Lecture2.ppt

Immunology BE433 Prof Christine Loscher Lecture 2 Innate Immunity Overview • Front line of host defence – mucosal surfaces and external epithelia • Phagocytosis • Pattern recognition receptors– how cells see pathogens • Function of pattern recognition receptors Stages Figure of Infection 2-3 E...

Immunology BE433 Prof Christine Loscher Lecture 2 Innate Immunity Overview • Front line of host defence – mucosal surfaces and external epithelia • Phagocytosis • Pattern recognition receptors– how cells see pathogens • Function of pattern recognition receptors Stages Figure of Infection 2-3 External Epithelia Figure 2-2 part 2 of 2 Internal Epithelia Figure 2-2 part 1 of 2 Epithelial Barriers • These barriers serve as effective protection against the majority of pathogens • Pathogens that get through epithelial barriers are usually removed by innate immune mechanisms that function in the underlying tissue and therefore prevent site of infection becoming established • Seldom cause clinical disease • Provide physical, chemical and competitive protection Mucosal Epithelia • Secrete mucus which contains many glycoproteins called mucins • Pathogen coated in mucus can be prevented from adhering to epithelium • Pathogen can be expelled in the flow of mucus driven by epithelial cilia • Deficiency in this process evident in cystic fibrosis and in conditions were peristalsis in the gut fails Other surface epithelia • Can produce chemical substances that are microbicidal or inhibit growth of pathogens • Lysozyme and phospholipase A are secreted in tears and saliva. • The acid pH of the stomach and the digestive enzymes, bile salts and lysolipids in the upper GIT create chemical barrier • Anti-bacterial and anti-fungal peptides called cryptdins/defensins made by cells in the crypts of the small intestine • Surfactant proteins A & D found in lung fluid – they bind to and coat the surfaces of pathogens for phagocytosis by macrophages (opsonization) After breaking epithelial barriers…….. • Phagocytosis by macrophages • Pattern recognition • Release of cytokines and chemokines (next lecture) • Activation of complement (next lecture) Phagocytosis • When pathogen binds receptor on macrophage it activates phagocytosis (pathogen may be coated in antibody) • Pathogen surrounded by phagocytic membrane and internalized in a membrane-bound vesicle – phagosome • Phagosome becomes acidified killing the pathogen • Also have lysosomes that contain enzymes, proteins and peptides that can mediate an intracellular microbial response • Phagosome fuses with lysosome to generate phagolysosome in which the lysosomal contents are released to destroy pathogen Phagocytosis contd.. • Upon phagocytosis cells also produce a variety of other toxic molecules that help kill the engulfed pathogen • Nitric oxide • Super oxide anion (NADPH oxidase) • Hydrogen peroxide • These are directly toxic to the pathogen • Pathogen try and evade the immune system - coat their surface so that they are not recognised by the phagocyte receptor - Grow in phagosome by inhibiting their acidification and fusion with lysosome Pattern Recognition • Innate immunity lacks specificity but can distinguish between self and non-self as it recognises patterns that are common to pathogens • Pattern recognition receptors • Not clonally distributed as in adaptive immunity – a given set of receptors will be present on all cells of the same type. • Binding of the pathogens to these receptor – rapid response – no clonal expansion necessary Pattern Recognition contd.. • Surfaces of pathogens bear repeating patterns of molecular structure as do their nucleic acids • Eg. Bacterial DNA contains unmethylated repeats of the dinucleotide CpG • Eg. Viruses express double-stranded RNA as part of their life cycle Function of PRR • Stimulate ingestion of the pathogen phagocytosis • Chemotactic receptors – guides cells to sites of infection • Induce effector molecules Mannose-binding lectin receptor • Free protein in blood plasma • It recognises a particular orientation of certain sugar residues and their spacing which is only found on microbes • The interaction of these soluble receptors with pathogens leads to the binding of this complex by phagocytes • Also important in complement system Figure 2-11 part 1 of 2 Non-self/pathogen Figure 2-11 part 2Self of 2 Macrophage mannose receptor • Cell surface receptor • Recognises pathogen surfaces directly • Binds certain sugar molecules found on the surface of bacteria and some viruses • Recognition properties are similar to the MBL Scavenger receptor • Cell surface receptor • Recognises various anionic polymers and low-density lipoproteins on pathogens • Some can recognise structures that are shielded by sialic acid on normal host cells Figure 2-5 part 1 of 2 Toll like receptors (TLR) • Function as signalling receptors – trigger the induced responses of innate immunity • 11 TLR in humans (13 in mice) • distinct set of molecular patterns that are not found on self antigen • These patterns are characteristic of components of pathogens at some stage of infection • Some TLR form heterodimers/homodimers to work but not all • Have limited specificity compared with antigen receptors of the adaptive immune system Figure 2-12 Toll Like Receptors- Immune Sensors Pattern recognition receptors expressed predominantly on immune cells. For recognition of foreign antigen – bacteria, viruses, fungi and parasites Salmonella typhi Figure 2-13 TLR4 • Recognises lipopolysaccaride (LPS) - a cell wall component of gram-negative bacteria • LPS binds to CD14 and then binds to TLR4 • Sends a signal into the cell nucleus that activates transcription factors necessary to make proteins such as cytokines Figure 2-14 part 1 of 2 Figure 2-14 part 2 of 2 Activation of TLR4 • Ligand for TLR4 – bacterial lipopolysaccharide (LPS) binds CD14 • LPS/CD14 complex binds TLR4 with MD2 • All components are necessary for signaling through the receptor • Signaling results in activation of transcription factors and cytokine production – IL-12 and TNFα - associated with Th1 response TLRs • Activation of TLRs triggers the production of cytokines, chemokines and the expression of co-stimulatory molecules • Adaptive immunity dependent on the molecules induced as a consequence of innate immune recognition and signaling Summary • Innate immunity provides first line of defence – epithelial surfaces • Phagocytic cells recognise pathogens through pattern recognition receptor • These receptors are important for phagocytosis, complement and triggering production of inflammatory mediators