#3 Anatomy of the Immune System I

1. #3 Anatomy of the Immune System I Immunology 297 July 28, 2015 Ikuo Tsunoda, MD, Ph.D. Associate Professor Department of Microbiology and Immunology LSUHSC Homepage: http://tsunodalaboratory.web.fc2.com/ E-mail: itsunoda@hotmail.com

2. Textbooks and online resources 2014 2011 2007 http://www.oup.com/uk/orc/defranco/ http://www.oup.com/uk/orc/bin/9780199206148/ Cellular and Molecular Immunology: with STUDENT CONSULT Online Access, 8e (Abbas, Cellular and Molecular Immunology)

3. http://lib-sh.lsuhsc.edu/ebooks/ebooks.php Dictionary

5. Stedman's Medical Dictionary - 28th Ed. (2006) • Immune • Free from the possibility of acquiring a given infectious disease; resistant to an infectious disease. • 2. Pertaining to the mechanism of sensitization in which the reactivity is so altered by previous contact with an antigen that the responsive tissues respond quickly on subsequent contact, or to in vitro reactions with antibody-containing serum from such sensitized people. [L. immunis, free from service, fr. in, neg., + munus (muner-), service]

6. The term immunity; derived from the Latin word immunitas, which was referred to the protection from legal prosecution offered to Roman senators during their tenures in office • Historically, immunity meant protection from infectious disease • The cells and molecules responsible for immunity constitute the immune system • Their collective coordinated response to the introduction of foreign substances is called the immune response • The physiologic function of the immune system is defense against infectious microbes • Noninfectious foreign substances can elicit immune responses

8. 1-0 Overview: The Protective Mechanisms of Immunity • The immune system protects us against infectious organisms • Four pathogens • Virus • Bacteria • Fungus • Parasites • The first critical barrier to infectious disease are the skin and the mucosal epithelia of the gastrointestinal, respiratory and urogenital tracts

9. Three lines of protection against infectious agents • Natural barrier • Restrict entry of infectious agents; skin, mucus, gastric acid • Innate immune response • Antigen-nonspecific; interferon, complement, neutrophil, macrophage • Adaptive immune response • Antigen specific; antibody and T cells

10. Table 2-3

11. Barriers to Infection • Skin and mucous membranes serve as barriers • Free fatty acid, lactic acid, low pH • Mucosal epithelium protected by mucus and cilia • Antimicrobial substances (defensins, lysozyme, lactoferin)

12. γδ T cells, B1 B cell (natural antibody), mast cells

13. Janeway’s Movie 3-6 Lymphocyte Homing https://www.facebook.com/photo.php?v=876855242363491

14. Two waves of the immune response innate adaptive

15. Immune mechanisms are divided into those of innate immunity and adaptive immunity Innate immunity • Distinguish host cells from those of infectious agents by recognizing conserved constituents of microorganisms • Activated within hours • Phagocytes: neutrophils and macrophages Adaptive immunity • Recognize a variable component of microorganisms • Effective after 96 hours (4 days) • B and T lymphocytes

16. Two waves of the immune response

17. Two waves of the immune response The nonspecific innate immune response is critical to control the early stages of infection and the extent of pathogen replication and spread. The adaptive immune response provides a mechanism to specifically target foreign pathogens, protecting the host from excessive damage. PMN: polymorphonuclear cell, neutrophil MAC: macrophage T/B: T and B lymphocytes

18. 1-1 Cells of the Immune System: Differentiation in the bone marrow Hematopoietic stem cell in the bone marrow gives rise to all immune cells (white blood cells), red blood cells (erythrocytes) and megakaryocytes, whose fragments form platelets that initiate blood clotting

20. The primary lymphoid organs Sites where cellular components of immunity are generated • All precursor cells are generated in the bone marrow. • Myeloid lineage cells develop in the bone marrow. • B lymphocytes mature exclusively in the bone marrow. • T lymphocytes start in the bone marrow as pre-T cells, but develop into mature T cells in the thymus.

21. Cytokines (haematopoietins) promote differentiation of immune cells • Erythrocytes: erythropoietin • Megakaryocyte (platelets): thrombopoietin • Lymphoid and myeloid cells: interleukins (IL) and colony-stimulating factors (CSFs) • Cytokines are produced constitutively by a number of different cell types • Infection induces the production of cytokines by immune cells and non-immune cells

22. All white blood cells (WBCs) develop from the HSC Effector cells can activate or destroy other cells

23. WBCs derive from common progenitors

24. Myeloid lineage

25. Figure 1-5 Cells of the myeloid lineage • Granulocytes / polymorphonuclear leukocytes (PMNs) • Neutrophil • Eosinophil • Basophil • Monocyte / macrophage lineage cells • Monocyte • Dendritic cell • Macrophage • Mast cells

26. Neutrophils are the most abundant WBC

27. PMNs are distinguished by the different staining properties of the granules • faint stain: neutrophil • red: eosinophil • blue: basophil • Short-lived (a few days) • Basophils and mast cells release molecules including histamine, important mediators of allergic responses

28. Figure 2-1 • Neutrophil • Mast cell • Basophil • Eosinophil

29. Mast cell • Blood-borne precursor is not well defined • Defense against parasites (helminth) • Allergic diseases • Blue (basophilic) granules

