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IMM250 - TEST NOTES Lecture 4.pdf
IMM250 - TEST NOTES Lecture 4.pdf

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University of Toronto St. George

Innate immunity: Cellular and humoral mediators of defense Pathogen breaches barrier and then …. • Releases MAMPs o Detected by TLR/Nod proteins (NLR) § Activates signal transduction § (Interaction between MAMP and PRM activates signal transduction) • Activates (TF) NFκB, IRF o (Which) Controls cytokine production • Releases DAMPs o Detected by NLRP (in the NLR family) § Activates signal transduction • Activates inflammasome o Controls IL-1β production Summary of TLRs and NLRs • TLRs o Detect MAMPs - through adaptor MyD88 for NFkB and TRIF for IRF § Signal transduction to NFκB and IRF • Leads to cytokine and interferon production • NLRs o Nod proteins § Detect MAMPs (peptidoglycan) - using adaptor RIP2 • Signal transduction to NFκB o Leads to cytokine production o NLRPs § Detect DAMPs (ROS) - through adaptor ASC • Signal transduction to inflammasome activation o production of IL-1β (a cytokine - we will talk about this today) Ok, the pathogen has been detected, now what…? • Innate immune mediators: both cellular and humoral (ie secreted) o Cells of the innate system § Killing mechanisms o Secreted mediators of the innate system § Killing and/or protective mechanisms General scheme of an innate immune response • Pathogen with MAMPs damages the epithelium to break through the epithelial barrier as they break through the barrier they release MAMPs o Epithelial cells ‘activated’ upon contact with microorganism - PRMs are triggered, NFκB, IRFs, Caspase 1 are activated § Mediators of innate immune defence are produced by activated epithelial cells • These are cytokines and chemokines (mediators) that call in re- enforcements! o INFLAMMATION Inflammation All these features are associated with inflammation (our body trying to fight off infection) • Heat - Swelling - Redness - Pain - Loss of Function What are Cytokines and Chemokines? • Mediators produced by epithelial cells that startinitiate the whole process of inflammation which include chemicals called cytokines and chemokines • Cytokine: o molecule that our body uses to communicate with other cells in our body o a category of signalling molecules that, like hormones and neurotransmitters, are used extensively in cellular communication; cytokines generally enhance the ability of our cells to get rid of an invading pathogen • Chemokine: o similar to a cytokine except its small and its job is chemotaxis, recruit cells to site of inflammation by following a chemical gradient of chemokine o a family of small chemotactic cytokines that act to attract other cells to the site where they are produced § A diverse collection of soluble proteins and peptides that modulate behaviour of cells at extremely small concentrations § Act both locally and systemically § Have many biological activities ( pleiotropic effects) • Some examples - Cytokines: Interleukin s (1-35 …!), Tumor necrosis factor alpha (TNFα) o Chemokines: Interleukin 8 (also known as CXCL8), monocyte chemotactic peptide 1 (MCP1) Cytokines and chemokines bring in “effector cells” - first step is to escape from blood vessels • endothelial cells o Cells that make up blood vessels underlying epithelium o are impermeable to cells in the blood stream and plasma • epithelial cell produces cytokines and chemokines • cytokines o cause vasodilatation of blood stream o cause the endothelial cells have more spaces in between them § makes them permeable to different factors present in the blood stream o consequence is that serum (the fluid blood is circulating in) starts to come out of the vessels so you get accumulation of serum factors in the sub mucosal space underneath the epithelial cells • Chemokines o attract effector cells which push their way across the epithelium to get into the inflammatory site § Effector cells - clean up infection and eat bacteria and try to restrict infection in a local area What are the cell types brought to the site of infection? • White blood cells ( leukocytes) o Leukocytes of the innate system o Leukocytes of the adaptive system - called “lymphocytes” (T and B cells) Mechanism of Cell Migration • how cells get to the site of inflamation • Tethering and rolling o Cytokine activated endothelial cells express adhesion molecules • Tethering and rolling are mediated by protein SELECTINS which allow leukocytes sticking to endothelial cells o Tethering - Adhesion molecules stick to leukocytes Migration and diap edesis • Firm adhesion flattens cell and allows for migration between the endothelial cells • Innate effector cells migrate towards site of infection by detecting and following a gradient of chemokines produced by infected epithelial cell. • diapedesis o interaction by selectin between the endothelial cell and the leukocyte - the leukocyte then flattens out and binds to a number of cells in the endothelial cell and it starts to push its way inbetween endothelial cells Cells Of The Immune System • pluripotent hemopoietic stem cell present in bone marrow and can differentiate to any leukocyte present in the immune system • myeloid proginator o differentiate to innate immune system • common lymphoid proginator o differentiate to cells of the adaptive immune system • NK cell sits on the line of adaptive and innate immunity o they are derived from common lymphoid progenitor but have more of an innate phenotype Types of phagcytes present in the blood I. Phagocytes - Monocyte/Macrophage • “Big eaters” • Are called “monocytes” in the blood - roundish cells • When