Immunology overview

1. INTRODUCTION TO IMMUNOLOGY Dr.T.V.Rao MD Dr.T.V.Rao MD 1

2. Immunology • Immunology is the study of our protection from foreign macromolecules or invading organisms and our responses to them. • Host – e.g. me!!!! • Foreign macromolecule, antigen – e.g. virus protein, worm, parasite (Everything that should not be in my body) Dr.T.V.Rao MD 2

3. • Protect against pathogens • Eliminate damaged or malignant cells Dr.T.V.Rao MD 3

4. A Short History of Immunology • ~ 430 B.C: Peloponesian War, Thucydides describes plague – the ones who had recovered from the disease could nurse the sick without getting the disease a second time • 15th centurry: Chinese and Turks use dried crusts of smallpox as ”vaccine” • 1798: Edward Jenner – smallpox vaccine Dr.T.V.Rao MD 4

5. Jenner - Smallpox vaccine • Noticed that milkmades that had contracted cowpox did NOT get smallpox • Test on an 8 year old boy, injected cowpox into him (NOT very nice……) • Follwed by exposure to smallpox • Vaccine was invented (latin vacca means ”cow”) Dr.T.V.Rao MD 5

6. Immunology is a Complex Subject Dr.T.V.Rao MD 6

7. Role of the immune Viruses Parasites Influenza system is to protect from: Tapeworms Malaria Polio mellitus Helminths Fungi Bacteria Candida albicans Tubercule bacillus Dr.T.V.Rao MD Staphylococci 7

8. PRINCIPAL FUNCTION OF THE IMMUNE SYSTEM • To protect humans from pathogenic microorganisms • Pathogenic microorganisms (Pathogens) – Microorganisms capable of causing infection and/or disease • Infection – Ability of pathogen to enter host, multiply and stimulate an immune response • Disease – Clinical manifestations associated with infection Dr.T.V.Rao MD 8

9. General Immunology Immunology stems from L.- immunis = “exempt;” Eng. = protection from disease *Protective adaptations in higher organisms to rid the body of foreign particles (microbial and otherwise) and abnormal cells Our Immune system involves the interplay between our Non-specific and our Specific Immune responses Non-specific immunities collectively referred to as our Innate immunity Specific immunities are referred to as our Adaptive immunity for which there are 2 branches: Humoral immunity Cell-mediated immunity Dr.T.V.Rao MD 9

10. Subjects In Immunology • Cell mediated host defense functions • Antibody related defense mechanisms • Hypersensitivity reactions ( Including Allergy ) • Auto Immunity • Immunodeficiency • Transplantation Dr.T.V.Rao MD 10

11. Divisions of Immunology Dr.T.V.Rao MD 11

12. Definitions • Immune system = cells, tissues, and molecules that mediate resistance to infections • Immunology = study of structure and function of the immune system • Immunity = resistance of a host to pathogens and their toxic effects • Immune response = collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system Dr.T.V.Rao MD 12

13. March towards modern times… War on smallpox… 1718- Lady Montague became aware of a practice, called variolation or inoculation, and introduced it to Britain after first having her own children treated. 1774 – Benjamin Justy 1776- Geo. Washington 1798 –Edward Jenner noticed immunity bestowed to milkmaids – injected fluid from cowpox blister into skin of patient (orphan or prisoner) Lady Mary Wortley Montague 1989- WHO announced smallpox was (1689-1762) eradicated from the world Dr.T.V.Rao MD 13

14. Jenner - Smallpox vaccine • Noticed that milkmades that had contracted cowpox did NOT get smallpox • Test on an 8 year old boy, injected cowpox into him (NOT very nice……) • Follwed by exposure to smallpox • Vaccine was invented (latin vacca means ”cow”) Dr.T.V.Rao MD 14

15. Pasteur inoculating sheep at Msr. Rossignol’s farm – May, 1881 Louis Pasteur 1879- discovered that aged bacterial cultures of Pasteurella lost virulence. Referred to injection of weakened culture a “vaccine” in honor of Jenner 1881- He applied the same technique vs. anthrax ….and then rabies Dr.T.V.Rao MD 15

16. Louis Pasteur watching as Joseph Meister receives attenuated rabies vaccine (1885) Dr.T.V.Rao MD 16

17. First insights into mechanics of immunity… Emil von Behring 1880’s- Metchnikoff discovered phagocytic cells that ingest microbes S. Kitasato and particles cells conferred immunity 1890- von Behring and Kitasato discovered blood sera could transfer immunity liquid of blood conferred immunity Q: Which confers immunity… cells or serum? Elie Metchnikoff Dr.T.V.Rao MD 17

