1. CELLS & ORGANS OF THE IMMUNE SYSTEM A Presentation By Isaac U.M., Associate Professor , Dept. of Microbiology & Parasitology, College of Medicine, International Medical & Technological University, Dar-Es-Salaam, Tanzania

5. The human body has a coordinated defense system more sophisticated than any other defense system in the world.

6. The system is never outdated or obsolete.

7. Human Circulatory System

8. Human Lymphoid System

9. Human Lymphoid System

10. Human Lymphoid System

11. Blood cells are produced in bone marrow where fighter cells are trained or sent to the thymus gland.

14. Hematopoiesis Self-renewing hematopoietic stem cells give rise to lymphoid and nyeloid progenitors. All lymphoid cells descend from lymphoid progenitor cells, and all cells of the myeloid lineage arise from myeloid progenitors.

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16. Hematopoiesis is Regulated At the Genetic Level

22. Comparison of Morphologic Changes that Occur in Apoptosis & Necrosis

23. Apoptosis Light micrographs of (a) normal thymocytes (developing T cells in the thymus) and apoptic thymocytes) and (b) apoptotic thymocytes. Scanning electron micrographs of © normal and © normal and (d) apoptotic thymocytes. [From B.A. Osborne and S. Smith, 1997, Journal of NIH Research 9: 35; courtesy of Osborne, University of Massachusetts at Amherst].

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26. - Apoptotic Genes & Regulation of Lymphocyte Life Span

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33. - Therapeutic Uses of Enriched Populations of HSC’s

35. Figure 11-1 Morphology and lineage of cells involved in the immune response. Pluripotent stem cells and colony-forming units are long-lived cells capable of replenishing the more differentiated functional and terminally differentiated cells. (From Abbas K et al: Cellular and molecular immunology, ed 5, Philadelphia, 2003, WB Saunders.) Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

36. Peripheral Blood Cells

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39. - Fate of Antigen-Activated Small Lymphocyte

42. Figure 13-3 T-cell receptor (TCR). The TCR consists of different subunits. Antigen recognition occurs through the α/β or γ/δ subunits. The CD3 complex of γ, δ, ε, and ζ subunits promotes T-cell activation. C, Constant region; V, variable region. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

43. Figure 13-5 Structure of class I and class II major histocompatibility (MHC) molecules. The class I MHC molecules consist of two subunits, the heavy chain and β2-microglobulin. The binding pocket is closed at each end and can only hold peptides of eight to nine amino acids. Class II MHC molecules consist of two subunits, α and β and hold 11 or more amino acid peptides. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

44. Figure 13-6 Genetic map of the major histocompatibility complex (MHC). Genes for class I and class II molecules, as well as complement components and tumor necrosis factor (TNF), are within the MHC gene complex. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

45. Figure 13-2 MHC restriction and antigen presentation to T cells. Left, Antigenic peptides bound to class I MHC molecules are presented to the T-cell receptor (TCR) on CD8 T killer/suppressor cells. Right, Antigenic peptides bound to class II MHC molecules on the antigen-presenting cell (APC) (B cell, dendritic cell, or macrophage) are presented to CD4 helper cells and delayed-type hypersensitivity T cells. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

46. Figure 13-7 Antigen presentation. A, Class I MHC: Endogenous antigen (produced by the cell and analogous to cell trash) is targeted by attachment of ubiquitin (u) for digestion in the proteosome. Peptides of eight to nine amino acids are transported through the TAP (transporter associated with antigen processing) into the endoplasmic reticulum (ER). The peptide binds to a groove in the heavy chain of the class I MHC molecule, allowing association with β2 microglobulin. The complex is processed through the Golgi apparatus and delivered to the cell surface for presentation to CD8 T cells. B, Class II MHC: Class II MHC molecules assemble in the ER with an invariant chain protein and are transported in a vesicle through the Golgi apparatus. Exogenous antigen (phagocytosed) is degraded in lysosomes, which then fuse with a vesicle containing the class II MHC molecules. The invariant chain is degraded, and peptides of 11 to 13 amino acids bind to the class II MHC molecule. The complex is then delivered to the cell surface for presentation to CD4 T cells. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

