Introduction to Immunology Dr. Ofer Mandelboim

1. Introduction to Immunology Dr. Ofer Mandelboim Portions adapted from Drs. David J. Topham and Colin R.A. Hewitt, web sites, ImmunoBiology by Janeway & Travers

2. What you should be aware of by the end of this lecture •  The basic terms used in immunology •  The characteristics and interdependence of adaptive and innate immunity •  The types and functions of cells in the immune system •  The structure and function of peripheral lymphoid organs • The purpose of lymphocyte recirculation •  How cells communicate and recognize antigen •  The concept of clonal distribution of antigen receptors

3. Edward Jenner, “ the founder of modern immunology” 1796- Introduction of protective vaccine against small pox: based on cow pox (in Latin - vaccinia )

4. Koch’s Postulates Metchnikoff Phagocytosis Kohler & Milstein Monoclonal Abs Miller T cells Jansen Microscope Müller Bacteria Jenner Vaccination Wright Antisera 200 years after Jenner WHO announce smallpox eradicated 1600 1700 1800 1900 2000 30 1955 Countries with more than one smallpox case per month 15 0 1965 1970 1975 1980 History & impact of immunology on human health

5. Reminder of basic immunological terms •ANTIGENS (Ag) aresubstances recognized by: •ANTIBODIES (Immunoglobulin, Ig, Ab) and • T LYMPHOCYTES (T CELLS) Antibodies are made by B CELLS T HELPER (Th)cells help B cells make antibodies: CYTOTOXICT cells(CTL) kill infected cells

6. Barriers Innate immunity Adaptive immunity Invasion & infection + Inflammation + Immune responses Skin & Mucous membranes rapidly regenerating surfaces, peristaltic movement, mucociliary escalator, vomiting, flow of urine/tears, coughing Cellular and humoral defenses lysosyme, sebaceous/mucous secretions, stomach acid, commensal organisms,complement proteins, phagocytosis, NK cells Cellular and humoral defenses Antibodies, cytokines, T helper cells, cytotoxic T cells

7. Innate immune response Inbuilt immunity to resist infection • Not antigen-specific (except from NK cells) • Not enhanced by second exposure • Has no memory • Uses cellular and humoral components • Is poorly effective without adaptive immunity Also involved in the triggering and amplification of adaptive immune responses

8. Adaptive immunity Immunity adapted to infection • Is antigen-specific • Learned by experience • Enhanced by second exposure • Has memory • Uses cellular and humoral components • Is poorly effective without innate immunity Immune memory reflects infections to which an individual has been exposed

9. Leucocytes Innate immunity is mediated largely by GRANULOCYTES Adaptive immunity mediated by LYMPHOCYTES The growth, development and activities of granulocytes and lymphocytes are interconnected and often co-operative.

10. Lymphocyte Adaptive immunity Macrophage Monocyte (* DC) Neutrophil (PMN) Eosinophil (PMN) Basophil (PMN) Mast cell Phagocytosis Ag presentation Phagocytic Anti-bacterial Anti-parasite immunity ?Protection of mucosal surfaces? Protection of mucosal surfaces Common lymphoid progenitor Pluripotent haemopoietic stem cell Myeloid progenitor Cells Of The Immune System

11. CLP T CELLS B CELLS Common lymphoid precursor T B Th CTL PC Activate B cells and macrophages T HELPER CELLS Kill virus- infected cells CYTOTOXIC T LYMPHOCYTES Produce antibodies PLASMA CELLS Lymphocyte subsets *DC, *NK

12. EOSINOPHIL RED BLOOD CELLS Cells of the blood NEUTROPHILS MONOCYTE BASOPHIL LYMPHOCYTES

14. MACROPHAGE Lymphocytes on the move Direction of travel

15. Lymphoid organs Organized tissue in which lymphocytes interact with non-lymphoid cells Sites of maturation & initiation of adaptive immune responses Central: THYMUS – T cell maturation BONE MARROW – B cell maturation Peripheral: LYMPH NODES SPLEEN PEYERS PATCHES T and B cell activation Antigen trapping

16. Lymph node 4. Germinal centre (site of intense B cell proliferation) 5. Medullary cords (Macrophage & plasma cell area) 3. Secondary lymphoid follicle 6. Efferent lymphatic vessel 2. Primary Lymphoid follicle (B cell area) Artery Paracortical (T cell) area Vein 1. Afferent lymphatic vessel. Lymph, Cells & Ag drained from tissues enters here Medullary sinus

17. LYMPH NODE HISTOLOGY Germinal centers Macrophage Lymphocytes

18. Spleen white pulp Transverse section Marginal sinus B cell corona Red pulp Germinal centre Marginal zone T cell area Central arteriole

19. Spleen white pulp Marginal sinus Red pulp Germinal centre T cell area Marginal zone Central arteriole

20. Lymphocyte recirculation NAIVE LYMPHOCYTES circulate from the blood into lymph nodes through high endothelial venules (HEV) EFFECTOR CELLS exit lymph nodes and traffic to inflamed tissue. MEMORY LYMPHOCYTES re-circulate from blood into tissue, and then into lymph nodes through afferent lymphatics. Some may reside in tissue.

