Introduction to The Immune System

1. Introduction to The Immune System • Pin Ling (凌 斌), Ph.D. ext 5632; lingpin@mail.ncku.edu.tw • References: 1. Male D., J. Brostoff, D. B Roth, and I. Roitt Immunology, 7th ed., 2006. 2. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapters 1 & 2

2. Keys toward Learning Immunology • Lectures => Deliver the “Key Concepts” of Immunology. • Workbook => Apply the “Knowledge” from Immunology to the “Solutions” of clinical problems. • Textbook reading => Help learn the details and build up the comprehensive knowledge of immunology 1. What we teach is the current knowledge about Immunology. 2. Some may stand forever and Some may change in the future. 3. So Keep your mind Open! You could be the next One to make a breakthrough in Immunology.

3. Outline • The Origin of the Immune Concept • Overview of Immunity to Microbes • Features & Components of Innate & Adaptive Immunity • Summary & Question

4. The Origin of Immune Concept-I • The term “Immunity” • => Latin word “Immunitas” => Protection from legal prosecution (Roman senators) • Biological definition => Protection from infectious diseases • 2. The concept of immunity => existed in ancient Greek & Chinese => the experienced view • The scientific view of immunity => Edward Jenner (1796) • Observation => Milkmaids generally get No Smallpox • Hypothesis => Pus from vaccinia (cowpox) • => Protect milkmaids from smallpox • Test => Inoculate materials from cowpox pus • => Protect a young boy from smallpox • (Protective immunity) Vaccinia => Vaccination (also called Immunization)

5. The Origin of Immune Concept-II • 4. The concept of “Immunity” developed gradually over time through many scientific findings: • => Robert Koch (1905 Nobel Laureate) => Infectious • diseases caused by microorganisms • => Louis Pasteur => Vaccines against cholera & rabies • => These clinical successes => The search of underlying mechanism of “Protection of Infectious Diseases” • => The development of “Immunology” • Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry, Genetic engineering…etc) have facilitated our understanding of the immune system and its functions. • “Descriptive Science” => “Experimental Science”

6. The first vaccination against smallpox Exudate from a cowpox pustule on the hand of milkmaid Sarah Nelmes was inserted into scratches on the arms of James Phipps, May 14, 1796. Adopted from www.ebinrushed.com/history/images/history_7.jpg

7. Eradication of smallpox Edward Jenner

8. Vaccines for common infectious diseases Still no effective vaccines for many infectious microbes, e.g., HCV, HIV, Dengue virus…..etc

9. Outline • The Origin of Immune Concept • Overview of Immunity to Microbes • Features & Components of Innate & Adaptive Immunity • Summary & Question

10. Intracellular & extracellular pathogens Immune responses are adapted to different types of pathogen.

11. Key concepts about immunity-I 1. The immune system has evolved to serve two major functions: (1) Protect against the invading pathogens (or foreign substances) (2) Maintain tissue homeostasis (damaged cells or cancer). Meanwhile, microbes (outside) and tumors (inside) have evolved to survive in the host. 2. The immune system (in mammals) consists of (1) Innate immunity and (2) Adaptive immunity => An integrated system of host defense => Cells & molecules function cooperatively Antigen-presenting cells => Lymphocytes => Effector cells 3. Innate immunity is evolutionally the more conserved host defense system: (1) Existed in both Invertebrates & Vertebrates; (2)Provides the first line of defenses against infections, and (3) “Activates” and “Programs” adaptive immune responses

12. Key concepts about immunity-II 5. Adaptive immunity evolved later: - Existed only in Vertebrates - Provides the more potent and diverse defenses against infections - Develops as a response to infection and adapts to the infection 6. The immune system may fail => Immunodeficiency, Hypersensitivity, & Autoimmune diseases. 7. Normal immune responses can be obstacles in medical cases, e.g., organ transplantation • Better Understanding of Immunology • Help manipulate immune responses • Solve the medical problems

13. Overview of immune responses

14. Innate vs Adaptive immunity The immune system has the ability to recognize some self components: - The Normal condition => prevent self-recognition - The “Pathological Conditions” => occur self-recognition

15. Phagocytosis by innate immunity-I 1. Cells w/ phagocytic ability: Macrophage, Neutrophil, & Dendritic cells. 2. Phagocytosis serves two key functions: (1) Killing microbes (2) Antigen (Ag) Presentation

16. Elie Mechnikoff:The Pioneer of Innate Immunity 1. The Discovery of Phagocytes & Phagocytosis 2. The Nobel Laureate in Medicine 1908 Adopted from Nature Immunology, July 2008

17. Paul Ehrlich: One of the pioneers of humoral adaptive immunity 1. The Discovery of Antibody functions 2. The Nobel Laureate in Medicine 1908 The development of modern Immunology in 20th century mainly centers on understanding the Adaptive Immune System. Adopted from Nature Immunology, July 2008

18. Interaction between innate and& adaptive immunity 1. Innate immunity => Ag presentation (by Dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

19. Interaction between innate and& adaptive immunity 1. Innate immunity => Ag presentation (by infected cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

20. Overview of adaptive immune responses

21. Outline • The Origin of Immune Concept • Overview of Immunity to Microbes • Features & Components of Innate & Adaptive Immunity • Summary & Question

22. The principle cells of the immune system Cellular components of the immune system will be discussed extensively in Lecture #2.