47. Figure 13-8 The molecules involved in the interaction between T cells and antigen-presenting cells (APCs). The various cytokines and their direction of action are also shown. GM-CSF, Granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule 1, IFN-γ, interferon-γ; TNF, tumor necrosis factor. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

48. Figure 13-10 Cytokines produced by TH1 and TH2 cells and their effects on the immune system. TH1 responses are initiated by IL-12 and interferon-γ, and TH2 responses by IL-4. TH1 cells promote inflammation and production of complement and macrophage-binding antibody (solid blue lines) and inhibit TH2 responses (dotted blue lines). TH2 cells promote humoral responses (solid red lines) and inhibit TH1 responses (dotted red lines). Colored square denotes end result. ADCC, Antibody-dependent cellular cytotoxicity; APC, antigen-presenting cell; CTL, cytotoxic T cell; DTH, delayed-type hypersensitivity; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF, tumor necrosis factor. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

49. Figure 13-11 Interactions between CD8 cytotoxic T lymphocyte (CTL) and target cells. The Fas-FasL interaction promotes apoptosis. ICAM-1, Intercellular adhesion molecule 1. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

50. Comparison of T & B Cells

51. Comparison of T & B Cells *Depending on subset. CTL, Cytotoxic lymphocyte; DTH, delayed-type hypersensitivity; Ig, immunoglobulin; MHC, major histocompatibility complex; TCR, T-cell receptor.

52. Figure 11-7 Surface markers of human B and T cells. Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

53. Natural Killer (NK) Cells

54. Monocyte & Macrophage

55. Phagocytosis

56. Mononuclear Phagocyte System

59. Figure 11-6 Macrophage surface structures mediate cell function. Bacteria and antigens either bind directly to receptors or through antibody or complement receptors (opsonization) and can then be phagocytized; the cell is activated and presents antigen to T cells. The dendritic cell shares many of these characteristics. Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

61. Morphology and Staining of Blood Cells

62. Granulocytic Cells

63. Different Kinds of Dendritic Cells & Their Origins

64. Figure 13-9 Dendritic cells initiate immune responses. Immature dendritic cells constantly internalize and process proteins, debris, and microbes, when present. Binding of microbial components to Toll-Like Receptors (TLRs) activates the maturation of the DC so that it ceases to internalize any new material, moves to the lymph node, up-regulates MHC II, B7 and B7.1 molecules for antigen presentation, and produces cytokines to activate T cells. Release of IL-6 inhibits release of TGF β and IL-10 by T regulatory cells. The cytokines produced by DC and its interaction with TH0 cells initiate immune responses. IL-12 and IL-2 promote TH1 responses while IL-4 promotes TH2 responses. Most of the T cells divide to enlarge the response, but some remain as memory cells. Memory cells can be activated by DC, macrophage, or B cell presentation of antigen for a secondary response. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

65. Cells of the Immune Response

66. Cells of the Immune Response

67. Cells of the Immune Response

68. Cells of the Immune Response

69. Cells of the Immune Response

70. Cells of the Immune Response *Monocyte/macrophage lineage. APCs, antigen-presenting cells; CNS, central nervous system; DTH, delayed-type hypersensitivity; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, lymphotoxin; MHC, major histocompatibility complex; TNF, tumor necrosis factor.

71. Selected CD Markers of Importance

72. Selected CD Markers of Importance

73. Selected CD Markers of Importance ADCC, antibody-dependent cellular cytotoxicity; APCs, antigen-presenting cells; CTLA, cytotoxic T-lymphocyte associated protein; EBV, Epstein Barr virus; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; IL, interleukin; LCA, leukocyte common antigen; LFA, leukocyte function-associated antigen; LPS, lipopolysaccharide; MHC, major histocompatibility complex; TAC, T-cell activation complex; TCR, T-cell antigen receptor; VLA, very late activation (antigen). Modified from Male D et al: Advanced immunology , ed 3, St Louis, 1996, Mosby. This table shows the recognized CD markers of hemopoietic cells and their distribution. A filled rectangle or + means cell population present; a half-filled triangle is subpopulation; *, activated cells only; **, markers that identity or are critical to the cell type.

