21/04/15 Three main lines of defense Evolu-on of the immune system 1 2 Plasma proteins Innate Immunity: the immediate response to infec-on •  Coagula-on system: A cascade of plasma enzymes that forms blood clots. •  Pentraxins: bridging molecules to bind pathogens and e.g., pahagocytes •  Protease inhibitors •  Complement System: Lecture by Piet Gros, 12th of June. •  Plasma proteins: limit the spread of the infec-on •  Defensins: kill pathogens via perturbing their membranes 3 4 1 21/04/15 Defensins vary from one individual to another Defensins •  Pep-des of 35-­‐40 amino acids long •  Mainly produced by neutrophils and Paneth cells 5 6 Immune cells Three main lines of defense 7 More in detail at the lecture of Leila Perie, Monday, 17th of June. 8 2 21/04/15 Innate immune cells have receptors that discriminate self from non-­‐self 9 10 Chapter 3
Following recogni-on Innate Immunity
Toll-­‐like receptors sense the presence of infec-on TLR are transmembrane proteins with a Toll-­‐interleukin receptor (TIR) signalling domain on the cytoplamic side of the membrane and a horse shoe shaped sensor domain on the other side 11 12 3 21/04/15 Sensing via TLR4 starts synthesis of inflammatory cytokines Ac-va-on of resident macrophages induces inflamma-on at sites of infec-on
13 14 Neutrophils are dedicated phagocytes that are summoned to sites of infec-on Protec-on and danger induced by Macrophages 40-­‐75% of leukocytes are neutrophils Neutrophil chasing a bacteria TNF-­‐α released by macrophages induces protec-on at the local level but can lead to a catastrophe when released systemically 15 16 4 21/04/15 Neutrophils express receptors for many bacterial and fungal cons-tuents A small wound made in the ventral tail fin of a 4-­‐day-­‐old zebrafish larva results in recruitment of fluorescently tagged neutrophils (red) to the wound site within minutes, where they persist for several hours, providing a miniature model of the human wound inflammatory response. Hydrogen peroxide is implicated as the earliest signal recrui-ng neutrophils to the wound. 17 Mar-n & Feng, Nature 2009. Chapter 3
18 Innate Immunity
Neutrophils die young! Macrophages live longer…. 19 20 5 21/04/15 Movie Movie Janeway 1.1 Innate recogni-on of the pathogens 21 Immunology in News 22 Immunology in News Significance Although we know much about the molecular mechanisms of cross-­‐presenta-on, its actual contribu-on to cytotoxic T cell (CTL) immunity under physiological condi-ons in vivo is s-ll unclear. Cross-­‐presenta-on is based on the idea that dendri-c cells (DCs) are the only professional an-gen-­‐presen-ng cells able to prime naïve T cells. If DCs are not directly infected, they must take up an-gen and present it indirectly. However, recent evidence suggests that other cells also may be involved in T cell priming, which probably makes cross-­‐
presenta-on less central. This study shows that cross-­‐priming DCs generate highly restricted CTL repertoires, biased to strong MHC I binding epitopes only. Furthermore, the presence of an-gen in CD169+ macrophages is sufficient for genera-on of CTLs with broader repertoires. 23 24 6 21/04/15 Other components of the innate immune system •  NK Cells: Lecture by Paola Carrillo-­‐
Bustamante, 29th of April. 25 7