#4 Anatomy of the Immune System II

1. #4 Anatomy of the Immune System II 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. Lymphoid organs • Primary (central) • Secondary (peripheral)

3. Primary lymphoid tissues • Lymphocytes are generated and differentiate into mature lymphocytes • Bone marrow for B cells • Thymus for T cells • Secondary lymphoid tissues • Tissues in which lymphocytes are brought with antigen and adaptive immune responses are initiated • Lymph nodes, spleen, Peyer’s patches

4. Adaptive immunity

5. The adaptive responses are divided into humoral vs. cell-mediated immunity CD4 CD8 (Th cell) (CTL) Figure 1-2: Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that prevent infections and eliminate extracellular microbes. In cell-mediated immunity, helper T lymphocytes activate macrophages to kill phagocytosed microbes, or cytotoxic T lymphocytes directly destroy infected cells.

6. CD: cluster of differentiation • The basis of a system for identifying cell surface molecules of immune cells • Each molecule is given a specific number prefixed by CD • Each molecules is usually recognized by a group (=cluster) of monoclonal antibodies • Used to classify cells • CD3; T cell • CD4; helper T (Th) cell • CD8; cytotoxic T cell or lymphocyte (CTL) • CD20; B cell

7. The key stages of lymphocyte differentiation (naïve, effector and memory cells) naïve lymphocytes are called small “resting” cells T lymphocytes B lymphocytes naïve B cells naïve CD4 T cells naïve CD8 T cells naive plasma cells helper T cells cytotoxic T cells (Th1, Th2) (CTL) effector memory memory B cells memory CD4 T cells memory CD8 T cells

8. Naïve lymphocytes re-circulate until they encounter their specific antigen Figure 2-5: Maturation of lymphocytes. Lymphocytes develop from bone marrow stem cells, mature in the generative lymphoid organs (bone marrow and thymus for B and T cells, respectively), and then circulate through the blood to secondary lymphoid organs (lymph nodes, spleen, regional lymphoid tissues such as mucosa-associated lymphoid tissues). Fully mature T cells leave the thymus, but immature B cells leave the bone marrow and complete their maturation in secondary lymphoid organs. Naive lymphocytes may respond to foreign antigens in these secondary lymphoid tissues or return by lymphatic drainage to the blood and recirculate through other secondary lymphoid organs.

9. Naïve B cells that encounter antigen differentiate into effector B cells (plasma cells) that secrete antibodies to protect against infection or memory B cells

10. Lymphocyte Plasma cell

11. Three classes of effector T cells to deal with multiple types of pathogens Stimulate antibody production to facilitate elimination of extracellular pathogens. Stimulate macrophages to kill intracellular pathogens. Kill infected cells displaying foreign antigen, typically virus infected cells.

12. 1-5 Major Histocompatibility Complex (MHC) Molecules and the Detection of Infection • T cells do not interact directly with intact antigen • T cells recognize fragments of antigen carried to the cell surface by MHC molecule • Two classes of MHC

13. Tissue Distribution Most cells Function Antigen presentation to CD8 + T cells Intracellular (cytoplasmic) antigen T cell responses initiate from interaction with antigen + MHC molecules MHC class I MHC class II Tissue Distribution • APCs • Macrophages • Dendritic cells • B cells • Thymic epithelium Function • Antigen presentation to CD4+ T cells • Extracellular (internalized) antigen MHC = major histocompatibility complex

14. Antigen presenting cells (APCs) APCs present antigen to CD4+ T cells on MHC class II molecules

15. T cell responses initiate from interaction with antigen + MHC molecules

16. Recognition of viral antigen and MHC class I molecules by CD8+ cytotoxic T cells

17. Recognition of internalized bacterial antigen and MHC class II molecules on APCs by CD4+ T cells

18. CD4+ helper T (Th)1 cells recognize fragments of bacteria internalized by macrophages • Th1 cells activate macrophage to destroy the internalized bacteria • CD4+ Th2 cells recognize antigen fragments internalized by B cells • Th2 cells activate B cell to proliferate and differentiate into an antibody-secreting plasma cells

19. Two waves of the immune response The innate immune response participates in activation of the adaptive immune response

20. The innate immune response and the adaptive immune response meet in the secondary lymphoid organs The innate immune response participates in activation of the adaptive immune response

21. The production of T-cell immune effector responses requires the cooperative function of both secondary and tertiary lymphoid sites Fundamental Immunology 4th edition chapter 10 Fig. 10

22. Initiation of adaptive immunity The entire process is initiated by the capture of antigen by APC, and the subsequent presentation of the antigen (on MHC molecules) to T cells

23. Naïve lymphocyte: • mature T or B cells that have never encountered foreign antigen • die after 1 to 3 months if they do not recognize antigens • Lymphocytes mature in the bone marrow (B cells) and thymus (T cells) and enter secondary lymphoid organs as naive lymphocytes • Antigens are captured by dendritic cells and concentrated in lymph nodes, where they activate naïve lymphocytes • Effector T cells develop in the lymph nodes, enter the circulation, and migrate to peripheral tissues

24. IV_8_2_Dendritic_Migration-H264 Janeway’s Immnobiology

25. Secondary lymphoid organs Peripheral Lymph Nodes(500-600 in humans) • connected to lymphatic network • drain peripheral tissues – migration of antigen / APCs into LNs • compartments optimize antigen / lymphocyte interactions

26. The lymphatic system The lymphatic system collects extracellular fluid from tissues and returns it to the blood. The fluid is continuously produced by filtration from the blood. It passes through the lymph nodes, drains into the thoracic duct and is then returned to the blood.

