Lecture3.ppt

Immunology BE433 Prof Christine Loscher Lecture 3 Innate Immunity After breaking epithelial barriers…….. • Phagocytosis by macrophages • Pattern recognition • Release of cytokines and chemokines • Activation of complement Complement • A system of plasma proteins that interacts with pathogens to...

Immunology BE433 Prof Christine Loscher Lecture 3 Innate Immunity After breaking epithelial barriers…….. • Phagocytosis by macrophages • Pattern recognition • Release of cytokines and chemokines • Activation of complement Complement • A system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes • Made up of a number of plasma proteins which react with one another to opsonize pathogens and induce an inflammatory response • Some are proteases which are activated by proteolytic cleavage – zymogens • These are widely distributed throughout body fluids and tissues without effect • At sites of infection they are activated locally and trigger a series of inflammatory events Complement • The complement system activates through a triggered-enzyme cascade • Cleavage of zymogen – active complement enzyme – cleaves its substrate (another zymogen…………… • The activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive reaction – large complement response • Very tightly regulated Figure 2-18 Function of Complement • 1. Activated complement proteins that bind covalently to pathogens, opsonizing them for phagocytosis • 2. The small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site and to activate these phagocytes • 3. The terminal complement components damage certain bacteria by creating pores in the bacterial membrane Figure 2-19 Figure 2-19 part 1 of 2 Figure 2-19 part 2 of 2 Figure 2-22 Complement • Complement activation is largely confined to the surface on which it is initiated • Tightly regulated – as C3 can be spontaneously activated • Host cells have a number of regulatory proteins – DAF, CD55, factor 1, factor H • Pathogen surfaces lack these proteins therefore C3 can work Complement • Ingestion of complement tagged pathogen by phagocytes is mediated by receptors for the bound complement – 6 known • Best characterised is CR1 • Binds C3b but needs C5a (small fragment) to activate • C2 on B cells binds breakdown product of C3b. • B cell whose antigen receptor is specific for a given pathogen will receive a strongly augmented signal on binding this pathogen if it is coated with this protein Figure 2-32 Small fragments of complement • Stimulate increased blood flow, vascular permeability and adherence of phagocytes to endothelial cells • Accumulation of fluid, cells and proteins • Increased lymphatic drainage – bringing pathogen to lymph nodes • The terminal complement proteins polymerise to form pores in membranes that can kill certain pathogens • Formation of the membrane attack complex – MAC Cytokines • Small proteins released by certain cells usually in response to an activating stimulus • They induce responses through binding specific receptors or a target cell (paracrine) or itself (autocrine) • Cytokines and receptors grouped according to their structure • 2 major structural families • - hematopoietin – growth hormones and many interleukins • - TNF family • Others are structurallt distinct and belong to neither Figure 2-39 Chemokines • Chemoattractant cytokines • Induce directed chemotaxis in nearby responsive cells by binding specific receptors • Function mainly as chemoattractant for monocyte/macrophage, neutrophils, leukocytes – cells involved in innate immunity – also guide lymphocytes in adaptive immunity • 2 broad groups • - CC – bind CCR • - CXC – bind CXCR • Work along with cytokines that induce vasodilation and adhesion molecules on endothelial cells Figure 2-41 part 1 of 2 Figure 2-41 part 2 of 2 What do we know so far?? • • • • Bacteria come in and cells see it Phagocytosis Production of cytokines and chemokines Activation of acute phase proteins (systemic response) • Activation of complement • This all enables the engulfing of bacteria and the recruitment of cells to the site of infection • Also need adhesion molecules – next lecture