Innate Immune Protection PDF

Innate Immune protection Dr Helen Collins Department of Immunobiology Faculty of Life Sciences & Medicine Immunology Roadmap Innate immunity Adaptive immunity Microbes B lymphocytes Antibodies Epithelial...

Innate Immune protection Dr Helen Collins Department of Immunobiology Faculty of Life Sciences & Medicine Immunology Roadmap Innate immunity Adaptive immunity Microbes B lymphocytes Antibodies Epithelial barriers T lymphocytes Phagocytes C3a C3b Effector T cells Complement NK cells $#@%! Innate immunity is a non specific defence mechanism that a host uses immediately or within several hours after exposure to antigen. 0-4 hours Innate immunity (natural immunity) 4-96 hours Early, induced response >96 hours Acquired immunity (adaptive immunity) Characteristics of the innate immune system: This is the immunity you are born with! Designed to be very fast - within hours Ancient evolution - components of the innate immunity found in invertebrates - amoebae, snails, fruit flies Responds exactly the same way each time Uses a handful of molecules to recognise that infection is present Induces and directs the acquired/adaptive immune response Components of the innate immune system: 1. Physical / anatomical barriers: skin GI tract respiratory tract mucosal epithelia 2. Secreted compounds: antibacterial compounds complement natural antibodies cytokines 3. Cellular components: phagocytes NK cells Goals of the innate immune response: Prevent entry of the pathogen!  Physical barrier protection: skin Produces anti-microbial compounds E Coli E Coli Physical barrier protection: GI Tract peristalsis hydrochloric acid production low pH Mechanical and secreted protection Eyes blinking tears Tears, sweat and saliva contain lysopzyme which destroys bacteria walls Internal protection: Microbial competition Immune protection: preventing pathogen entry Physical Mechanical Secreted 0-4 hours Innate immunity (natural immunity) 4-96 hours Early, induced response >96 hours Acquired immunity (adaptive immunity) Goals of the innate immune response: Recognise the pathogen! One of the first things that the body must do is to detect the presence of microorganisms  Recognising the pathogen The innate immune response does not recognise every possible antigen. Recognises a few highly conserved molecular structures present in many different microorganisms Pathogen Associated Molecular Patterns = PAMP Present in the microorganism but not the host Essential for the survival of the pathogen Lipopolysaccharide (LPS) Lipoteichoic acid from Gram negative bacteria from Gram positive bacteria Recognising the pathogen Pattern Recognition Receptors = PRR 1. Collectins - serum 2. Toll like receptors - membrane 3. Nod like receptors - cytoplasm Collectins Family of proteins present in solution Collagen-like region and a lectin region = collectin Interacts with effector parts of immune system Binds to sugar molecules on surface of pathogen eg. mannose Toll like receptors (TLR) Toll proteins first identified in the fruit fly - Drosophila melanogaster At least 10 mammalian homologues  Gram- bacteria Toll like receptors (LPS) Gram+ bacteria TLR4 Flagellin (peptidoglycan, TLR2 lipopeptide) RNA virus TLR5 (dsRNA, polyl:C) TLR1 TLR3 Mycoplasma (lipopeptide) TLR7 TLR6 RNA virus (ssRNA) TLR10 TLR8 TLR9 ? Unmethylated CpG DNA NOD like receptors NOD 1 senses g-glutamyl diaminopimelic acid NOD 2 senses Muramyl dipeptide NOD like receptors NOD 1 senses g-glutamyl diaminopimelic acid NOD 2 senses Muramyl dipeptide Effector mechanisms of the innate immune response Complement Phagocytosis & killing Cytokines Activation of adaptive immunity Complement Series of proteins that circulate in blood and tissue fluids Operates via a cascade ie. One product induces the formation of the next Classical MB-lectin Alternative Antigen: Mannose on Key protein is C3 which pathogen Pathogen antibody complex C1q, C1r, C1s MBL, MASP C3, B, D is activated by C3 C4, C2 C4, C2 convertase C3 convertase C4a, C3a, C5a C3b Terminal components C5b, C6,7,8,9 membrane attack complex Recruitment Opsonisation phagocytosis Lysis Classical MB-lectin Alternative Antigen: Mannose on pathogen Pathogen antibody complex C1q, C1r, C1s MBL, MASP C3, B, D C4, C2 C4, C2 C3 convertase C3a C3 C3b C4a, C3a, C5a C3b Terminal components C5b, C6,7,8,9 membrane attack complex Recruitment Opsonisation phagocytosis Lysis Phagocytosis Monocyte/ Neutrophil macrophage Mature from circulating monocytes Found only in blood Found in large numbers in GI tract, Short lived lung, liver, spleen Relatively long lived Phagocytosis Recognition of the pathogen by receptors on the phagocyte leads to the ingestion and destruction Killing mechanisms of macrophages and neutrophils Reactive oxygen intermediates (more in neutrophils) Following phagocytosis there is an increase in O2 uptake respiratory burst Oxygen is reduced by NADPH oxidase to form hydroxyl radicals and hypochlorite DNA damage and alterations in bacterial membranes Killing mechanisms of macrophages and neutrophils Reactive nitrogen intermediates Interferon gamma (more in macrophages) Tumor necrosis factor L-arginine to L-citrulline generates NO radicals Catalysed by the enzyme inducible nitric oxide synthase (iNOS, NOS2) induced by cytokines and bacterial components NO synthetase DNA damage and alterations O2 + L-arginine NO + citrulline in bacterial membranes Cofactor tetrahydrobiopterin  Skin prevents pathogen entry Recognise Recruit Ingest Cytokines Proteins “Intercellular messengers” Bind to specific receptors Can be activating or deactivating In the innate immune response they are mainly activating IL-1 (interleukin 1) IL-6 (interleukin 6) TNFa (tumour necrosis factor a) Chemokines Class of cytokines with chemoattractant properties Promote inflammation by enabling cells to adhere to the surface of blood vessels and migrate to infected tissue Eg. IL-8 produced by macrophages and endothelial cells MCP (monocyte chemotactic protein) Interferons Type 1 interferons IFNa and IFNb produced in response to virally infected cells Natural Killer Cells Kill virally infected cells and tumour cells Responsive to TNFa, IL-12 Produce IFNg Critical cytokine - activates macrophages upregulates MHC molecules together with IL-12 stimulates differentiation of CD4 Th1 cells Innate immunity to adaptive immune response Signal 1 Antigen presenting cell Effector T cell Naïve T cell MHC TCR CD86 CD28 Signal 2: ‘co-stimulation’ TLR recognise Pathogen PAMPS Cytokines (IL-12, IL-6, TNFα) Antigen presenting cells Macrophage B cell Dendritic cell Dendritic cell (DC) Mature DC present antigen to activate T cells MHC CD40 Immature DC Mature DC MHC MHC MHC Summary 0-4 hours Innate immunity (natural immunity) 4-96 hours Early, induced response >96 hours Acquired immunity (adaptive immunity) Recognises pathogen - pattern recognition receptors complement receptors Ingests pathogen - Phagocytosis opsonisation by complement Recruits cells - inflammation cytokine/chemokine production Induces specific immune - production of IL-12, IFNg response antigen processing Summary Skin prevents pathogen entry Recognise PRR to determine self from non self PAMPS Recruit Complement Lysis Opsonisation Recruitment of macrophages and neutrophils C3a C3 C3b Ingest Phagocytosis Cytokines and chemokines Induce adaptive immunity