PRINCIPLES OF INNATE IMMUNITY

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PRINCIPLES OF INNATE IMMUNITY
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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

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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

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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
• Antibody not involved

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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

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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

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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

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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

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COMPLEMENT RECEPTORS REMOVE IMMUNE COMPLEXES

• 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

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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

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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

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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
• Inflammatory mediators
• Prostaglandins, leukotrienes, plasminogen
  activator, platelet-activating factor (PAF)

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Figure 8-15
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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

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Figure 8-19
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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

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Figure 8-16 part 1 of 3
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Figure 8-16 part 2 of 3
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Figure 8-16 part 3 of 3
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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

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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

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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

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Figure 8-25
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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

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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

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