L1 2 Innate Immunity and the inflammatory res_240710_155652.pdf

INNATE IMMUNITY AND THE INFLAMMATORY RESPONSE Yap Wei Boon, Ph.D Programme of Biomedical Sciences, Faculty of Health Sciences, UKM, KL Email: [email protected] LEARNING OUTCOMES In the end of the lecture, students are able to:...

INNATE IMMUNITY AND THE INFLAMMATORY RESPONSE Yap Wei Boon, Ph.D Programme of Biomedical Sciences, Faculty of Health Sciences, UKM, KL Email: [email protected] LEARNING OUTCOMES In the end of the lecture, students are able to: a) describe components in innate immunity. b) explain mechanisms involved in the activation of innate immunity. c) explain consequences of innate immunity activation (inflammatory response). INNATE IMMUNITY Pre-existing Prevent infection by pathogens. Mount an immediate defense against infectious agents.  FIRST-LINE BARRIERS TO INFECTION Physical Chemical and biochemical PHYSICAL BARRIERS  CHEMICAL AND BIOCHEMICAL Lysozyme in tears , sweat and Saliva Fatty acids HCL Lactic acid, propionic acid in vagina and urinary tract  ANTIMICROBIAL PEPTIDES IN SECRETIONS Defensins – mucosal and skin secretions Cathelicidins – mucosal secretion Collectins – bind to polysaccharides on microbes  LYMPHOID ORGANS Primary ❖ Bone marrow (B cell maturation) ❖ Thymus (T cell maturation) Secondary (immune cells encounter pathogens and become activated) ❖ Lymph node ❖ Spleen ❖ MALT (Payer’s patch)  Lymphatic vessels connect tissues with lymph nodes. lymph – contain lymphocytes (T and B cells) and tissue dendritic cells. Spleen not connected to lymphatic vessels. dealing with antigens shed into the bloodstream. Innate immune cells Mast cell  Mast cell Hypersensitivity Basophil histamine, heparin and proteolytic enzymes. Allergens surface-bound antibodies ❖ Eosinophil Hypersensitivity and parasitic infection. Production and release of toxic agents, peroxidase, eosinophil cationic protein.  Neutrophil phagocytose/engulf small pathogens. Monocyte (blood circulation) & macrophage (tissues) Engulfs pathogens and larger particles (dead cells and damaged tissues) Antigen presentation on MHC class I or class II. NK CELLS Induces IFN-γ production (activates macrophages and cell-mediated immunity). Kill tumor cells. Kill viral, intracellular pathogen and protozoan infected cells (granzyme/perforin). INFLAMMATORY RESPONSE Mediated by: Cytokines (activation and enhance responses). Chemokines (attract and recruit immune cells). Innate immune cells (phagocytosis & inflammatory response). CYTOKINES Paracrine Released by producer and acts on neighboring cells CYTOKINES Autocrine Produced, released and acts on the producer. Endocrine Released by producer into the circulation (lymphatic and blood) and acts on a distant cell. INTERFERONS Interferons IFN-α, IFN-β Produced by macrophages, fibroblast, endothelial and epithelial cells. Activated by viral dsRNA. Antiviral effects. IFN-γ Produced by lymphocytes and NK cells. Activates macrophages. MIGRATION OF CELLS FROM BLOOD STREAM INTO INFECTED TISSUES pathogens A cut Rolling a) IL-1 released by epithelial cells and polymorphonuclear (PMN) cells (innate immune cells) in the damaged tissues activates neighboring PMN. b) Activated PMN cells release TNF-α to induce vasodilation (enlargement of blood vessel). c) During vasodilation, activated endothelial cells form ligands (VCAM and ICAM) that allow rolling phagocytes such as neutrophils and macrophages in the blood to anchor on the endothelial layer.  A cut pathogens Activation and firm attachment (adhesion) a) Ligands on endothelial cells interact with receptors (selectin and integrin) on phagocytes in order to slow down their rolling. b) Activated endothelial and PMN cells also released chemokine, IL-8 to increase the number of innate immune cells including phagocytes gathered at the affected site. c) When phagocytes attach firmly to the endothelial layer, they are ready to exit from the endothelial layer.  pathogens A cut Transendothelial migration (extravasation / transexudation) a) Firm contact of phagocytes with the basement membrane. b) Phagocytes release digestive enzymes to loosen up the endothelial junctions. c) Together with the action of cytokines, phagocytes cross the endothelial layer into the affected site and engulf the pathogens. PHAGOCYTOSIS (a process involved in the inflammatory response) Recognition and Attachment - mediated by surface receptors on macrophages/neutrophils. INGESTION Formation of pseudopodia to engulf microbial cells. Inclusion of microbes in the phagosome. pseudopodia KILLING AND DEGRADATION Lysosomal dependent Chlorine product Defensins Proteolytic enzymes (active at low pH) Non-lysosomal dependent Respiratory burst Oxygen radicals NO (inhibits viral replication)  Antigen presentation (a very important process for activating cell mediated immunity, esp T cells) Antigen presenting cells (APC): macrophages, dendritic cells, B cells. MHC class I MHC class II - Endogenous - Extracellular peptides. antigens - Intracellular (bacteria). antigens - Found on APC. (viruses, - Signals the mycobacteria). activation of the - Found on all other immune nucleated cells. cells and their - Leads to inflammatory cytotoxicity. responses. THE INFLAMMATORY RESPONSE SYSTEMIC LOCAL ACUTE PHASE RESPONSE (also part of the inflammatory response) Cytokine and the brain IL-1 🡪 brain, induces fever, somnolence and anorexia (reduces energy consumption and physical activity) Cytokine and the liver IL-6 🡪 promotes acute phase proteins (APPs) synthesis in the liver. Eg. fibrinogen, haptoglobulin, C3, mannose- binding protein, serum amyloid A, C- reactive protein (CRP is an inflammatory marker). Functions of APPs Clotting system cleavage of fibrinogen into fibrin to promote blood clot (limit the entry of pathogens into the bloodstream) fibrinogen is also cleaved into fibrinopeptides (chemotactic for phagocytes) Complement system C3a, C5a mast-cell degranulation (release of histamine and degradative enzymes) Kinin system cleaved by esterases into bradykinin (pain and vasodilation).