30. Monocyte / macrophage lineage cells

31. Myeloid lineage “phagocytes” [phago- + G. kytos, cell] phago-     Eating, devouring. [G. phago, to eat]

32. PMNs, Polymorphonuclear leukocytes, neutrophils Polymorphonuclear: Possessing a nucleus consisting of several parts or lobes connected by fine strands Mononuclear: Having one nucleus, particularly a blood cell such as a monocyte or lymphocyte Mononuclear cell (MNC) = monocyte and lymphocyte Monocytes Figure 2-6 A and B. Monocyte; C. Macrophage

33. IV_10_2_Chemotaxis-H264 (Janeway’s Immunobiology)

34. Phagocytosis of intracellular destruction of microbes http://www.studentconsult.com/content/9780323054706/abbas_sped-up_animations/index.html

35. Macrophages induce the inflammatory response macrophages encounters antigen activation of the macrophage phagocytosis killing induction of inflammatory response neutrophils complement pro-inflammatory cytokines

36. Inflammatory response An immune process involving components of innate immune response, especially macrophages and neutrophils

37. Inflammation A pathologic process consisting of a dynamic complex of histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in the affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by a physical, chemical, or biologic agent, including the local reactions and resulting morphologic changes; the destruction or removal of the injurious material; and the responses that lead to repair and healing. The cardinal signs of inflammation are rubor, redness; calor, heat (or warmth); tumor, swelling; and dolor, pain; a fifth sign, functio laesa, inhibited or lost function, is sometimes added. All these signs may be observed in certain instances, but none is necessarily always present. [L. inflammo, pp. -atus, fr. in, in, + flamma, flame] Stedman's Medical Dictionary - 28th Ed. (2006)

38. Inflammation • A protective response to get rid of damaged or necrotic tissues and foreign invaders, such as microbes and toxins • A complex reaction in tissues that consists of responses of blood vessels and leukocytes • Acute inflammation versus chronic inflammation • Inflammation may be harmful in some situations; immunopathology • Characterized by • four signs : • rubor (redness) • calor (heat) • tumor (swelling) • dolor (pain) http://globalwarming-arclein.blogspot.com/2011/01/inflammation-thoughts.html

39. Infection triggers inflammation The accumulation of fluid and cells causes the redness, swelling, heat and pain

40. Acute inflammation • A rapid host response that serves to deliver leukocytes and plasma proteins to sites of infection or tissue injury • 1) Expansion of vascular caliber to increase blood flow • Causing redness or a rash and releasing heat • 2) Increase in permeability of the microvasculature structure to allow escape of fluid, plasma proteins, and leukocytes from the circulation • Swelling, edema • 3) Recruitment and activation of leukocytes Edema: a local or generalized condition in which body tissues contain an excessive amount of tissue fluid in the interstitial spaces

41. Two roles of phagocytes of innate immunity • Release cytokines and chemokines which are signaling molecules with a wide range of functions: eg. interleukin (IL)-1, IL-6, tumor necrosis factor (TNF) • Activate the adaptive immunity phagocytes (dendritic cells) display a component (antigen) of microoorganism for recognition by T cells (antigen presentation), and activate T cells Antigen: molecule or part of a molecule recognized by antibody or T cell receptor

42. Macrophages and dendritic cells are known as “antigen presenting cells” (APCs): they engulf pathogens and present antigens to activate T cells

43. The innate response acts very early to: (a) control the pathogen (b) activate the adaptive immune response Figure 1-1: Innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later and require the activation of lymphocytes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections. ILC, innate lymphoid cell; NK, natural killer.

44. PAMPs Table 2-1

45. 1-3 Macrophage and Dendritic Cell Subsets Macrophage • Defense against infection, scavenging debris and tissue repair and maintenance • Spleen; marginal zone macrophage, metallophilic macrophage • Brain; microglia • Lung; alveolar macrophage • Liver; Kupffer cell • Bone; osteoclast Figure 2-2: Maturation of mononuclear phagocytes. Tissue resident macrophages, which differentiate into specialized forms in particular organs, are derived from precursors in the yolk sac and fetal liver during fetal life. Monocytes arise from a precursor cell of the myeloid lineage in the bone marrow, circulate in the blood, and are recruited into tissues in inflammatory reactions, where they further mature into macrophages. Subsets of blood monocytes exist, which have distinct inflammatory or reparative functions (not shown).

46. Dendritic cell • Antigen capture and the induction of T cell responses to protein antigen • Epidermis; Langerhans cell • Dermis; dermal dendritic cell • Blood; plasmacyotoid dendritic cell Follicular dendritic cell (FDC) • Lymph nodes, spleen, mucosal lymphoid tissues • Not derived from bone marrow; non-hematopoietic cell • Capture antigen for recognition by B cells

47. NK cells • Large granular lymphoid-like cells • Kill tumor cells and infected cells • Lack antigen specific receptor • Part of the innate immune system: Group 1 innate lymphoid cell (ILC)

48. New online resources http://www.oup.com/uk/orc/defranco/ http://www.oup.com/uk/orc/bin/9780199206148/

49. 1-1 Cells of the Immune System: Differentiation in the Bone Marrow 1. Which of the following cells belong to the myeloid lineage? 2. Which of the following statements are true?

50. http://tsunodalaboratory.web.fc2.com/