they reach the tissue they are called “macrophages” – flat with lots of protrusions to seek out pathogens • Their job: eat pathogens, kill pathogens and help present chewed up pieces of pathogen to T cells (ie “antigen presentation”), production of soluble mediators • t cells start to produce adaptive immune responce “Resident” macrophages have different names • They all differentiate from blood monocytes o Liver - Kuppfer cells o Brain - glial cells o Lung – avelolar macrophage o Bone - osteoclast Phagocytosis • engulph the bacteria, then the lysosome connects with phagosome and it spits enzymes and ROS in the vacuole to kill the bacteria present in the vacuole 1. macrophage senses the bacteria by the MAMPs, TLRs and NLRs reocgnize bacteria and tell macrophage to engulph it 2. bacteria is engulphed and present in the phagosome, aka phagocytic vesicle 3. the phagosome then fuses with lysosome which is a bag of enzymes and ROS which delivers its products to the phagosome 4. at the same time we have a respiratory burst occurring within the lysosome and this is what produces ROS in order to kill the bacteria 5. the bacteria is digested by the enzymes and killed by the ROS and the phagosome spits out whats left of the bacteria in the body The mechanisms by which phagocytes kill pathogens • bactericidal - kill bacteria, • bacteriostatic - stop growth • NO has same function as ROS • defensins poke holes in the membrane • bacteria require iron for normal growth • Lactoferrin binds to iron and mops up free iron in the cell à the bacteria has no iron to survive Macrophages produce mediators that act locally and systemically • acting locally • cytokines o can tell the endothelial cells to grab leukocytes from the blood o can cause vasodilation and increase the access of the effector cells to the site of infection • TNFaplha similar effects affecting vascular permeability • IL6 brings in different immune cells and start their activation process • IL8 chemotactic factor produced by epithelial cells that brings in other cells to the site of infection • IL12 acts locally to activate cells of the adaptive immune system • G-CSF goes to progenitor cells and says start producing more phagocytes we need more effector cells • intestinal epithelium - macrophages are within the submucosal space they are interacting with the bacteria that have just crossed the epithelial barrier and they start to produce cytokines that have local effects within the area under the epithelium • macrophages produce soluble mediators - humoral factors that initiate and start to amplify the initiation at the site of infection when the macrophage starts to eat the bacteria at the site of infection they start to produce cytokines and chemokines Acting systemically: macrophage -produced mediators help to coordinate the body’s response to infection Macrophage cytokines act systemically to induce the “acute phase response” • C-reactive protein (CRP) and mannose-binding lectin (MBL) are soluble PRMS that link to the complement system (see later in this lecture) o cytokines IL1,IL6, TNFalpha when they go into the blood stream and interact with cells in the liver, the liver starts pumping out CRP and MBL which are soluble PRMS • CRP is measured in the clinic as a marker of infection • Acute phase response can go out of control - sepsis (see next week’s lecture) II. Phagocytes - Dendritic cells (DCs) • Resident cells in our mucosal tissues - “roam around” looking for pathogens • Huge extensions or “dendrites” • Their job: survey musosal sites, “sample” bacteria, chew them up and present pieces to T cells o DCs are professional “antigen presentation cells” – present antigen to T cells § DCs are key to prime adaptive immunity (more about them in later lectures) III. Phagocytes - Neutrophils • Phagocytic neutrophils respond to the epithelial chemokines interleukin-8 (IL- 8) o are highly sensitive to levels of IL8 that are produced by epithelial cells • Cells migrate from the blood into the tissue underlying the infection - usually the “first cells at the scene” Neutrophils • Also called polymorphonucelar leukocytes (“PMNs”) • Main role is to get to site of infection rapidly and ingest and kill microorganisms. o Their cytoplasm is full of granules that contain toxic products to kill pathogens o After taking up microorganisms and releasing their granules, the neutrophil will die. § Neutrophils cause a lot of “collateral” damage • Produce NETS (see subsequent slide) • high number in blood • multi lobular nuclei, and have dark granules Neutrophils trap pathogens in NETS • NETs = neutrophil extracellular traps • As neutrophil dies it extrudes its DNA o DNA is very sticky and traps bacteria § Macrophages come and clean up the mess DNA Other Innate Cells - “degranulating cells” • Basophils o Least common of the innate immune leukocytes o Are granulocytes like neutrophils- lots of toxic substances contained in granules o Their job: anti-parasitic?, produce a lot of histamine - often involved in allergic responses • Eosinophils o Also granulocytes o Their job: involved in parasitic infections and allergy • Mast cells o Also granulocytes o Their job: parasitic and allergy o Also produce lots of histamine Mast Cells Effects of degranulated substances by mast cells: • Vasodilation, increased vasopermeability, contraction of smootmuscle, bronchoconstriction, increased eosinophil, neutrophil and monocyte chemotaxis, anticoagulation • Not surprising therefore that these cells play key role in asthma, allergic diseases, eczema • They are why we need antihistamines! Degranulating cells & worms •
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