27. The lymphatic system Peripheral LNs are located at the points of convergence of lymphatic vessels. Afferent lymphatic vessels drain fluid from the tissues into the LN. Activated lymphocytes leave the LNs in the lymph fluid, which exits via the efferent lymphatic vessels to return to the blood.

28. Antigens are captured from a site of infection, and transported to the draining lymph node, where the immune response is initiated Figure 2-11: The lymphatic system. The major lymphatic vessels, which drain into the inferior vena cava (and superior vena cava, not shown), and collections of lymph nodes are illustrated. Antigens are captured from a site of infection and the draining lymph node to which these antigens are transported and where the immune response is initiated.

29. http://study.com/academy/lesson/functions-of-the-lymphatic-system.htmlhttp://study.com/academy/lesson/functions-of-the-lymphatic-system.html

30. In tissues, dendritic cells pick up antigen, then migrate to regional lymph nodes via lymphatics.

31. The lymph nodes are the sites where the lymph and blood circulatory pathways come together

32. Peripheral lymph node structure cortex medulla LNs are highly organized structures that are specialized to trap APCs for presentation of antigen to circulating lymphocytes. B cells are organized in follicles (some are germinal centers). T cell are diffusely distributed in the paracortical areas – T cell zones.

33. Lymphocytes move from circulation into the lymph node via extravasation in the post-capillary venules

34. Lymphocytes move from circulation into the lymph node via extravasation in the post-capillary venules The venules located in lymphoid organs are lined with specialized endothelial cells. Thus the vessels are termed “high endothelial venules (vessels)” or HEVs.

35. Lymphocytes move from circulation into the lymph node via the post-capillary venules called high endothelial venules (HEV) • HEVs display certain adhesion molecules and chemokines on their surfaces Chemokine: small cytokines whose main function is as chemoattractants

36. A naïve T cells extravasates through HEVs using a process termed ‘diapedesis’ Adhesion receptors and chemokines mediate this process

37. The lymph node is designed to bring T and B cells into contact with APCs

38. Naïve T and B cells enter the node through HEV • Dendritic cells • T cell zone • Resident cells capture antigen entering through the afferent lymphatic vessels • Dendritic cells in the periphery migrate into the lymph node • Follicular dendritic cells • B cell areas • Capture antigen for B cell recognition

39. B cells are in follicles • Proliferating B cells are concentrated in the germinal center • T cells in the paracortical area

40. IV_10_5_Germinal_Centers Janeway’s Immunobiology

41. Figure 2-12: Morphology of a lymph node. A, Schematic diagram of a lymph node illustrating the T cell–rich and B cell–rich zones and the routes of entry of lymphocytes and antigen (shown captured by a dendritic cell). B, Light micrograph of a lymph node illustrating the T cell and B cell zones.

42. Naïve T and B cells enter through an artery, and are drawn to different areas of the node by chemokines • Dendritic cells enter through afferent lymphatic vessels, and migrate to the T cell-rich area

43. III_7_2_Lymph_Node_DevJaneway’s Immunobiology

44. Peripheral Lymph Node Structure

45. IV_10_1_The_Immune_Response-H264 Janeway’s Immunobiology

46. Secondary lymphoid organs Spleen(1) • acts as a filter of antigen from the blood • white pulp is structurally similar to peripheral LNs • compartments optimize antigen/lymphocyte interactions

47. Blood borne antigens are picked up by antigen presenting cells (eg, macrophages, dendritic cells) in the spleen

48. Spleen structure The spleen functions as a ‘filter’ for the blood – removes pathogens, collects antigens for presentation, and collects/disposes of old RBCs. The bulk of the spleen is the red pulp – the site of RBC disposal. Lymphoid cells are organized in the white pulp.

49. The spleen is the major site of immune responses to blood-borne antigens • White pulp • Lymphocyte-rich region • Periarteriolar lymphoid sheaths around central arteries: T cell zone • B cell zone • Marginal zone • Marginal zone B cell • Red pulp • Erythrocytes, macrophages, dendritic cells, lymphocytes, plasma cells

50. Spleen structure • Antigens enter the spleen via arterioles (instead of lymphatics) • Sinuses pass through the white pulp where the lymphocytes reside. • Antigens are trapped in the marginal zone by resident APCs. • Lymphocytes and antigen meet in the periarteriolar lymphoid sheath (PALS).