Immunology 146:474

1. Immunology 146:474 • Tu, Fri 1st period (8:40-10:00 AM) • Serc 118 • Dr. Lori Covey-Office hrs: 9-10:30 Thursday • Dept. of Cell Biology & Neuroscience Nelson Hall, B314 • covey@biology.rutgers.edu • Class web site: http://lifesci.rutgers.edu/~covey/Immuno/index.htm

2. Resting T or B lymphocyte

3. Figure 1-6

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Circulation of lymphocytes in response to infection

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

15. 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

16. 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)

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

18. 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

20. 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

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

22. 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

23. 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

24. Organization of the White Pulp in the Spleen

25. Organization of a germinal center in the spleen • PFZ-perifollicular zone • PALS-periarticular lymphoid sheath • Co-follicular B-cell corona • MZ-marginal zone • RP-red pulp

26. Loss of spleen (splenectomy) • Severity depends on age • In children, splenectomy often leads to increased incidence of bacterial sepsis • Few adverse effects in adults, can lead to some increase in blood-borne bacterial infections (bacteremia)

27. MALT or Mucosa-assoc. Lymphoid Tissue • Mucous membranes lining digestive, respiratory and urogenital system are the major sites of entry for most pathogens. BALT -Bronchus-associated (respiratory) GALT-gut-associated (digestive tract)

28. MALT… • Have different organizations. • Peyer’s patches in intestinal lining well organized • Barely organized clusters of lymphoid cells in lamina propria of intestinal villi • Tonsils • appendix • Large nos. of plasma cells (more than in the spleen and lymph Nodes)

29. Figure 1-10 part 1 of 2

30. epithelium Gut lumin dome T-cell area GC follicle

31. Antigen transport carried out by specialized cells called M Cells. Flattened epithelial cells lacking microvilli M cells have deep invagination which is filled with B, T cells And Macrophage. dome GC follicle

32. M Cells. Have a deep invagination or pocket, in the basolateral plasma membrane, which is filled with a cluster of B cells, T cells and Macrophage. Antigens in intestinal lumen are endocytosed into vesicles and Transported from the luminal membrane to underlying pocket Membrane Vesicles fuse with the pocket membrane, delivering antigens To lymphocytes and macrophage

33. Epithelial surfaces-largest barrier to infection Skin Epithelial surfaces of the: Gastronintestinal tract Urogenital tract Respiratory tract

34. Cutaneous-Associated Lymphoid Tissues. Skin-anatomic barrier to the external environment. Surface-kertinocytes-secrete cytokines that set up local inflam- Matory reactions Langerhans cells-type of Dendritic cell-antigens are phago- cytosed Migrate from skin to lymphnodes Intraepidermal lymphocytes-mostly T cells Dermal layer also contains scattered T cells and macrophage

35. Different phases of an immune response innate

36. Pathogens enter the body through mucosal and epithelial tissue

37. Figure 2-2 part 2 of 2

38. Internal epithelia = mucosal membranes Secrete mucins-prevent adherence of microorganisms. Mucus flow driven by beating of epithelial cilia Tears and saliva contain lysozyme and histatins pH of the stomach and digestive enzymes Alpha and beta-defensins-antimicrobial peptides Fixed Defenses of the immune response

39. Distinction between pathogens that replicate in spaces between human cells and within cells • Extracellular forms of pathogens • Accessible to soluble molecules of the immune system • Intracellular pathogens attacked by killing infected cells • Both types can be attacked by antibodies at some point

40. Receptors involved in the adaptive immune response • Immunoglobulin receptor (B cell receptor) or antibody molecule • T cell receptor (TCR) • CD4 and CD8 co-receptors • MHC class I and class II receptors

41. Blood can be separated in a centrifuge into a fluid and a cellular fraction. The fluid fraction is the plasma and the Cellular fraction contains red blood cells, leukocytes, and platelets. Plasma contains all of the soluble small molecules and macromolecules of blood. If the blood or plasma is allowed to clot, the fluid phase that remains is called serum. Antibodies reside in the serum, separated by electrophoresis-->saw four distinct peaks Albumin, alpha () globulin, beta () globulin and gamma () globulin

42. Figure 1-16 Structure of an antibody molecule two distinct parts-Antigen recognition and effector function. MATURE, naïve or resting B CELL

43. Structure of an Ab molecule

44. Structure of Ab molecules, cont’d • Each Ab molecule is composed of 4 polypeptide chains • 2 identical heavy chains and two identical light chains • L chains are linked to H chains and H chains to each other via disulfide bonds

45. Structure of Ab molecules, cont’d • Light chains are either of lambda () type of kappa () type. Encoded at different loci in the DNA • Light chain polypeptide is designated: VLCL

46. Ig heavy chains • IgG most abundant- in humans have 4 IgG subclasses- IgG1, IgG2, IgG3 and IgG4 • Confer effector function of the molecule

47. Structure of the Ab molecule Protease papain cleaves Ab-->2(Fab) and Fc region Fab= “fragment antigen binding”, Fc= “Fragment chrystallization”

48. Structure of the Ab molecule Protease pepsin cleaves Ab molecule into F(ab’)2 + pFc’

49. Classes or “Isotypes” of immunoglobulins • Antibody (Ab) = immunoglobulin (Ig) • Each B cell expresses a unique Ig • The “C” part of the antibody molecule is conserved among classes of antibodies

50. Antibody Isotypes, cont’d • An isotype refers to the class of heavy chain polypeptides • isotypes, IgM, IgD, IgG, IgA and IgE. Heavy chain polypeptide is designated: VHCH Mature, naïve or resting B cells express only IgM and IgD on their surfaces