1. The innate immune response

2. Innate and Adaptive Immunity

3. Characteristics Vertebrates and invertebrates First line of defense
Rapid
Non-specific recognition of molecular patterns
Induces the adaptive response

4. Infection Inflammation Immunity
Innate immune system

5. Functions of the (innate) immune system
Barriers:
Recognition:
Remove and destroy:
Distinguish self and non-self:
Memory?
Ask for examples

6. Functions of the innate immune system
Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells

7. Barriers to microbial invasion
Figure 2-4
Microbiota

8. Respiratory tract
Mucociliary escalator
Skin

10. Infection can occur when mechanical barriers fail
Skin wound
Pneumonia
Cystic fibrosis
Primary ciliary dyskinesia (immotile cilia)
Snakes
Urinary tract infection
Obstruction
Failure of peristalsis

11. Antimicrobial peptides
Defensins and others
Produced by epithelial cells
Broad specificity:
Bacteria
Fungi
Viruses
Actions:
Direct killing
Modulation of microbiota
Epithelial surfaces

13. Microbiota
The communities of microorganisms on normal mucosal surfaces
Bacteria, fungi, viruses, protozoa
Mechanisms of protection:
Competition
Antibacterial products
Stimulation of host defenses

14. Functions of the innate immune system
Barriers: Physical, chemical, microbial
Recognition: PAMPs, other receptors
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells

15. Toll: A drosophila gene
Discovered in 1985: embryology of drosophila
1996: Required for innate immunity
1997: Toll-like genes in mammals
Lemaitre, et al, Cell 86: (1996)

16. Recognizing pathogens: Pathogen-Associated Molecular Patterns (PAMPs)
Characteristic molecules expressed by classes of microorganisms:
Bacteria: Cell wall and cell membrane components, capsules
Viruses: DNA, RNA, coat proteins
Fungi, parasites: Surface molecules
Microbe-associated (MAMPs)
Pathogen response receptors (PRRs)

17. Toll-like receptors

18. } Ligand Recognition domain Receptor Signaling domain
Signal transduction
Gene expression

19. Other Pathogen Response Receptors

20. The inflammasome
IL-1
Endogenous pyrogen

21. Pathogen?
Helpful microbe?
Non-pathogen?
Damaged host cell?
Some of each?

22. Danger signals: DAMPs and PAMPs
Damage-associated molecular patterns (DAMPs)
Molecules released by damaged cells
Extracellular/extranuclear DNA
ATP
Lysosomal contents
Etc.
Recognize damaged host cells
Distinguish pathogens from non-pathogens

23. Classes of PAMP and DAMP receptors receptors
NOD = Nucleotide-binding oligomerization domain: activation site
NOD-like receptors, NLR
Intracellular/intracytoplasmic PRRs
RIG-like receptors (retinoid acid-inducible gene):
RLR
Cytosolic DNA and dsRNA
PAMP, DAMP receptor
RAGE:
Receptor for Advanced Glycosylation End-Produces
DAMP receptor

24. Tang D, et al Immunological Reviews. 2012;249(1):158-175.

25. Functions of the innate immune system
Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy: Phagocytes
Distinguish self and non-self: NK cells

26. Phagocyte functions
Phagocytes: Neutrophils, Macrophages, Dendritic cells
Recognition, removal and killing of pathogens
Release of necrotizing enzymes
Cytokine and chemokine secretion
Induction of an adaptive response

27. Consequences of pattern recognition by phagocytes
Binding, internalization and degradation (killing)
Release of toxic products/tissue destruction
Cytokine production
Inflammation
Activation of adaptive immunity

30. Lysosomal degradation
Kill microbes
“Collateral damage”

31. Collateral damage: Frustrated phagocytosis
Normal

34. Reactive Oxygen Species (ROS)
Enzymes:
Phagocyte oxidase
Nitric oxide synthetase (iNOS)
Myeloperoxidase
Products:
Superoxide
Hydrogen peroxide
Nitric oxide
Halides
Respiratory burst
Myeloperoxidase

35. Gross photo alert!

36. Phagocyte toxic products: Microbe killing and tissue destruction

37. Functions of the innate immune system
Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells

38. Natural killer (NK) cells: self-recognition
“Innate lymphoid cells”
Kill cells on contact
Pre-programmed
Recognize self by the presence of the Major Histocompatability Complex (MHC)
Self MHC present: no activation
Self MHC absent or abnormal: activation and killing

39. Natural Killer Cells: recognition of self
Foreign cell
Virus infected cell

40. Major Histocompatibility Molecules
Principal determinants of self-recognition
Surface-expressed
Functions:
Compatibility of transplanted tissues: Histocompatibility
Recognition by Natural Killer cells
Antigen presentation to T cells
Two classes:
MHCI: present on all nucleated cells: recognition of self
MHCII: Present on antigen presenting cells

41. When is self-MHC absent or abnormal?
Non-self MHC (example?)
Abnormal self-MHC (examples?)
Foreign cell (transplant) = non self mhc
Tumor cell = abnormal mhc
Infected cell = abnormal mhc

42. Killing by NK cells Kill by contact: “Kiss of death” Pore formation
Induce apoptosis
Toxic granules secreted directly into target cells
Cytokine production

43. IFNg
TNFa

44. Complement 20+ plasma proteins and cleavage products
Proteolytic cascade(s)
Designated by C#
Innate and adaptive immunity

45. Complement: History 1890-1900 Bactericidal serum factors
Heat-labile: Non-specific, bactericidal
Heat-stable: micro-organism specific
Heat-labile factor is necessary for (“complements”) activity of the heat stable factor
Heat-stable = antibodies
Heat-labile = complement

46. What is complement? Multiple proteins An enzyme cascade
Many functions:
Entire cascade: Direct killing
Components:
Activation of phagocytes
Chemotaxis
Different components have different functions

47. The complement cascade
Adaptive
Innate
C3 lysis

48. Actions of complement Innate Adaptive
Opsonization = the process of coating particles to make them recognizable by phagocytes

49. Membrane attack complex

50. Overview of innate immunity
Physical and chemical barriers
Phagocytosis:
Bacterial killing
Lysosomal enzymes
Toxic oxygen radicals
Cytokine and chemokine secretion
Antigen presentation
Complement activation:
Chemotaxis
Membrane attack complex
Opsonization
Adaptive immunity
Adaptive immunity