21. LYMPHOCYTE RECIRCULATION Arterial circulation High Endothelial Venule LYMPH NODE Efferent Lymphatic SPLEEN Afferent lymphatic Venous circulation Dendritic Cell (APC)

23. CD62L (L-selectin) Integrins LFA-1 VLA-4 VLA-1 CD44 Lymph node homing Vascular endothelium ICAM-1 VCAM ECM Tissue binding (ECM) ADHESION MOLECULES IMPORTANT TO LYMPHOCYTE RECIRCULATION

24. T and B cells are essentially inactive until they encounter antigen. T and B cells express ANTIGEN RECEPTORS Lyc The B cell antigen receptor is a membrane-bound antibody SURFACE IMMUNOGLOBULIN *Antibodies recognize intact antigens B The T cell antigen receptor is a heterodimer of alpha and beta chains T CELL RECEPTOR (TCR) *TCR’s recognize peptide antigens presented by MHC molecules T Lymphocyte antigen receptors Each antigen receptor binds to a unique epitope

25. Major Histocompatibility Complex – MHC In mice the MHC is called H-2 Rapid graft rejection segregated with a cell surface antigen, Antigen-2 Inbred mice identical at H-2 did not reject skin grafts from each other MHC genetics in mice is simplified by inbred strains In humans the MHC is called the Human Leukocyte Antigen system – HLA Only monozygous twins are identical at the HLA locus The human population is extensively outbred MHC genetics in humans is extremely complex

26. MHC class I MHC class II Peptide Peptide binding groove Cell Membrane MHC molecules b2M

27. a-chain a-chain Peptide b-chain Peptide b2-M Cleft geometry MHC class I accommodate peptides of 8-10 amino acids MHC class II accommodate peptides of 12-20 amino acids

28. Differential distribution of MHC molecules Tissue MHC class I MHC class II T cells +++ +/- B cells +++ +++ Macrophages +++ ++ Other APC +++ +++ Epithelial cells of thymus + +++ Neutrophils +++ - Hepatocytes + - Kidney + - Brain + - Erythrocytes - - Cell activation affects the level of MHC expression The pattern of expression reflects the function of MHC molecules: Class I is involved in anti-viral immune responses Class II involved in activation of other cells of the immune system

29. MHC molecules sample both the intracellular and extracellular environments

30. MHC Summary: T Cells recognize a combination of MHC and peptide contact points • T cells can only be activated by interaction between the antigen receptor and peptide antigen in an MHC molecule • Without T cells there can be no effective immune response • MHC molecules • • Present antigens to T cells • • Sample extracellular and intracellular antigens • Class I MHC present intracellular antigens • Class II MHC present extracellular antigens • Use anchor residues to tether the peptide • Fold around the peptide to create a stable complex

31. Clonal nature of the adaptive immune response Each lymphocyte expresses a single antigen receptor specificity. There are millions of lymphocytes in the body, and thus millions of different antigen receptors. Each naive lymphocyte bearing a unique receptor is the progenitor of a genetically identical CLONE of daughter cells. PROBLEM: The CLONAL DISTRIBUTION of antigen receptors means that lymphocytes of a particular specificity will be too infrequent to mount an effective response. A process akin to natural selection, CLONAL SELECTION raises the clonal frequency of cells with a particular antigen specificity

32. Each lymphocyte bears a single type of receptor of unique specificity. Antigen interaction leads to lymphocyte activation. Daughter cells bear identical antigen specificity to the parent cell. Clonal selection theory: MacFarlane Burnet 1957

33. Threshold of protective effector function Clonal selection induces proliferation and increases effector cell frequency No. of cells with useful specificity No. of cell divisions

34. 2° response to antigen A 1° response to antigen B A A B Lymphocyte proliferation to Ag B Clonal nature of adaptive immune response allows for immunological memory 1° response to antigen A Magnitude of specific response Days 4 8 12 16 20 64 68 72 Lymphocyte proliferation to Ag A Lymphocyte apoptosis

35. Soluble virus + Ab Fc receptor OPSONISATION Phagocytosis Example: humoral effector mechanisms against viruses OPSONISATION binding

36. CTL CTL CTL Target cell death Example: CD8+ T cell mediated virus elimination CYTOTOXICITY Viral infection Lethal hit

37. Summary:  Characteristics and components of adaptive and innate immunity  Peripheral lymphoid organs & lymphocyte recirculation  Clonal selection: Ag recognition and memory