Workshop on Infectious Disease Ontology

1. Workshop on Infectious Disease Ontology http://www.bioontology.org/wiki/index.php/Infectious_Disease_Ontology

2. Introduction to the Human Immune System

3. The immune system serves as an interface between host and microorganisms. • >90% of the cells in/on our body are bacterial • 1013 human cells in our body • 1012 bacteria on the skin • 1010 bacteria in the mouth • 1014 bacteria in the gastrointestinal tract • much of the DNA in the human genome is of viral origin • 10% of your body weight is microbial

4. The immune system serves as an interface between host and microorganisms. • commensals (normal microflora) • We provide warmth, moisture, glucose, amino acids. • They aid in the digestion of cellulose. • They stimulate capillary growth and development of mucosal immunity. • Protect us from pathogenic microorganisms. • Parasites (pathogens)

5. Commensalism and parasitism • Organism: vast number of coupled biochemical networks organized as modules. • Commensals and parasites: mobile modules. • Different types attach to a different piece of our network: • Bacteria have plugged into our metabolic network • Viruses use our replicative network

6. Human versus microbial evolvability • Generation times: • Human: ~ 25 years • Microbe: ~ hours to days • The constraint of multi-cellularity • Our cells have evolved special functions and must cooperate with each other. • Prokaryotes and viruses are not constrained this way. They have evolutionary flexibility.

7. The immune system is an interface between multi-cellular organization and unicellular autonomy, a reversion back to a prokaryotic system of organization. Unicellular lifestyle Extreme somatic diversification Rapid adaptation

8. Immune Specificity Somatic diversification Immune Memory

9. Innate Immunity Conferred by proteins whose genes are inherited Adaptive Immunity Conferred by proteins whose genes are somatically diversified

10. Innate Immunity Adaptive Immunity Somatically diversified receptor genes Proteins recognize pathogen-specific epitopes Inherited receptor genes Proteins recognize evolutionarily conserved patterns • Always ready – respond immediately • Provide constant surveillance • Can adapt – requires exposure • Provide specificity and memory Pattern Recognition Receptors Antigen Receptors Antigen Pathogen-associated Molecular Patterns

11. B lymphocytes • T lymphocytes • Antigen receptors • Antibodies • Epithelial barriers • Phagocytic cells (neutrophils, macrophages, dendritic cells) • Pattern recognition receptors • NK cells • Complement system

12. Dendritic cell activation of T lymphocytes Dendritic Cells Detect pathogen Adaptive Immune System Innate Immune System Confer immune specificity and memory Antigen Receptors TH cell activation of macrophages BCR marking of pathogen for phagocytosis and complement

13. Components of the Immune System and their Role in Immune Responses

14. Figure 1-3

15. Cells of innate immunity !

16. Figure 1-3

17. Primary lymphoid tissue Secondary lymphoid tissue Importance of unicellular lifestyle

19. Innate Immune Response Components of the Immune System and their Role in Immune Responses

20. Figure 2-4 Epithelial Barriers:what happens after a breach?the immune response

21. Macrophages and immature dendritic cells are resident in tissues. Communication: cytokines and chemokines Phagocytosis by macrophages and dendritic cells Macropinocytosis by immature dendritic cells.

22. Inflammation and Recruitment

24. The adaptive immune response is initiated by the recognition of non-self by the innate system. Adjuvant: material added to innoculum to stimulate the innate immune system.

25. Receptors of the innate immune system recognize features common to many pathogens (repeated patterns). • Expressed on: • Macrophages • Neutrophils • immature dendritic cells • and are secreted. • Stimulate: • Ingestion of pathogen • Expression of co-stimulatory molecules, cytokines, chemokines

26. Four main types of cell-associated receptors: • C-type lectins (carbohydrate-binding): • Mannose receptor: recognizes particular orientation and spacing of certain sugar residues • Dectin: binds glucans present in fungal cell walls Scavenger receptors: 6 forms; recognize anionic polymers and acetylated low-density lipoproteins. Chemotactic receptors: for example, the Met-Leu-Phe receptor on neutrophils that binds N-formylated peptides produced by many bacteria and guides neutrophils to the site of infection.

27. toll-like receptors of innate immunity

29. Innate Immune System Epithelial barriers Soluble pattern recognition receptors Phagocytosis Cell-associated pattern recognition receptors Macrophages Neutrophils Dendritic cells Chemokine secretion Cytokine secretion Initiation of Adaptive Immune Response

30. Innate Immune System • Initial response to microbes (surveillance and detection of non-self) • Recognizes structures characteristic of microbial pathogens • Not on mammalian cells • Necessary for survival of microbe • Receptors are encoded in germline DNA • will also recognize stressed or injured tisssue Stimulates adaptive response and can influence its nature

31. Adaptive Immune Response Components of the Immune System and their Role in Immune Responses

32. The specificity of the adaptive immune system is mediated by antigen receptors: • B cell receptor (BCR), immunoglobulin (Ig), antibody (Ab) • T cell receptor (TCR) Each developing lymphocyte expresses a unique antigen receptor whose gene was somatically generated. In any individual, the naïve lymphocyte population has a highly diverse antigen receptor repertoire. How do we get them activated?

33. The adaptive immune response is initiated by the recognition of non-self by the innate system. Adjuvant: material added to innoculum to stimulate the innated immune system.

34. Adaptive Immune Response • Naïve lymphocyte encounters mature dendritic cell. • Lymphocyte stops re-circulating, becomes a lymphoblast. • 1 lymphoblast can give rise to ca. 1000 daughter cells. • B cells undergo somatic diversification of the immunoglobulin genes (somatic hypermuation) • Lymphocytes differentiate to become effector cells: • B cells  plasma cells • T cells  cytotoxic T cells or helper T cells • Activation induces changes in cell-adhesion molecules • Cells execute their effector functions. • Contraction of the response: a small number of effector cells remain as memory cells.

35. Figure 8-4

36. Figure 9-9 part 1 of 2

37. Figure 9-11

38. Figure 9-12 Germinal Center Reaction (Affinity Maturation)

39. Experiments to study motility. Motility: two-photon microscopy Mike Cahalan UC Irvine http://crt.biomol.uci.edu/index.html

40. Mike cahalan videos. I plan on 3 but maybe 4. they run fast.

43. Adaptive Immune Response Dendritic cells T lymphocyte Cytotoxic T cell T helper cell B lymphocyte What effector functions? Plasma cell Antibody

44. Figure 1-16

45. Figure 1-17

46. B cell Receptor T cell Receptor

48. Figure 3-8

49. Antibody Neutralization Complement activation Induction of phagocytosis

50. Figure 8-27 T helper cells Activate macrophages and B cells