1. Chapter 2 Cells and Organs of the Immune System Sept 26,28 & Oct 3, 2006

2. 你需要學習的課題 : 1. 「淋巴器官」 (lymphoid organ) 分為哪兩大類 ? 2. 初級 (primary) 淋巴器官有哪些 ? 有什麼功能 ? 3. 次級 (secondary) 淋巴器官有哪些 ? 有什麼功能 ? 4. 免疫系統包含哪些細胞、器官及組織 ? 各有什 麼特色及功能 ?

3. Outline 1. Hematopoiesis ( 造血 ) 2. Cells of the Immune System 3. Organs of the Immune System 4. Lymphoid Cells and Organs – Evolutionary Comparisons

4. Hematopoiesis

5. All blood cell arise from the hematopoietic stem cell (HSC). Locations of Hematopoiesis (humans): embryo yolk sac (first weeks)  fetal liver & spleen (3 rd to 7 th mo of gestation)  bone marrow

6. Properties of hematopoietic stem cells (HSC): 1. Capability to give rise to all differentiated blood cells 2. Self-renewing; each division of a stem cell creates at least one stem cell.

7. Hematopoiesis Progenitor cells proliferate and differentiate into various cell types through the action of growth factors, cytokines and stromal ( 基質 ) cells. Stromal cells: fat cells, endothelial cells, fibroblasts, macrophages. 骨髓系淋巴系

8. [Clinical Focus] Stem Cells ( 幹細胞 ) - Clinical Uses and Potential Providing a functional immune system to individuals with: 1. a genetically determined immunodeficiency, such as severe combined immunodeficiency (SCID). 2. life-threatening genetic disorder in hematopoiesis, such as sickle-cell anemia or thalassemia. 3. treatment of high-dose chemotherapeutic agents or radiation, such as cancer patients.

9. Transplantation Autologous : The recipient is also the donor. Syngeneic : The donor is genetically identical, i.e., an identical twin of the recipient. Allogeneic : The donor and the recipient are not genetically identical within the same species. Xenogeneic : The donor and the recipient are from different species.

11. 儲存臍帶血的意義是什麼 ?

12. Cells of the Immune System

13. 3.7 – 5.1 x 10 3 1.5 – 3.0 x 10 3 1 – 4.4 x 10 2 1 – 2.2 x 10 2 < 1.3 x 10 2 12341234 Total leukocytes (%)

14. Cells of the Immune System - Lymphoid cells B lymphocytes, T lymphocytes – bearing antigen receptors Natural killer cells (NK cells) - Mononuclear phagocytes Monocytes, Macrophages - Granulocytic cells Neutrophils, Eosinophils, Basophils, Mast cells, Dendritic cells

15. Lymphoid Cells - 20% - 40% of the body’s white blood cells - 99% of the cells in the lymph - ~ 10 10 - 10 12 in the human body - Circulate in the blood and lymph - Migrate into the tissue spaces and lymphoid organs

16. B Lymphocytes: Bursa of Fabricius ( 黏液囊 ) or Bone Marrow T Lymphocytes: Thymus

17. Cluster of Differentiation (CD) All of the monoclonal antibodies (mAb) that react with a particular membrane molecule on the cell are grouped together as a cluster of differentiation (CD).

19. B Lymphocyte Markers Immunoglobulin (Ig, Ab) as receptors for Ag B220 (CD45R) MHC Class II CR1 (CD35) & CR2 (CD21) Fc  RII (CD32) B7-1 (CD80) & B7-2 (CD86) CD40

20. T Lymphocyte Markers T cell receptor (TCR) as Ag receptors CD3 CD4 or CD8 CD28; a receptor for B7 on B cells and APC CD45

21. Two Major Subpopulations of T Lymphocytes CD4+ T cells: only recognize Ag bound to class II MHC molecules (also called class-II restricted) : generally function as T helper (T H ) cells CD8+ T cells: only recognize Ag bound to class I MHC molecules (also called class-I restricted) : generally function as T cytotoxic (T C ) cells The ratio of CD4+/CD8+ T cells is ~ 2:1 in human peripheral blood.

