Lecture4.ppt

Immunology BE433 Prof Christine Loscher Lecture 4 Innate Immunity What do we know so far?? • • • • • Bacteria come in and cells see it Phagocytosis Production of cytokines and chemokines Activation of complement This all enables the engulfing of bacteria and the recruitment of cells to the site o...

Immunology BE433 Prof Christine Loscher Lecture 4 Innate Immunity What do we know so far?? • • • • • Bacteria come in and cells see it Phagocytosis Production of cytokines and chemokines Activation of complement This all enables the engulfing of bacteria and the recruitment of cells to the site of infection • Also need adhesion molecules Cell-Adhesion molecules • Recruitment of cells to site of infection is mediated by chemokines and cell-adhesion molecules • Cell adhesion molecules are induced on the surface of the local blood vessel endothelium and on the infiltrating cells • Three familes – Selectins, integrins, ICAM/ImmG • First step – reversible adherence • Second step – stronger adherence • Third step – extravasion/diapedesis • Final step – migration under the influence of chemokines Figure 2-42 Step 1 • Depends on selectins • At inflammatory sites the vessels are dilated and the slower blood flow allows the cells to come out of the centre of the blood vessel and interact with the endothelium • P-selectin appears on endothelial cell surface within minutes of exposure to inflammatory mediators eg. C5a, TNFa, LPS or histamine • This activates transcription of E-selectin and expression on cell surface a few hours later • These recognise certain glycoproteins on cells (sulfated –sialyl-Lewisx) • This interaction allows cells to adhere reversibly to vessel wall – roll along the wall Figure 2-44 part 2 of 3 MOVIE Step 2 • Depends on integrins and ICAMs • Integrins LFA-1 and CR3 involved – expressed on the infiltrating cell • Bind to ICAM1&2 on endothelium • These normally adhere weakly but chemokines bound to the surface of endothelial cells trigger a conformational change on the rolling cell – increases it adhesive properties – attaches firmly and halts the rolling Figure 2-44 part 3 of 3 MOVIE X2 Step 3 • Cell crosses the endothelial cell wall – extravasion • Also involves LFA-1 and CR3 and other molecules…….CD31 • CD31 expressed at junctions of endothelial cells – the interaction between this and LFA-1, CR3 allows cells to squeeze through these junctions • Then penetrates the basement membrane by producing enzymes that break down the extracellular matrix protein - diapedesis Step 4 • Migration of cells through tissue to the infection under the influence of chemokines • Chemokines produced at site of infection and bind to either endothelial cells (increase adherence) or protoeglycans in the extracellular matrix • Matrix-associated concentration gradient of chemokine on a solid surface along which the cell migrates • Phagocytosis – destruction of pathogen Figure 2-44 part 3 of 3 MOVIE X2 Acute phase response • Cytokines produced by macrophage have long range effects that contribute to host defence – eg. Fever • IL-1/IL-6/TNF induce the hepatocytes in the liver to synthesise acute phase proteins • Some of these mimic the action of antibodies but they have broad specificity C reactive protein • Pathogen recognition molecule • Binds to the phosphocholine portion of certain bacterial and fungal cell-wall lipopolysaccharide • C reactive protein binds to pathogen and opsonizes it but can also activate the complement cascade by binding C1 Mannose binding lectin • Increased production during acute phase response • Opsinizes pathogens and triggers complement cascade FigureFigure 2-47 part 2-471 of 2 Figure 2-46 What do we know so far?? • Bacteria come in and cells recognise it through pattern recognition receptors • Phagocytosis • Production of cytokines and chemokines • Activation of acute phase proteins (systemic response) • Activation of complement • Need adhesion molecules for cells to get into site from blood stream • This all enables the engulfing of bacteria and the recruitment of cells to the site of infection Adaptive Immunity • Lymphocyte development • Antigen recognition by T cell • T cell-mediated immunity