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PRINCIPLES OF INNATE IMMUNITY. THE INNATE IMMUNE SYSTEM *First line of defense against pathogens *Components *Complement system *Macrophages and neutrophils.

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Presentation on theme: "PRINCIPLES OF INNATE IMMUNITY. THE INNATE IMMUNE SYSTEM *First line of defense against pathogens *Components *Complement system *Macrophages and neutrophils."— Presentation transcript:

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

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 *Antibody not involved

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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

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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

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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

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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

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18 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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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

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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

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

30 Figure 8-15

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

32 Figure 8-19

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

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35 Figure 8-16 part 2 of 3

36 Figure 8-16 part 3 of 3

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

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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

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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

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45 Figure 8-25

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

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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

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