22. T H cells (usually CD4+) : proliferate and secrete various cytokines T H 1 response – produces a cytokine profile that supports inflammation and activates mainly T cells and macrophages. T H 2 response – activates mainly B cells and immune responses that depend upon antibodies. T C cells (usually CD8+): proliferate and differentiate into cytotoxic T lymphocytes (CTL) which can eliminate altered self-cells.

23. Fate of Antigen-activated Small B Lymphocytes

25. Natural Killer (NK) Cells - large, granular lymphoid cells - cytotoxic against certain tumor cells and virus- infected cells with no previous immunization - Part of the innate immune system - constitute 5 - 10% of the lymphocytes in human peripheral blood - using NK cell receptors or CD16 (Fc  RIII) as recognition molecules - NK T cells: possessing both TCR and NK cell receptors

26. Mononuclear Phagocytes - Monocytes: circulating in the blood - Macrophages: in the tissues

27. Macrophages 1. 5- to 10-fold larger than monocytes 2. contain more and complex organelles, especially lysosomes 3. increased phagocytic ability 4. produce higher levels of hydrolytic enzymes 5. increased ability to kill ingested microbes 6. increased secretion of inflammatory mediators, and 7. increased ability to activate T cells

28. Tissue Macrophages Alveolar macrophages in the lung Histiocytes in connective tissues Kupffer cells in the liver Mesangial cells in the kidney Microglial cells in the brain Osteoclasts in bone

29. Macrophages can be activated by: - components of bacterial cell walls - phagocytosis of particulate Ag - cytokines secreted by T H cells (the most potent one is interferon- , IFN-  ) - mediators of the inflammatory response

30. Phagocytosis is Followed by Digestion and Presentation of Ag

31. Opsonin: A substance (e.g., Ab) that binds to both ( 調理素 ) Ag and phagocytes, thereby enhancing phagocytosis. The process by which opsonins render particulate Ags more susceptible to phagocytosis is called opsonization.

32. Granulocytic Cells (granulocytes) - Neutrophils (polymorphonuclear leukocytes, PMN) - Eosinophils - Basophils

34. Neutrophils : - phagocytic and microbicidal (similar to macrophages) - extravasation: movement of circulating neutrophils into tissues Eosinophils: - less phagocytic - defend parasitic organisms Basophils: - nonphagocytic - release pharmacologically active substances - play a major role in certain allergic responses

35. Mast Cells: - not differentiated until leaving the blood and entering the tissues, such as the skin, connective tissues, and mucosal epithelial tissues - release histamine and other pharmacologically active substances - play an important role in the development of allergies

36. Dendritic Cells - Langerhans dendritic cells in the epidermal layer of skin - Interstitial dendritic cells in the interstitial space of all organs except the brain - Monocyte-derived dendritic cells arise from monocytes that have migrated from the bloodstream into tissues. - Plasmacytoid dendritic cells arise from plasmacytoid cells They play roles in innate immune defense and act as antigen-presenting cells (APC).

37. Dendritic cells (DC) and their origins

38. All DCs constitutively express high levels of class I & class II MHC molecules, costimulatory molecules B7 (CD80,CD86) and CD40 molecules, which can interact with T cells. major functions of DC: - immature DC in periphery: sense of invasion capture of foreign Ag - mature DC migrate into lymphoid organs: presentation of Ag to T cells

39. Organs of the Immune System

40. The Human Lymphoid System secondary lymphoid organs primary lymphoid organs

41. Primary (central) lymphoid organs - Provide appropriate microenvironments for the development and maturation of lymphocytes. - thymus and bone marrow Secondary (peripheral) lymphoid organs - Trap antigen from tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with that antigen. - lymph nodes, spleen and various mucosal-associated lymphoid tissues (MALT), e.g., tonsil, appendix and Peyer’s patches

42. Various lymphoid organs (primary & secondary) are connected by blood vessels and lymphatic systems.

43. Lymphatic System ( 淋巴系統 ) - Once mature lymphocytes have been generated in the primary lymphoid organs, they circulate in the blood and lymphatic system, a network of vessels that collect fluid that has escaped into the tissues from capillaries of the circulatory system and ultimately return it to the blood.