18. Types Of Immunity • Inborn or innate immunity: It is present at birth; This is our First Line Of Defense. • Acquired or specific: It is not present at birth but becomes part of our immune system as the lymphoid system develops. • 1970: WHO defined immunity as immune response to antigen ( Foreign body) in form of • Humoral ( activation of B-lymphocytes) • Cellular (by activation of T-lymphocytes Dr.T.V.Rao MD 18

19. Different types of Immunity A - Non specific 1 Species 2 Racial 3 Individual B Specific 1.Species 2 Racial 3 Individual Dr.T.V.Rao MD 19

20. Two types of immunity 1. Innate (non-adaptive) – first line of immune response – relies on mechanisms that exist before infection 2. Acquired (adaptive) – Second line of response (if innate fails) – relies on mechanisms that adapt after infection – handled by T- and B- lymphocytes – one cell determines one antigenic determinant Dr.T.V.Rao MD 20

21. Distinction Between Innate and Adaptive Immune Responses • Innate immunity is non-adaptive and helps to initiate adaptive immune responses (= first line of defense – but LIMITED) – Immediate (0-4 hours) • Adaptive immunity provides a more universal line of defense and has long-lived memory to provide protection upon re-infection – Second line of defense – Generation of Ag-specific effector cells – Early (4-96 hours) – Late (>96 hours) Dr.T.V.Rao MD 21

22. Immunology Overview • Lymphocytes •Antigen-presenting cells •Effector cells • Responses •The innate immune response •Capturing and displaying antigens •Cell-mediated immunity •Humoral immunity •Immunologic memory Dr.T.V.Rao MD 22

23. THE EVOLUTION OF IMMUNITY Immunity Non-specific Immediate onset Specific Delay onset Innate immunity Acquired immunity Humoral Cellular Immune Response Immune Response Antibodies production T-cell activation Dr.T.V.Rao MD 23

24. DEFENSE MECHANISMS OF THE HUMAN HOST • Innate Mechanisms (Innate immunity) – First line of defense – Non-specific • Adaptive Mechanisms (Adaptive immunity) – Second line of defense – Highly specific with memory • Cooperation between mechanisms Dr.T.V.Rao MD 24

25. Organs Of Immune System • Primary Lymphoid Organs – Bone Marrow and Thymus – Maturation Site • Secondary Lymphoid Organs – Spleen, lymph nodes, – MALT (mucosal associated lymph tissue) – GALT (gut associated lymph tissue) – Trap antigen, APC, Lymphocyte Proliferation Dr.T.V.Rao MD 25

26. ORIGIN OF CELLS OF THE IMMUNE SYSTEM • Derived from common progenitor cell in bone marrow – Pluripotent hematopoietic stem cell • Progenitor Stem Cells – Erythroid lineage • Erythrocytes and Megakaryocytes – Myeloid lineage • Monocyte/macrophage, dendritic cells, PMN’s, mast cells – Lymphoid lineage • Small and large lymphocytes Dr.T.V.Rao MD 26

27. HUMAN Lymphoid Organs Dr.T.V.Rao MD 27

28. The immune system Immune system Innate (non-specific) immunity Adaptive (specific) immunity •Anatomic barriers (Skin, mucous •Antigen specificity membranes) •Diversity •Physiological barriers (temperature, pH) •Immunological memory •Phagocytic Barriers (cells that eat •Self/nonself recognition invaders) •Inflammatory barriers (redness, swelling, heat and pain) Dr.T.V.Rao MD 28

29. Dr.T.V.Rao MD 29

30. Central Immune organs Central Immune Organs are the sites of generation, differentiation and maturation of immunocytes.  Bone marrow  Thymus  Bursa of Fabricius (the site of B cells maturation in birds) But absent in Humans Dr.T.V.Rao MD 30

31. Innate Immunity • Nonspecific host defenses that exist prior to exposure to an antigen. Involves the following components: – Anatomic – Physiologic – Phagocytic – Inflammatory Dr.T.V.Rao MD 31

32. Barriers to Antigenic Insult • Anatomic – Skin – Mucous membranes • Physiologic – Temperature – pH – Chemical mediators Dr.T.V.Rao MD 32

33. THE INNATE IMMUNE RESPONSE • Mediated (initiated) by phagocytes, NK cells and soluble proteins • Phagocytes – Cells specialized in the process of phagocytosis • Macrophages – Reside in tissues and recruit neutrophils • Neutrophils – Enter infected tissues in large numbers – Recognize common molecules of bacterial cell surface using a few surface receptors • Phagocytosis – Capture, engulfment and breakdown of bacterial pathogen Dr.T.V.Rao MD 33

