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PRINCIPLES OF INNATE IMMUNITY

PRINCIPLES OF INNATE IMMUNITY. 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 . THE COMPLEMENT SYSTEM.

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PRINCIPLES OF INNATE IMMUNITY

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  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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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)

  13. Figure 8-15

  14. 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

  15. Figure 8-19

  16. 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

  17. Figure 8-16 part 1 of 3

  18. Figure 8-16 part 2 of 3

  19. Figure 8-16 part 3 of 3

  20. 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

  21. 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

  22. 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

  23. Figure 8-25

  24. 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

  25. 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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