Immunology 146:474

1. Immunology 146:474 • Tu, Fri 1st period (8:40-10:00 AM) • SRC 118 • Dr. Lori Covey • Dept. of Cell Biology & Neuroscience Nelson Hall, B314 • covey@biology.rutgers.edu • Class web site: http://lifesci.rutgers.edu/~covey/Immuno/index.htm

2. Concepts to be covered today • Properties of innate and adaptive immunity • Different cell types involved in each type of immunity • Lymphoid tissues • Function of each lymphoid tissue

3. Innate Derived from primordial immune responses First line of protection Immediate No memory Adaptive Antigen-specific Delayed Development of immunological memory 2 functional arms Humoral Ab-mediated Cell-mediated-primarily CD8+ T cells Types of immunity“The state of protection from infectious disease”

4. Innate Immunity • Components present before onset of infection • Disease-resistance mechanisms that are not specific to a particular pathogen • Pathogens must first breach barriers that protect hosts

5. Pattern Recognition • Many of the molecules involved in innate immunity have property of pattern recognition • Patterns unique to microbes not found in multicellular organisms • May be soluble molecules (lysozyme or complement proteins) or cell-associated receptors (Toll-like receptors (TLRs)

6. Natural Barriers to infections • Skin • Mucosal membranes • Acidity of the stomach & perspiration • Lysozyme in tears • Barrier loss occurs in response to bites by animals, insects, burns, cuts, etc…

7. Innate Immunity • Provides the first line of defense right after exposure • Most microorganisms are readily cleared within a few days by innate immune system before adaptive immune system is activated.

8. Adaptive Immunity • Comes into play after there is a recognized antigenic challenge to the organism • Not the same in all members of a species but are reactions to specific antigenic challenges • 4 characteristic attributes • Antigenic specificity • Diversity • Immunological Memory • Self-non-self recognition

9. Adaptive Immunity • Humoral Immune responses mediated by serum antibodies produced by B lymphocytes, I.e. the effector molecule is the antibody molecule • Cell-Mediated Responses depends on the function of T cells • Depends on both T helper (TH) and cytotoxic T lymphocytes (CTLs) serve as effector cells

10. Stem Cells • Differentiate into all other cell types • Self-renewing, maintaining their population level by cell division • In humans, begins in embryonic yolk sac during first weeks of development • By 3rd month, stem cells have migrated from ys to fetal liver and then colonize the spleen (hematopoesis from 3-7 months)

11. Hematopoiesis

12. Figure 1-3 part 1 of 4 The Hematopoietic system develops in the bone Marrow Ability for self-renewal Give rise to all classes of cells CMP CLP

13. Figure 1-3 part 2 of 4

14. Figure 1-3 part 3 of 4

15. Purification of Bone marrow stem cells Take bone marrow Stem cell Stem cells <0.05% of cells Differentiation Antigen-Stem cell antigen 1 or Sca-1

16. Bone marrow reconstitution Reconstitute Irradiated mouse with Bone marrow from Genetically identical (syngeneic) Mouse. The Complete Hematopoietic system is restored. Take spleen Take bone marrow or Sca1+ cells

17. Mononuclear phagocytes Monocytes (blood)--> migrate to tissues and differentiate, Cell enlarges 5-10-fold Acquires increased phagocytic ability Specific tissue macrophage Intestinal macrophage (gut) aveolar macrophages (lungs) histiocytes (connective tissues) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain) Osteoclasts (bone)

18. Dendritic cells Extensions that resemble Dendrites Four Major Categories Langerhans DCs epidermal layers of skin Interstitial DCs interstitial spaces of all tissues except brain Monocyte-derived DCs migrated from blood to tissues Plasmacytoid-derived DCs arise from plasmacytoid cells

19. Figure 1-4 part 1 of 3

20. Granulocytic Cells • Neutrophils-ciruculate 7-10 h before migrating into the tissues (short life span approx. 2 days), Usually first cells to arrive at site of infections-are phagocytes • Eosinophils-motile phagocytic cells, defense of parasitic organisms • Basophils-non-phagocytic granulocytes

21. Figure 1-4 part 2 of 3

22. Granulocytic Cells… Basophils-non-phagocytic granulocytes, release pharmacologically active substances from their cytoplasmic granules-Allergy Mast Cells-precursors are formed in the Bone Marrow, released into the blood as undifferentiated cells Differentiate when they leave the blood and enter the tissues Large nos. of cytoplasmic granules that contain histamine and other pharmacologically active substances, play important role in allergy

23. Figure 1-4 part 3 of 3

24. B lymphocytes • Display membrane-bound immunoglobulin or antibody-serve as receptors for antigen (ag) • Once ag is encountered, B cells differentiate into plasma cells or memory B cells; plasma cells produce lg amounts of Ab but have a short life span-end stage cell.

