1. PRINCIPLES OF INNATE IMMUNITY

2. THE INNATE IMMUNE SYSTEM
First line of defense against pathogens
Components
Complement system
Macrophages and neutrophils
Defensins
Coagulation system
Cytokines and inflammatory cytokines
Inflammatory response
Natural killer cells

3. THE COMPLEMENT SYSTEM
A set of proteins widely distributed throughout body fluids and tissues
Proteins act in a cascade of reactions to attack extracellular forms of pathogens
Complement activation results in
Inflammatory response
Pathogens coated with complement
Complement coating of pathogens
Enhanced engulfment and destruction by phagocytes
Direct killing of pathogens 3

4. PATHWAYS OF COMPLEMENT ACTIVATION
Classic pathway
Activated by antibody
First discovered
Alternative pathway
Activated by some bacterial cell surfaces
Antibody not involved
Lectin pathway
Activated by mannose binding lectin

6. THE COMPLEMENT SYSTEM Nomenclature has developed haphazardly
Proteins of classic pathway named with capital “C” followed by a numeral (C1, C2, C3…..C9)
Cleavage fragments named as parent followed by lower case letter
“a” for smaller fragment (C3a)
“b” for larger fragment (C3b)
Some classic components participate in other 2 pathways

9. CLASSIC PATHWAY OF COMPLEMENT ACTIVATION
C1 binds to Fc region of antibody part of Ab/Ag complex
C1 is complex of 3 proteins
C1q is binding protein
C1r and C1s are proteases
C1q binds to Fc region of antibody which activates
C1r which activates C1s
Most efficient at activating complement
IgM, IgG1 and IgG3

12. CLASSIC PATHWAY OF COMPLEMENT ACTIVATION
Activated C1s cleaves C4 to
C4a and C4b
Activated C1s cleaves C2 to
C2a and C2b
C4b and C2b form complex covalently bonded to pathogen surface
C4b/C2b complex (C3 convertase) cleaves C3 to
C3a and C3b

14. ANTIBODY AND COMPLEMENT ENHANCE PHAGOCYTOSIS
Enhanced phagocytosis especially important
Streptococcus pneumoniae
Haemophilus influenzae
Cryptococcus neoformans
Macrophages and neutrophils have receptors for
Antibody
Fc-gamma for Fc region
Complement
Complement receptor 1 (CR1) for C3b

18. COMPLEMENT RECEPTORS REMOVE IMMUNE COMPLEXES
Soluble antibody/antigen complexes
Form after immune response to most infections
IC must be removed to prevent precipitation and deposition on endothelial membranes
Kidneys
Removal of IC
Complement binds to IC
Erythrocytes bind to complement by CR1

20. DIRECT KILLING OF PATHOGENS BY COMPLEMENT SYSTEM
Terminal complement proteins form “membrane attack complex”
Mechanism of attack by classic pathway
C3b binds to C3 convertase (C4b,2b) / (C4b,2a) results in
C5 convertase (C4b,2b,3b) / (C4b,2a, 3b)
C5 binds C3b of C5 convertase
C5 cleaved to
C5a and C5b
C5b initiates assembly of attack membrane components
C6 – C9
Deficiency increases susceptibility to Neisseria meningitidis and Neisseria gonorrhoeae

24. RECOGNITION OF PATHOGENS FOR PHAGOCYTOSIS
Mechanism of recognition
Toll-like receptors (innate immune receptors)
Toll-like receptors
Named for ‘Toll’  receptor in fruitfly
Polypeptides with horseshoe-shaped structure
Recognition by macrophages initiates activation
Phagocytosis
Secretion of cytokines 24

29. ACTIVATION OF MACROPHAGES
Activated macrophages secret
Cytokines
Chemokines (chemoattractant cytokines)
Inflammatory mediators
Cytokines and chemokines
Interleukin-1 (IL-1), IL-6, IL-8, IL-12 and TNF-alpha
Prostaglandins, leukotrienes, plasminogen activator, platelet-activating factor (PAF) 29

30. Figure 8-15 30

31. MIGRATION OF NEUTROPHILS INTO TISSUE (EXTRAVASATION)
Rolling adhesion
Slowing down leukocytes (margination)
Weibel-Palade bodies in vascular endothelial cells secreting P and E selectins
Tight binding
Interaction between LFA-1 and ICAM-1
Diapedesis
Passage between vascular endothelial cells
Migration to infection site 31

32. Figure 8-19 32

33. Chemokines (Chemoattractant Cytokines)
Family of small soluble molecules that stimulate activation and migration of cells
Group classification CC
Two adjacent cysteine amino acids
Chromosome 4
CXC
Two separated cysteine amino acids
Chromosome 17 33

34. Figure 8-16 part 1 of 3 34

35. Figure 8-16 part 2 of 3 35

36. Figure 8-16 part 3 of 3 36

37. BIOLOGICAL ACTIVITY OF IL-1, IL-6 AND TNF-ALPHA
Induce hepatocytes to produce acute-phase proteins
C-reactive protein (CRP)
Mannose binding lectin (MBL)
Induce bone marrow to release neutrophils
Induce hypothalamus to raise temperature
Induce fat and muscle cells to generate heat 37

38. 38

39. 39

40. DEFENSINS Family of amphipathic antimicrobial peptides
35 to 40 amino acids
Mechanism of action
Disruption of cell membranes
Classification
Alpha
Neutrophils and Paneth cells
Beta
Epithelial cells of skin, respiratory tract and UG tract 40

43. THE INNATE RESPONSE TO VIRAL PATHOGENS
Virus infected healthy cells produce
Interferon-alpha (IFN-alpha)
Interferon-beta (IFN-beta)
IFN-alpha and IFN-beta are type 1 interferons
Type 1 interferons
Inhibit virus replication
Activate natural killer (NK) cells
Increases expression of MHC-1 molecules 43

44. 44

45. Figure 8-25 45

46. NATURAL KILLER (NK) CELLS
Large granular lymphocytes that circulate in blood
Functions
Killing infected cells (cytotoxic)
Secretion of cytokines
Activation by
Type 1 interferons
Infected cells
Stimulates cytotoxic function
IL-12 and TNF-alpha
Macrophages
Stimulates cytokine secretion 46

47. 47

48. NATURAL KILLER (NK) CELLS
Activated NK cells release IFN-gamma which activates
Macrophages
Release IL-12
Positive feedback system for NK and macrophages
Differentiate infected from uninfected cells
NK cells express receptors for MHC class I molecules
Binding of NK cells to MHC class I molecules turn off NK cells
NK cells provide innate immunity to intracellular pathogens 48