74. Normal Blood Cell Counts From Abbas AK, Lichtman AH, Pober JS: Cellular and molecular immunology, ed 4, Philadelphia, 2000, WB Saunders.

76. Cytokines & Chemokines

77. Cytokines & Chemokines

78. Cytokines & Chemokines

80. Figure 11-2 Organs of the immune system. Thymus and bone marrow are primary lymphoid organs. They are sites of maturation for T and B cells, respectively. Cellular and humoral immune responses develop in the secondary (peripheral) lymphoid organs and tissues; effector and memory cells are generated in these organs. The spleen responds predominantly to blood-borne antigens. Lymph nodes mount immune responses to antigens in intercellular fluid and in the lymph, absorbed either through the skin (superficial nodes) or from internal viscera (deep nodes). Tonsils, Peyer's patches, and other mucosa-associated lymphoid tissues (blue boxes) respond to antigens that have penetrated the surface mucosal barriers. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

81. Human Lymphoid System

82. Thymus

86. Thymus Diagrammatic cross section ofa portion of the thymus, showing several lobules separated by connective tissue strands (trabeculae). The densely populated outer cortex contains many immature thymocytes (blue), which undergo rapid proliferation coupled with an enormous rate of cell death. The medulla is sparsely populated and contains thymocytes that are more mature. During their stay within the thymus, thymocytes interact with various stromal cells, including cortical epithelial cells (light red), medullary epithelial cells (tan), dendritic cells (purple), and macrophages (yellow). These cells produce regulatory factors and express high levels of class I and class II MHC molecules. Hassall’s corpuscles, found in the medulla, contain concentric layers of degenerating epithelial cells. [Adapted with permission from W.van Ewijk, 1991, Annual Review of Immunology 9: 591 by Annual Reviews.]

88. Changes in the Thymus with Age

90. Figure 13-1 Human T-cell development. T-cell markers are useful for the identification of the differentiation stages of the T cell and for characterizing T-cell leukemias and lymphomas. Tdt, Cytoplasmic terminal deoxynucleotide transferase. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

91. Figure 13-4 Structure of the embryonic T-cell receptor (TCR) gene. Note the similar approach to generation of a diverse recognition repetoire as for the immunoglobulin genes. Downloaded from: StudentConsult (on 16 December 2007 01:29 PM) © 2005 Elsevier

92. Bone Marrow

95. Blood cells are produced in bone marrow where fighter cells are trained or sent to the thymus gland.

97. Structure of a Lymph Node The three layers of a lymph node support distinct microenvironments.

98. Structure of a Lymph Node . The left side depicts the arrangement of reticulum and lymphocytes within the various regions of a lymph node. Macrophages and dendritic cells, which trap antigen, are present in the cortex and paracortex. T H cells are concentrated in the paracortex; B cells are primarily in the cortex, within follicles and germinal centers. The medulla is populated largely by antibody-producing plasma cells. Lymphocytes circulating in the lymph are carried into the node by afferent lymphatic vessels, they either enter the reticular matrix of the node or pass through it and leave by the efferent lymphatic vessel. The right side depicts the lymphatic artery and vein and the postcapillary venules. Lymphocytes in the circulation can pass into the node from the postcapillary venules by a process called extravasation (inset)

99. Figure 11-3 Organization of the lymph node. Beneath the collagenous capsule is the subcapsular sinus, which is lined with phagocytic cells. Lymphocytes and antigens from surrounding tissue spaces or adjacent nodes pass into the sinus via the afferent lymphatic system. The cortex contains aggregates of B cells (primary follicles), most of which are stimulated (secondary follicles) and have a site of active proliferation or germinal center. The paracortex contains mainly T cells and dendritic cells (antigen-presenting cells). Each lymph node has its own arterial and venous supplies. Lymphocytes enter the node from the circulation through the specialized high endothelial venules in the paracortex. The medulla contains both T and B cells, as well as most of the lymph node plasma cells organized into cords of lymphoid tissue. Lymphocytes can leave the node only through the efferent lymphatic vessel. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