34. Important components of innate immunity Factors that limit growth of microorganisms within the body • Natural killer cells • Kill virus infected cells • Neutrophils • Ingest and destroy microbes • Macrophages and dendritic • Ingest and destroy microbes, and present cells antigen to helper T-cells • Interferons • Inhibit viral replication • Complement • C3b is an opsonin, membrane attack complex creates holes in bacterial membranes • Sequester iron required for bacterial • Transferrin and Lactoferrin growth • Elevated temperature retards bacterial • Fever growth • Inflammatory response • Limits spread of microbes • APOBEC3G (apolypoprotein is RNA • Causes hyper mutation in retroviral DNA editing enzyme) and mRNA Dr.T.V.Rao MD 34

35. Main Components of Innate and acquired Immunity that contribute to humoral ( antibody-mediated ) immunity and cell mediated immunity Humoral Cell mediated Immunity Immunity Innate Complement Macrophages Neutrophil Natural killer cells Acquired B cells Helper Tcells Antibodies Cytotoxic T cells Dr.T.V.Rao MD 35

36. Major Functions Of T Cells and B cells Antibody-Mediated Immunity (B Cell Mediated Immunity Cells) 1) Host defense against 1) Host defense against infection infection (especially M.tuberculosis, fungi and virus infected cells) 2) Allergy (hypersensitivity )eg 2) (Opsonize bacteria, neutralize poison oak toxins and viruses) 3) Graft and tumor rejection 3) Allergy (hypersensitivity) eg, hay fever anaphylactic shock 4) Regulation of antibody response 4) Autoimmunity (help and suppression) Dr.T.V.Rao MD 36

37. Cellular and Inflammatory Components of Innate Immunity • Cellular –Phagocytic cells • Inflammatory –Vasodilation –Capillary permeability Dr.T.V.Rao MD 37

38. CELLS OF INNATE AND ADAPTIVE IMMUNITY • Myeloid Lineage – Neutrophil • Principal phagocytic cell of innate immunity – Eosinophil • Principal defender against parasites – Basophil • Functions similar to Eosinophils and mast cells – Referred to as • Polymorph nuclear leukocytes (PMN’s) – Nuclei are multilobed (2 to 5) • Granulocytes – Cytoplasmic granules MD Dr.T.V.Rao 38

39. CELLS OF INNATE AND ADAPTIVE IMMUNITY • Myeloid lineage – Monocytes • Leukocytes with bean shaped or brain-like convoluted nuclei • Circulate in blood with half life of 8 hours • Precursors of tissue macrophages – Macrophages • Mononuclear phagocytic cells in tissue • Derive from blood monocytes • Participate in innate and adaptive immunity Dr.T.V.Rao MD 39

40. CELLS OF INNATE AND ADAPTIVE IMMUNITY • Myeloid lineage – Dendritic cells • Cells with dendriform (star shaped) morphology • Interdigitating reticular cells (synonym) • Capture and present antigens to T lymphocytes – Mast cells • Located in mucous membrane and connective tissue throughout body • Major effector cell in allergy • Modulation of initial immune response Dr.T.V.Rao MD 40

41. CELLS OF INNATE AND ADAPTIVE IMMUNITY • Lymphoid Lineage – Large lymphocytes (large granular lymphocytes) • Natural killer (NK) cells (CD16, CD56) • Innate immunity to viruses and other intracellular pathogens • Participate in antibody-dependent cell-mediated cytotoxicity (ADCC) – Small lymphocytes • B cells (CD19) • T cells (CD3, CD4 or CD8) • Adaptive immunity – Lymphocytes refers to Dr.T.V.Raolymphocytes small MD 41

42. THE CLUSTER OF DIFFERENTIATION (CD) • A protocol for identification and investigation of cell surface molecules • CD number assigned on basis of 1 cell surface molecule recognized by 2 specific monoclonal antibodies • CD nomenclature established in 1982 – 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA) Dr.T.V.Rao MD 42

43. THE CLUSTER OF DIFFERENTIATION (CD) • CD markers on leukocytes Granulocyte CD45+, CD15+ Monocyte CD45+, CD14+ T lymphocyte CD45+, CD3+ T helper lymphocyte CD45+, CD3+, CD4+ T cytotoxic lymphocyte CD45+, CD3+, CD8+ B lymphocyte CD45+, CD19+ Natural killer cell CD45+, CD16+, CD56+, CD3- Dr.T.V.Rao MD 43

44. Physiologic Mediators of Innate Immunity • Chemical mediators – Enzymes –Interferon – Complement • Three pathways – Classical – MB Lectin – Alternative Dr.T.V.Rao MD 44

45. Physiologic Mediators of Innate Immunity(cont’d) • Chemical mediators –Collections –Toll-like receptors –Acute phase proteins Dr.T.V.Rao MD 45