44. The Thymus stromal cells: maturation

45. The Function of the Thymus The function of the thymus is to generate and select a repertoire * of T cells that will protect the body from infection. Those T cells which do not recognize Ag-MHC or react with self-Ag-MHC will undergo apoptosis in the thymus. * repertoire : 總目錄 ( 即對抗外物的所有 T 細胞 )

46. Changes in the Thymus with Age

47. 想一想 : 胸腺的重量自出生到青春期直線上升， 青春期以後胸腺就逐漸萎縮 35-yr-old: 20% 65-yr-old: 2% 有無特殊意義？

48. Bone Marrow In mice and humans, immature B cells proliferate and differentiate within the bone marrow, and the stromal cells interact with the B cells and secrete various cytokines that are required for development. Like thymic selection during T-cell maturation, a selection process within the bone marrow eliminates B cells with self-reactive antibody receptors.

49. Lymphatic System The lymphatic system serves as a means of transporting lymphocytes and Ag from tissues to organized lymphoid organs, where the lymphocytes may interact with the trapped Ag and undergo activation.

50. Lymph – Interstitial fluid derived from blood plasma that contains a variety of small and large molecules, lymphocytes and some other cells. It circulates through the lymphatic vessels. The largest lymphatic vessel, the thoracic duct ( 胸管 ), empties into the left subclavian ( 鎖骨下 ) vein near the heart.

51. Lymphatic Vessels

52. Secondary Lymphoid Organs 1. Organized lymphoid organs : lymph nodes & spleen 2. Less organized lymphoid tissues, collectively called mucosa-associated lymphoid tissue (MALT) : - Peyer’s patches - tonsils - appendix - numerous lymphoid follicles (within intestines, upper airways, bronchi and genitourinary tract)

53. Lymph nodes are the sites where immune responses are mounted to antigens in lymph and the spleen plays a major role in mounting immune responses to antigens in the blood.

54. Lymphoid organs contain primary follicles which comprise a network of follicular dendritic cells and small resting B cells. After an antigenic challenge, a primary follicle becomes a larger secondary follicle – a ring of concentrically packed B lymphocytes surrounding a center (the germinal center) in which proliferating B lymphocytes and some T H cells intersperse with macrophages and follicular dendritic cells.

55. germinal center (B cells, T H cells, M , follicular DC) dense mantle of small B lymphocytes A Secondary Lymphoid Follicle

56. Follicular dendritic cells - different from other Ag-presenting dendritic cells - do not express class II MHC molecules - do not function as Ag-pesenting cells for T H cell activation - exclusively located in lymphoid follicles (in organized secondary lymphoid organs) - express high levels of receptors for Ab - play an important role in the maturation of B cells

57. A Lymph Node

58. The Spleen 血管神經 出入口

59. 上顎 舌 咽 Tonsils

60. Peyer’s Patch

61. Structure of M Cells

62. Production of IgA Ab in the Gut

63. Evolutionary Distribution of Lymphoid Tissues Adaptive immunity only evolved in the subphylum Vertebrata. However, neither T nor B lymphocytes have been found in the jawless fishes.

64. Questions: 1. What can activate macrophages? How does the activity of macrophages change after activation? 2. What are the functions of dendritic cells? 3. What are the surface molecules characteristic for T and B lymphocytes? 4. What are the primary and secondary lymphoid organs? What are their functions?