100. Structure of the Spleen The spleen, which is about 5 inches long in the adult, is the largest lymphoid organ. It is specialized for trapping blood-borne antigens. Diagrammatic cross section of the spleen. The splenic artery pierces the capsule and divides into progressively smaller arterioles, ending in vascular sinusoides that drain back into the splenic vein. The erythrocyte-filled red pulp surrounds the sinusoids. The white pulp forms a sleeve, the periarteriolar lymphoid sheath (PALS), around the arterioles; this sheath contains numerous T cells. Closely associated with PALS is the marginal zone, an area rich in B cells that contains lymphoid follicles that can develop into secondary follicles containing germinal centers.

101. Figure 11-4 Organization of lymphoid tissue in the spleen. The white pulp contains germinal centers and is surrounded by the marginal zone, which contains numerous macrophages, antigen-presenting cells, slowly recirculating B cells, and natural killer cells. The red pulp contains venous sinuses separated by splenic cords. Blood enters the tissues via the trabecular arteries, which give rise to the many-branched central arteries. Some end in the white pulp, supplying the germinal centers and mantle zones, but most empty into or near the marginal zones. PALS, Periarteriolar lymphoid sheath. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

102. Mucosa Associated Lymphoid Tissue (MALT) Cross-sectional diagram of the mucous membrane ling the intestine, showing a Peyer’s patch lymphoid nodule in the submucosa. The intestinal lamina contains loose clusters of lymphoid cells and diffuse follicles.

103. Mucosa Associated Lymphoid Tissue (MALT) Structure of the M cells and production of Ig A at inductive sites. M cells,situated in mucous membranes, endocytose antigen from the lumen of the digestive, respiratory, and urogenital tracts. The antigen is transported into the large basolateral pocket.

104. Mucosa Associated Lymphoid Tissue (MALT) Antigen transported across the epithelial layer by M cells at an inductive site activates B cells in the underlying lymphoid follicles. The activated B cells differentiate into IgA-producing plasma cells, which migrate along the submucosa. The outer mucosal epithelial layer contains intraepithelial lymphocytes, of which are T cells.

105. Figure 11-5 Lymphoid cells stimulated with antigen in Peyer's patches (or the lungs or another mucosal site) migrate via the regional lymph nodes and thoracic duct into the bloodsteam, then to the lamina propria of the gut and probably other mucosal surfaces. Thus lymphocytes stimulated at one mucosal surface may become distributed throughout the MALT (mucosa-associated lymphoid tissue) system. IgA, Immunoglobulin A. (From Roitt I et al: Immunology, ed 4, St Louis, 1996, Mosby.) Downloaded from: StudentConsult (on 16 December 2007 01:16 PM) © 2005 Elsevier

106. Bronchus Associated Lymphoid Tissue (BALT)

107. Cutaneous Associated Lymphoid Tissue (CALT) The skin is the largest organ in the body and plays an important role in nonspecific (innate ) defences. The epidermal (outer) layer of the skin is composed of specialized cells called keratinocytes. These cells secrete a number of cytokines that may function in local inflammatory reaction. Scattered among the epithelial-cell matrix of the epidermis are Langerhann’s cells, atype of dendritic cell, which internalize antigen by phagocytosis or endocytosis. They undergo maturation and migrate from the epidermis to regional lymph nodes, where they function as potent activators of naïve T H cells. In addition to Langerhans cells, the epidermis also contaions so-called intraepidermal lymphocytes, which are mostly T cells. The underlying dermal layer of the skin also contains scattered T cells and macrophages. Most of these dermal cells appear to be either previously activated cells or memory cells.

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