25. B lymphocytes… • Memory B cells, very long-lived, express same membrane-bound Ig as parent cell.

26. T lymphocytes (T cells) • Mature in the thymus • Expresses a membrane-bound receptor called T cell receptor (TCR) • Two well-defined subpopulations • T helper (TH) • T cytotoxic (TC) Recent subpop. Termed T regulatory (Treg)

27. T lymphocytes (T cells)… • TH cells generally express CD4 • TC cells generally express CD8 • Ratio in human blood of CD4:CD8 is approx. 2:1 • Primary function of TH cells is to help other cells produce an immune response suggest as B cells, macrophage, Tc cells.

28. T lymphocytes (T cells)… • TC cells kill virally infected cells • Tregs, suppress immune responses • Once activated, T cells become either effector cells or memory cells

29. Resting T or B lymphocyte

30. Figure 1-6

31. Maturation of the immune response • Lymphoid organs are separated into primary and secondary organs • Primary--> bone marrow, thymus • Secondary or peripheral--> lymphnodes, spleen, mucosal lymphoid tissues (GALT, MALT), provide sites for mature lymphocytes to interact with antigen

32. Ti Different organs of the immune system Figure 1-7

33. The role of bone marrow in immune maturation • Microenvironment for differentiation of stem cells • Site of origin of B and T lymphocytes, all other cells of the immune response • “Antigen-independent” maturation of B cells. • Site for mature re-circulating lymphocyte populations

34. Bone Marrow • Cells move out of Bone Marrow into blood • The bursa in the bird plays the same role for B cell maturation; appendix in rabbit

35. Primary immune tissue Located in the thorax Sequestered from antigen Two lobes, surrounded by a thin capsule of connective epithelium Involutes with Age- maximal size at puberty and then atrophies The thymus is the site of T cell differentiation

36. Thymus-structure/function • Thymic stroma--> network of epithelia-contains T cell precursors. • Dendritic cells, macrophage and medullary epithelial cells in thymic medulla • Sub-capsular epithelium underlying capsule-acts as barrier tr cortex m HC

37. Lymphatic System • Blood circulates under pressure, fluid component (plasma) seeps through capillaries into surrounding tissues • Called interstitial fluid • An adult-3 liters or more per day • Returned to blood through walls of the venules (prevents edema) • Remainder of fluid enter lymphatic system

38. Lymphatic System… • Porous architecture of lymphatic vessels (allows fluids and cells to enter) • Thoracic duct = largest lymphatic vessel • Empties into L. subclavian vein (lymph from all the body except r. arm and r. side of head) • Ensures steady-state levels of fluid within the circulatory system

39. Lymphatic System… • Heart does not pump lymph • Lymph flow is achieved by movements of the body’s muscles • Series of one-way valves produces one-way movement through vessels • Foreign antigen is picked up by the lymphatic system and carried to lymph nodes

40. Circulation of lymphocytes in response to infection

41. Peripheral or Secondary lymphoid tissues • Trap antigen-bearing dendritic cells • Initiation of adaptive immune response • Provide signals that sustain recirculating lymphocytes

42. Lymph Nodes • Sites of Immune responses • Encapsulated bean-shaped structures, reticular network, full of lymphocytes, macrophages, and dendritic cells. • First organized lymphoid structure to encounter antigens-reticular structures trap antigen • Morphologically divided • Cortex • Paracortex • medulla

43. Lymph Nodes • Cortex • Contains mostly B cells, macrophages and follicular dendritic cells • Paracortex • Primarily T lymphocytes, and dendritic cells • Medulla • Sparsely populated with lymphoid lineage cells (mostly plasma cells)

44. Structure/function of the Lymph Node Figure 1-8 part 1 of 2

45. Figure 1-8 part 2 of 2 Structure/function of the Lymph Node Germinal center foci Reach maximum Size within 4 to 6 days of antigen challenge. capsule Med. sinus Paracortical GC

47. Spleen • Major role in mounting immune responses to antigens in the bloodstream • Filters blood and traps antigens • Not supplied with lymphatic vesicles • Splenic artery carries antigens and lymphocytes

48. Structure of the Spleen • Surrounded by a capsule from which a number of trabeculae extend into interior (compartmentalized structure)

49. Structure of the Spleen • Spenic red pulp consists of a network of sinusoids • Populated by macrophages, RBCs, and a few lymphocytes • Site where old and defective RBCs are destroyed and removed • Macrophage engulf RBCs

50. Structure of the Spleen… • Spenic white pulp surrounds the branches of the splenic artery • Forms periarteriolar lymphoid sheath (PALS), populated primarily by T cells. • Primary lymphoid follicles are attached to the PALS, are rich in B cells and some contain germinal centers • Marginal zone, peripheral to the PALS, is populated by lymphocytes and macrophages