1. Immunology (elective) MLIM-101 Lecture: 1 Prepared by: Dr. Mohamed S. Abdel-Latif

3. Learning Outcome: At this time you should know the following: 1. Differences between the non-specific and specific immune functions. 2. Humoral components of the non-specific immune system and their action. 3. Cellular components of the non-specific immune function and their action. 4. Pathways of intracellular killing of bacteria by phagocytes and their characteristic features. 5. Effect of humoral components such as interferon, TNF, IL-2, complement etc. on cellular components of the non-specific immune system.

4. "When the mind is ready,a teacher appears.“ Chinese Proverb

5. Development of the Immune System ery pl mye neu mφmφ lym nk thy CD8 + CD4 + CTL TH2 TH1

6. Cells of the Immune System Basophils Neutrophils Eosinophils Granulocytic Langerhans & Macrophages Kupffer cells Dendritic cells? Monocytic Cytotoxic Helper Suppressor T-cells Plasma cells B-cells Dendritic cells? lymphoid cells Myeloid cells

7. Components of the Immune System Humoral Cellular Humoral Cellular Specific Nonspecific complement, interferon, TNF etc. macrophages, neutrophils T cells; other effectors cells antibodies

8. Balance between Infection and Immunity infection immunity Bolus of infection x virulence immunity Disease =

9. Response to Infection infection x disease Innate immunity no disease recovery adaptive immunity re-infection no disease x

10. u Beneficial: u Protection from Invaders u Elimination of Altered Self u Detrimental: u Discomfort (inflammation) u Damage to self (autoimmunity) u Beneficial: u Protection from Invaders u Elimination of Altered Self u Detrimental: u Discomfort (inflammation) u Damage to self (autoimmunity) Significance of the Immune System

11. Innate Immunity Adaptive Immunity Characteristics of Innate and Adaptive Immunity No Immunologic memory Antigen independent No time lag Not antigen specific Antigen dependent A lag period Antigen specific Development of memory

12. Innate Immunity Adaptive Immunity Components of Innate and Adaptive Immunity skin, gut Villi, lung cilia,etc many protein and non-protein secretions phagocytes, NK cell eosinophils, K cells physical barriers soluble factors cells non e Immunoglobulins (antibody) T and B lymphocytes

13. Physical Barriers to Resistance

14. SiteComponentFunctions Effector mechanisms in Innate Immunity -1 Peristalsis, low pH bile salts, fatty acids columnar cells GI tract Skin squamous cells sweat desquamation flushing, fatty acids tracheal cilia Lung mucociliary elevator surfactants

15. SiteComponentFunctions Effector mechanisms in Innate Immunity -2 Nasopharynx and eye mucus, saliva, tearsflushing, lysozyme Phagocytes Blood and Lymphiod organs phagocytosis and intracellular killing K, NK & LAK cells direct and antibody dependent cytolysis

16. SiteComponentFunctions Effector mechanisms in Innate Immunity -3 Serum and other serous fluids lactoferrin, transferrin iron deprivation interferons, TNF-  antiviral proteins phagocyte activation lysozyme peptidoglycan hydrolysis Fibronectin & complement opsonization, enhanced phagocytosis, inflammation

17. Phagocytes are the Most Important Cells Influenced by the work of Eli Metchnikoff, George Bernard Shaw wrote: “There is at bottom only one genuine treatment for all diseases,…to stimulate the phagocytes. Drugs are a delusion. …(when) the phagocytes are stimulated; they devour the disease…”

18. All phagocytes eat, digest and extrude

19. Phagocytes: Neutrophils  phagocytosis, intracellular killing, inflammation and tissue damage  characteristic nucleus, cytoplasm  granules and CD66 membrane marker.

20. Phagocytes: Macrophages  phagocytosis, intracellular and extra- cellular killing, tissue repair, antigen presentation for specific immune response  characteristic nucleus and CD14 membrane marker.

