Jude Uzonna Phone: 977-5659 Email: uzonna@cc.umanitoba

1. Welcome to Immunobiology IMMU 7020 6 credit hours Course Coordinator: Jude Uzonna Phone: 977-5659 Email: uzonna@cc.umanitoba.ca

2. LECTURES: January 10-May 3 2012 Tues & Thurs 9.30-11.30 AM Venue: Alec Sehon Seminar Room EXAMS: MIDTERM: Feb 28 2012 FINAL: May 01, 2012 Time: 9.00 AM -12.00 PM Venue: Room 061 Apotex Bldg

3. Why are you taking this course? • It is a core/required Dept course • My supervisor/committee members recommended it • It is easy, (A or A+ course) • To have an in-depth understanding of immunologic principles • Do not have a definite reason

4. Today’s Objectives • Course overview, objectives and structure; changes in course design • Today’s “established truths” in immunobiology: Flaws • Overview of the immune system: • Basic concepts • Innate vs adaptive immune system and integration

5. Course Objective: • To develop an in-depth understanding of the development, functioning and regulation of the mammalian immune system.

6. TARGET AUDIENCE: • This course is aimed at senior graduatestudents in immunology or those in related disciplines who wish to have an advanced perspective on immunologic knowledge and current research. • Prerequisite:IMMU7070 - Introductory Immunology (or equivalent). Course instructors will assume that students are familiar with immunology at the level of the Abbas Textbook, Basic Immunology (2010)

7. Resources: • Murphy, Travers et al, Immunobiology (2011) 8th edition • W. Paul, Fundamental Immunology 6th edition (2008) • Research papers and reviews as assigned by individual instructors (Publications accessible via PubMed)

8. Evaluation • Midterm Exam: 35% • One take home assignment: 15% • Must be submitted on or before the stipulated time. 1% will be deducted for every hr of late submission to a maximum of 10% for every assignment • Debate (on assigned topics): 10% • 2 students per topic (pros and cons) • Each student must participate/contribute • Final Exam: 40% • Will cover lectures given after midterm PLUS two questions from lectures given before midterm • All Exams are closed book (~ 3hr) • Grades: U of M standard grading system

9. Important Dates • Withdrawals: • January 17, 2010: Date to withdraw with a full refund • Feb 23, 2012: Study Break (No classe) • Feb 28, 2012: Midterm Exam (closed book) • April 17, 2012: Make up class • April 19, 2012: Make-up class; Take Home Assignment • April 24 & 26, 2012: Debate • May 1 2012: Final Exam (closed book) • May 3 2012: Take Home Assignment Due (12.00 PM) * Note: No more voluntary withdrawal with 50% refund.

10. Our Goal: Provide you with most up-to-date information on recent advances in immunology through lectures, discussions and reviews/critiques of literature

11. Your Goal: Develop a detailed understanding of how immune defenses operate so you can apply this info in your research and your understanding and/or reading of the literature

12. Recommended Solutions: • Focus on the big picture– integrate the details and use your critical thinking (not memorization) skills. • Do the supplementary readings. • Make noise if / when you get lost. • Keep up with current literature. • Course outline on web-updated regularly.

13. What we have done to help • Multiple instructors, teaching in their field of expertise • Emphasis on critical thinking and experimental design skills –Debate, 1 Take home assignment, midterm. • Objective of each lecture on web. Some hand-out notes with key concepts identified, key references identified. • Assigned readings and paper-based discussion approaches in some lectures • Recommended text: Janeway Immunobiology (8th Edition) • Immunology web site. http://umanitoba.ca/faculties/medicine/units/immunology/teaching • Student participation seriously encouraged

14. Advanced Immunology: why bother?

15. Vaccination is the single most important means of controlling infectious diseases Fact, Overstatement, False? VOTE

16. When we successfully manipulate the immune system to go right…

17. Smallpox Eradicated!!

20. When the immune system goes wrong… • Examples?

21. Asthma: airway inflammation and remodeling

22. FACT: sometimes, deficient immune response is beneficial!! VOTE

23. “Truths” In Immunology What is “Truth”? Dogma vs “Truth” • In late 1980s to early 1990s: • Th1/Th2 paradigm could explain virtually any immunologic process • Th1 cells (IFN) responsible for inflammatory disorders including autoimmunity e.g. EAE, Inflammatory arthritis etc • In late 2005s: • Th17 and IL-17 are master regulators of inflammation • Most immunologic phenomena attributed to Th1 cells now reversed and ascribed to Th17 cells