23. Features of Adaptive immunity (107 ~ 109) (vaccination)

24. Specificity, Memory, and Homeostasis of Adaptive Immunity

25. Principle of Vaccination

26. Clonal expansion of lymphocytes

27. Antigens, Epitopes, & Antibodies • Antigens (immunogens) initiate adaptive immune responses. • 2. Antigens may contain several different Epitopes for recognition by lymphocyte receptors or antibodies

28. Types of adaptive immunity 1. Humoral immunity => Molecules in body fluid, e.g. Antibody (Ab) => Key player => B cells => Target extracellular microbes & toxins 2. Cell-mediated immunity => Key player => T cells => regulate other immune cells => Target intracellular microbes, e.g. viruses, bacteria

29. Functions of different types of lymphocyte

30. Active vs. Passive immunity Active immunity => A host response to a microbe (Ag) => specific and long-term immune defense (memory) Passive immunity => Adoptive transfer of Ab or lymphocytes specific for a microbe (or Ag) => specific, instant but transient immune defense

31. Serum therapy => Humoral immunity & Passive immunity Serum (Ab) from animals recovered from diphtheria infection => Naïve animals => Resistant to diphtheria infection

32. Innate vs. Adaptive Immune Recognition Adaptive immune recognition:1. Antigen (Ag) receptors on T & B lymphocytes.2. These Ag receptors generated by “somatic gene recombination”3. They recognize diverse Antigens (peptides) from microbes or non-self. Innate immune recognition: Q: How do host cells recognize invading pathogens at the first place? Scientists have no answer to this until the end of the 20th century.

33. The “Renaissance” of innate immunity In 1989, Janeway => Immune recognition of microbes => Detection of conserved molecular patterns, referred to PAMPs (Pathogen-Associated Molecular Patterns) with features: 1. Invariant among a given class of microbes. 2. Have essential roles in microbial physiology. 3. Recognized by receptors of the innate immune system, called PRRs (Pattern-Recognition Receptors). 4. Innate immunity regulates adaptive immunity Charles A. Janeway, M.D. Yale Univ.

34. The Discovery of Toll and Toll-like receptor (TLR) • Cell. 1996 Sept 20; 86(6):973-83 • The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. • Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. • Institut de Biologie Moleculaire at Cellulaire, UPR 9022 du Centre National de la Recherche Scientifique, Strasbourg, France Nature388, 394 - 397 (24 July 1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity.Medzhitov R, Preston-Hurlburt P, Janeway CA Jr.Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.

35. Key concepts in innate immunity 1. The innate immune system mainly recognizes common structures shared by classes of microbes, => Pathogen Associated Molecular Patterns (PAMPs), e.g., LPS, Peptidoglycan, Microbial DNA & RNA. 2. Host receptors that recognize PAMPs are called Pattern- Recognition Receptors (PRRs), which are encoded in “Germline” DNA=> limited Diversity. 3. Innate immunity not only provide the first line of defenses but link to the program of adaptive immunity. 4. PRRs may also recognize components from injured or dead host cells => Autoimmune diseases

36. Toll-like Receptors

37. Locations of Different PRRs Body fluids -Soluble PRRs Cellular PRRs - Cell surface - Endosomes - Cytosol

38. Soluble Pattern Recognition Receptors-Complement activation pathways

39. Functions of Complement

40. Epithelial barriers prevent the entry of microbes

41. Failure of the immune system • 1. Ineffective response • - Immunodeficiency • 2. Overactive response • - Hypersensitivity • 3. Auto-reactive response • - Autoimmunity

42. Outline • The Origin of Immune Concept • Overview of Immunity to Microbes • Features & Components of Innate & Adaptive Immunity • Summary & Question

43. SUMMARY • 1. Protective immunity against microbes is mediated by the • early response of innate immunity and the later response of • adaptive immunity. • 2. Innate immune responses are initiated by recognition of • common microbial structures (PAMPs) by Pattern- • Recognition Receptors (PRRs) on innate immune cells. • - Provide the first line of host defense • - Activate and regulate the adaptive immunity • 3. Adaptive immune responses are initiated by recognition of • foreign antigens by specific lymphocytes. • - Provide more potent, specific (Ag), & broad protection • - Develop immune memory for the next exposure • - Feedback regulate innate immunity

44. Questions 1. Why is it necessary to vaccinate against tetanus only every 10 years, though antibodies against the toxoid disappear from the circulation within a year? 2. Why is the vaccine against tetanus always effective, whereas the vaccine against influenza protects on some epidemics but not others?

45. The End & Thank you

46. Phagocytosis during innate immunity-II • Inflammation: • A “Hallmark” of innate immune response (Call for help) • Local accumulation of immune cells & molecules against microbes • 3. Function to eliminate infections but often cause tissue damage & diseases • 4. Link to the development of many diseases, e.g., Cancer, • Cardiovascular disease, ….etc.