46. Mechanism's of Immunity • Epithelial surfaces Skin and Epithelial surfaces cover the body and protects the individuals Healthy skin poses bactericidal influence, salt, drying sweat , Long fatty acids Wet hand predisposes to Mycotic and pyogenic infections Dr.T.V.Rao MD 46

47. Dynamics of Phagocytosis Dr.T.V.Rao MD 47

49. White Blood Cell Development Dr.T.V.Rao MD 49

50. LYMPHOCYTES, LYMPHOID TISSUES AND ORGANS • Lymphocytes originate in bone marrow • Lymphoid tissues and organs – Primary • Development and maturation of lymphocytes • Bone Marrow (B cells) and thymus gland (T cells) – Secondary • Mature lymphocytes meet pathogens • Spleen, adenoids, tonsils, appendix, lymph nodes, Peyer’s patches, mucosa-associated lymphoid tissue (MALT) Dr.T.V.Rao MD 50

51. THE LYMPHATIC SYSTEM • Lymph – Fluid and cells in lymphatic vessels • Lymphatic vessels – Collect and return interstitial fluid to blood – Transport immune cells throughout body – Transport lipid from intestine to blood • Lymph nodes – Kidney shaped organs at intervals along lymphatic vessels • Other secondary lymphatic tissues and organs Dr.T.V.Rao MD 51

53. SECONDARY LYMPHOID TISSUES ASSOCIATED WITH MUCOUS MEMBRANES • Primary portals of entry for pathogens – Respiratory tract – Gastrointestinal tract • Secondary lymphoid tissues – Bronchial-associated lymphoid tissue (BALT) – Gut-associated lymphoid tissues (GALT) • Tonsils, adenoids, appendix, Peyer’s patches • Pathogens are directly transferred across mucosa by “M” cells Dr.T.V.Rao MD 53

54. Innate immunity: mechanisms • Mechanical barriers / surface secretion – skin, acidic pH in stomach, cilia • Humoral mechanisms – lysozymes, basic proteins, complement, interferons • Cellular defense mechanisms – natural killer cells neutrophils, macrophages,, mast cells, basophils, Eosinophils NK Cell Eosinophils Monocyte Neutrophil Basophils & Mast Dr.T.V.Rao MD cells 54 Macrophage

55. Adaptive immunity: second line of response • Based upon resistance acquired during life • Relies on genetic events and cellular growth • Responds more slowly, over few days • Is specific – each cell responds to a single epitope on an antigen • Has anamnestic memory – repeated exposure leads to faster, stronger response • Leads to clonal expansion Dr.T.V.Rao MD 55

56. Adaptive immunity: mechanisms • Cell-mediated immune response (CMIR) – T-lymphocytes – eliminate intracellular microbes that survive within phagocytes or other infected cells • Humoral immune response (HIR) – B-lymphocytes – mediated by antibodies – eliminate extra-cellular microbes and their toxins Plasma cell (Derived from B-lymphocyte, produces antibodies) Dr.T.V.Rao MD 56

57. Cell-mediated immune response 1. T-cell – recognizes peptide antigen on macrophage in association with major histo-compatibility complex (MHC) class – identifies molecules on cell surfaces – helps body distinguish self from non-self 2. T-cell goes into effectors cells stage that is able to kill infected cells Dr.T.V.Rao MD 57

58. Cell mediated immune response Primary response – production of specific clones of effector T cells and memory clones – develops in several days – does not limit the infection Secondary response – more pronounced, faster – more effective at limiting the infection Example - cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g., Tuberculin test) and allograft rejection Dr.T.V.Rao MD 58

59. Humoral immune response 1. B lymphocytes recognize specific antigens – proliferate and differentiate into antibody-secreting plasma cells 2. Antibodies bind to specific antigens on microbes; destroy microbes via specific mechanisms 3. Some B lymphocytes evolve into the resting state - memory cells Dr.T.V.Rao MD 59

60. Antibodies (immunoglobulin's) •Belong to the gamma-globulin fraction of serum proteins •Y-shaped or T-shaped polypeptides – 2 identical heavy chains – 2 identical light chains • All immunoglobulin's are not antibodies •Five kinds of antibodies – IgG, IgM, IgA, IgD, IgE

61. Acute Phase proteins too play a great role in Immunity • Infection and Injury produces Acute phase proteins • C- Reactive proteins CRP • Mann in binding proteins • CRP activates alternative pathway • Increases host defenses • Prevents issue injury • Repair inflamed lesions. Dr.T.V.Rao MD 61

62. Natural Killer cells NK cells Dr.T.V.Rao MD 62

63. Role of Natural killer Cells • Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the Innate immune system. NK cells play a major role in the rejection of tumours and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis Dr.T.V.Rao MD 63

64. • Programme created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 64

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