24. “Truths” and its shelf life… • The mammalian immune system represents a finely tuned balance between activating and inhibitory stimuli to produce immunity. • Th17 cells and IL-17 are master regulators of inflammation • The major negative regulatory system that controls quality and magnitude of adaptive immune responses is Regulatory T cell

25. Modern Times • We know that pathogens can be destroyed by the innate or adaptive immune system. • Which is more important? Vote • We know that the immune response consists of a humoral and a cell-mediated component. • Which is more important? Vote

26. Components of the immune system • List them (cellular and non cellular components)

27. The cellular components: Functions • Macrophages • Dendritic cells • Neutrophils • Eosinophils • Basophils • Mast cells • Lymphocytes • T cells • B cells • NK cells

28. The non-cellular components • Bone marrow • Thymus • Spleen • Lymph nodes

29. Designing the perfect immune system • If you were to “design” the immune system, what components would you “upgrade” or “downgrade”?

30. Innate Immunity: The Starting Point • Tell us what you know… • Roles, constituents…

31. Initial lines of defense: • Epithelial surfaces • Role of mucins in preventing attachment • Constitutive innate responses: Lysozyme, a,b defensins, etc • Underlying innate responses: cellular and humoral • List them • When this is insufficient (minority of cases) • Adaptive immune response kicks in • Inflammation : Pain, redness, heat , swelling.

32. Pathophysiology of Inflammation

33. Goals of Inflammation: • Localize threat / prevent spreading infection 2. Deploy appropriate defenses to remove it 3. Seek immediate assistance—of the correct sort. (augmenting immediate response) 4. Seek long term/ adaptive immunity assistance by recruiting, activating and programming APC 5. Promote repair

34. Innate Receptors: Does the innate immune system carry out self/non-self discrimination?

35. PAMP and PRR • PRRs (Patter Recognition Receptors): recognize PAMPs that are not (or are rarely) expressed on host cells. • PAMPS (Pathogen Associated Molecular Patterns: Highly conserved structures essential to microbial physiology • These are characteristic of broad families of pathogens from virus to protozoa. • Three main categories of PRRs • Secreted PRR: ie. Mannose receptors, C reactive protein. • Transmembrane PRR: includes Scavenger receptors and some TLRs (ie TLR2, TLR4) • Intracellular PPR: some TLR (eg TLR7, TLR9)

36. Why so many PRR? Redundancy is key for detection (why important?) Diff receptors lead to diff outcomes (why important?)

37. TLR: a good idea reused and expanded throughout evolution. • 11 known receptors in Humans and Mice (plants, fruitflies…) • Intra/extra cellular • Monomer/dimers • Key role in initiating innate immunity • Also regulate the nature of the adaptive immune response

38. Toll-like receptors • The contribution of TLRs to development and maintenance of human immune responses remains poorly understood.

39. TLR expression on human leukocytes Widely distributed, diverse, regulated TLR expression.

40. Key points • For most stimuli, the innate immune system -- not the adaptive -- provides all the protection we need. • Only when the innate is overwhelmed is the adaptive started. • Major differences: • Frequency of cells capable of responding • Diversity of Ag receptors Why? • Speed vs Precision • Memory

41. “Innate” is all you need if you’re a frog and planning on a short lifespan with lots of babies... • The trade off for “quick to respond to widely expressed danger signals that bind to pattern receptors is an absence of : • Ag specificity • Specialization • Adaptability to new pathogens • Hence, we evolved an Ag-specific immune response… ADAPTIVE IMMUNITY!!!

42. Why adaptive immunity evolved? • Shortcomings of innate immunity: • Non-specific • Similar pattern of response for all pathogens • Poor regulation • Control mechanisms are poor or lacking • Poor amplification • Response magnitude same for all insults • Lack of self discrimination • Harm to self results for lack of specificity • Short duration • No memory

43. Clonal Selection theory: single most important principle in adaptive immunity

44. Clonal selection of lymphocytes

45. Phases of the adaptive immunity

46. The two-signal requirement for lymphocyte activation • Requirements: Two signals • Signal 1: specific recognition of antigen • TCR-Peptide-MHC • BCR-Native antigen • Signal 2: Non-specific • Microbial-induced molecules on/from APC • Microbial molecule (LPS, CpG etc) • Signal 1 alone leads of unresponsiveness • Anergy, Deletion, Apoptosis

47. Immunologic memory: another key aspect of adaptive immunity

48. The players (and when you need them)

49. For Innate Immunity: Time, not specificity, is of essence…

50. For adaptive immunity: Specificity, self/non-self discrimination, quality and memory, not time, are of essence…