1. Innate Immune Response innate soluble mediators & receptors ( innate soluble mediators & receptors ) Lecture 3 8/9/2015

2. Pattern Recognition Receptors (PRRs) Cell surface receptors for pathogens Expressed by phagocytic cells/APCs Bind saccharides / lipids absent from host Recognise bacteria, viruses and yeasts via PAMPs (Pathogen Associated Molecular Patterns)

3. PRRs and their Specificities Phagocyte PRR Bacterial ligand (PAMP) 1- Mannose receptor Terminal mannose 2-Toll-like receptors Different bacterial/viral/ fungal components

4. Toll-like Receptors (TLRs) Pattern recognition receptors Expressed on antigen presenting cells Recognise structures common to bacteria Also recognise some viruses, parasites etc. Antigen binding leads to cell activation

5. Cell surface and intracellular TLRs 1- Cell surface receptors TLRs 1, 2, 4, 5, 6, 10 & 11 2- Intracellular receptors TLRs 3, 7, 8 & 9

6. Why so many innate soluble mediators and receptors? Vast range of pathogens potentially able to attack us Bacteria and viruses have ability to evade immune response

7. Consequences of TLR binding 1- Upregulates cytokine production, 2- Stimulates antigen presentation to T and B lymphocytes of the adaptive immune response

8. Intracellular killing of bacteria by phagocytes Phagocytosis into phagosomes Fuse with lysosomes to give phagolysosomes pH 3.5-4 is toxic to bacteria Acid proteases kill some bacteria

9. Interaction between Innate & Adaptive Immune Response Soluble mediators facilitate antigen uptake by antigen presenting cells (APC) Cell surface receptors also enhance uptake of antigen Triggers adaptive immune response

10. Summary: Innate Receptors Soluble molecules of the Innate Immune Response and phagocyte-associated Pattern Recognition Receptors recognise microbial saccharides/lipids or nucleic acids, or host stress proteins These enhance opsonisation/phagocytosis and stimulate the Adaptive Immune Response

11. The Complement System A cascade of plasma proteins that provide rapid defence against infectious agents

12. Classical pathway Immune complexes etc. Lectin pathway Bacterial carbohydrate Alternative pathway Bacterial carbohydrate C1q MBL C3b Membrane attack complex (C5b-9) C1r C1s C4 C2 C3 MASP-1 MASP-2 C4 C2 C3 fB fD Properdin C3 C5 C6 C7 C8 C9 Membrane attack pathway

14. Complement functions Activation Macrophages Neutrophils inflammation Cytolysis target cell death COMPLEMENT Ab/Ag complex removal Opsonisation Bacteria phagocytosis Increased Adaptive immunity T and B cell