21. Characteristics of Neutrophil Granules primary granules contain cationic proteins, lysozyme, defensins, proteases and myeloperoxidase secondary granules contain lysozyme, NADPH oxidase, lactoferrin and B12- binding protein azurophilic; characteristic of young neutrophils; specific for mature neutrophils

22. Phagocyte Response to Infection u The SOS Signals – N-formyl methionine – Clotting system peptides – Complement products u Phagocyte response – Vascular adherence – Diapedesis – Chemotaxis – Activation – Phagocytosis and killing u The SOS Signals – N-formyl methionine – Clotting system peptides – Complement products u Phagocyte response – Vascular adherence – Diapedesis – Chemotaxis – Activation – Phagocytosis and killing

23. Initiation of Phagocytosis Attachment via IgG FcR ScavengerR CR Toll-like R

24. Respiratory Burst Oxygen Dependent Myeloperoxidase Independent Reactions 2O 2 - + H 2 O 2.OH + OH - + 1 O 2 Glucose +NADP + G-6-P-dehydrogenase Pentose-P + NADPH NADPH + O 2 Cytochrome b558 NADP + + O 2 - 2O 2 - + 2H + Superoxide dismutase H 2 O 2 + 1 O 2

25. Respiratory Burst Oxygen Dependent Myeloperoxidase dependent reactions H 2 O 2 + O 2 - 2O 2 - + 2H + Superoxide dismutase H 2 O 2 + Cl - myeloperoxidase OCl - + H 2 O H 2 O + O 2 - 2 H 2 O 2 catalase 2OCL - + H 2 O 1 O 2 - + Cl - + H 2 O

26. Pathways of Intracellular Killing

27. Effector MoleculeFunction Mediators of Oxygen Independent Killing in the Phago-lysosome Cationic proteins (cathepsin)Damage to microbial membranes Lysozyme Hydrolyses mucopeptides in the cell wall Lactoferrin Deprives pathogens of iron Hydrolytic enzymes (proteases)Digests killed organisms

28. Nitric Oxide Dependent Killing IFNγ  TNF Nitric Oxide

29. Non-specific Killer Cells NK and LAK cells ADCC (K) cell Activated macrophages Eosinophils NK and LAK cells ADCC (K) cell Activated macrophages Eosinophils They all kill foreign and altered self targets

30. Natural Killer (NK) cells u also known as large granular lymphocytes (LGL) u kill infected and malignant cells u are identified by the presence of CD56 & CD16 and absence of CD3 u activated by IL2 and IFN-γ to become LAK cells u also known as large granular lymphocytes (LGL) u kill infected and malignant cells u are identified by the presence of CD56 & CD16 and absence of CD3 u activated by IL2 and IFN-γ to become LAK cells

31. Lymphokine Activated Killer (LAK) cell IL2 IFN IL2 kills malignant cells kills transformed and malignant cells

32. Regulation of NK Cell Function

33. K Cells u morphologically undefined u have IgG Fc receptor u recognize antibody coated targets u could be NK cells (IgG), macrophages (IgG), eosinophils (IgE) or other cells (IgG) u morphologically undefined u have IgG Fc receptor u recognize antibody coated targets u could be NK cells (IgG), macrophages (IgG), eosinophils (IgE) or other cells (IgG)

34. Macrophages u phagocytose & kill intracellularly u identified by CD14 u adherent of plastic and glass surfaces u activated by cytokines u kill both intracellular organisms u kill malignant and altered self targets u phagocytose & kill intracellularly u identified by CD14 u adherent of plastic and glass surfaces u activated by cytokines u kill both intracellular organisms u kill malignant and altered self targets

35. Elements of Nonspecific Immunity Summary u Physical Barriers u skin, muco-ciliary escalator, secretions, peristaltic movement, etc. u Serous Proteins u Acute phase proteins, Interferon(s), lysozyme, lactoferrin, cationic proteins, etc. u Physical Barriers u skin, muco-ciliary escalator, secretions, peristaltic movement, etc. u Serous Proteins u Acute phase proteins, Interferon(s), lysozyme, lactoferrin, cationic proteins, etc.

36. Elements of Nonspecific Immunity Summary u Cells u pagocytes u Oxygen-independent killing u O2-dependent - MPO independent killing u O2-dependent - MPO dependent killing u Nitric Oxide mediated killing u cytotoxic cells u NK, LAK, K (ADCC) u Cells u pagocytes u Oxygen-independent killing u O2-dependent - MPO independent killing u O2-dependent - MPO dependent killing u Nitric Oxide mediated killing u cytotoxic cells u NK, LAK, K (ADCC)

37. Assignment: As a part of the semester activity, group of students is selected every week to prepare a short seminar about his/her point of interest in one of the lecture topics. That to be discussed and evaluated during the next lecture.