of immunological memory (to be dealt with later). Clonal selection (i.e., clonal deletion) deals with the problem of a “complete” repertoire (enough specificities in the individual to recognize everything) having the capacity to recognize and destroy self. Clonal deletion removes (kills) self-reactive (anti-self) B and T cells.