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IMM250 - TEST NOTES Lecture 3.pdf
IMM250 - TEST NOTES Lecture 3.pdf

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University of Toronto St. George

Innate immunity • Innate denotes a property of some thing or action which is essential and specific to that thing or action, and which is wholly independent of any other object, action or consequence. Also known as “inborn”. • Dont need prior exposure • Represents THE immune system in most multicellular organisms (from plants, sea urchins, flies etc.) Innate versus adaptive immunity Innate immunity • Conserved throughout evolution • In all multicellular organism • Organisms possess a set number of recognition molecules • Cells are immediately active • Has no memory Adaptive immunity • Evolved 500 million yrs ago? • Unique to vertebrates • Infinite number of recognition molecules (antibodies) • Cells require priming • Provides memory of infection o memory - immunized à react quicker Innate and adaptive immunity work together in humans • In normal individuals, infections are cleared by the innate and adaptive immune responses. • In the absence of adaptive immunity, infection are first controlled by innate immunity but cannot be cleared. • In the absence of innate immunity, infections cannot be controlled. Need innate immunity to initiate adaptive immunity. The discovery of the innate immune system • Metchnikoff first described role of phagocytes in invertebrates (star fish) • when he pricked a starfish with a rose thorn there are a bunch of cells thcame to the injury site o saw phagocytes try to engulf and capture little particles that are being liberated from the thorn How can our cells tell that something is foreign ? • Recognition of exogenous microbial products - Dr. Charles Janeway o the splinter is covered with bacteria and the bacterial products are being brought in and that is what your body is responding to. • Recognition of endogenous “danger signals” - Dr. Polly Matzinger o when you poke yourself with splinter it will cause damage to cells in the env ironment and it’s the products released from the dieing cells that initiates innate system Turns out they are both right! Innate immunity depends upon the recognition of: • MAMPs (microbial-associated molecular patterns) o “Signatures” of microbial infection - pieces of microbes • DAMPs (danger-associated molecular patterns) o Danger signals released from dead or dying cells Overview of innate immunity • Interaction between a danger signal and pattern recognition molecule will give a signal transduction event that occurs in the cell. This leads to changes in the cell so it can initiate a defence programme and hopefully the microbe will be destroyed and remo ved from the body What are MAMPs? • Also known as PAMPs (pathogen -associated molecular patterns) o Represent structural components of microorganisms unable to be modified § ie. Structural components that hold the shape of the organism Bacteria can be differentiated into 2 groups based on the “Gram -stain” Procedure: isolate bacteria of interest 1. fix them on microscope slide (with heat) 2. use crystal violet stain (purple stain) 3. use iodine to complex with crystal violet stain in order to form large complexes that are not easily removed by decolourization step 4. Decolourization step - use alcohol to try to get rid of crystal violet by bacteria 5. Counter stain with safranin (pink stain) • Using differentiation process we can classify bacteria o gram positive retain crystal violet stain throughout o gram negative lose the crystal violet stain at decolourization step and take up safranin § The basis for this stain is due to the cell walls of these bact eria Gram-positive cell wall • Example: Staphylococcus • Cell wall complex has a thick layer of peptidoglycan that takes up most of the mass or weight of the bacteria • within the cell you also have plasma membrane that’s in the inner part of the bacteria and have pieces and extension of the bacteria that hold the peptidoglycan onto the membrane called lipoteichoic acid (anchors onto cytoplasmic membrane) Gram-negative cell wall • Example: E. Coli • inner membrane - plasma membrane • then thin layer of peptidoglycan is in the space between membranes • then have an outer membrane that have lipopolysachharide (lps) aka (endotoxin) MAMPs include these bacterial cell wall products 1. Lipotechoic acid (Gram +) 2. LPS (Gram -; also called “endotoxin”) 3. Peptidoglycan (both; also the target of some antibiotics) • lipidated carbohydrates (lps) and peptide carbohydrates (peptidoglycan) o some antibiotics form holes in peptidoglycan and this releases contents of bacteria and kills them o Lipopolysaccharides  (LPS),  also  known  as  lipoglycans,  are  large  molecules  consisting  of  a   lipid  and  a  polysaccharide  joined  by  a  covalent  bond;  they  are  found  in  the  outer   membrane  of  Gram -­‐negative  bacteria,  act  as  endotoxins  and  elicit  strong  immune   responses  in  animals. o Peptidoglycan,  also  known  as  murein,  is  a  polymer  consisting  of  sugars  and  amino  acids   that  forms  a  mesh-­‐like  layer  outside  the  plasma  membrane  of  bacteria,  forming  the  cell   wall. • innate immune system acts against these products and e xtensions And also “extensions” • Flagella o base unit making up flagella is called “flagellin” § flagellin which is a *protein • flagella are present in large amounts of bacteria and our innate immune system evolved to recognize flagella MAMPs also include   • Genetic material of bacteria and viruses o *Nucleic acid: o RNA: double or single stranded § genetic material often associated with viruses o DNA: CpG sequences (cytosine and guanine separated by a phosphate, “p”) § Quite unique to microbes • These sequences are suppressed and/or modified in mammalian genetic material • Microbes have a large number of sequences CpG sequences which are long repeats of C and G separated by P, if we have this sequence in our DNA its methylated to hide it from our immune system MAMPs associated with fungus • Zymosan - carbohydrate from the cell wall of yeast • Beta-glucan - carbohydrate from the cell wall of other fungi • yeast can be recognized by our innate immune system through the recognition of a cell wall component called zymosan and a lso beta glucan o they are pure *carbohydrate and specific to fungus o we dont have these carbohydrates in our make up What are DAMPs? • Release of potassium (K+) o Released by cells with damaged membranes § K exits the cell and its another way our bodies can sense and respond to damage • High intracellular levels of reactive oxygen species (ROS) o Produced by cells that are “blocked” in phagocytic process (and probably destinedto die) o recognized as DAMP because cells blocked in phagocytosis produce a lot of ROS and high levels or ROS are associated with DAMP • ROS are extremely toxic oxygen derivatives that can kill microbes when they are in the same environment as bacteria o Our immune cells use ROS to kill bacteria K+ efflux • K+ is kept at high concentrations INSIDE the cell • Leakage means something is wrong - cell is dying o sensed as a danger signal and initiates an inflammatory event What are ROS? • Highly toxic oxygen -derived molecules o Generated by “oxidative burst” - use of oxygen by cells of the innate immune system to form ROS in order to kill microbes ROS as a DAMP • “Frustrated” phagocytosis leads to high amounts of intracellular ROS o Triggers: asbestos (lung disease), uric acid crystals (gout), aluminium (vaccine adjuvant), amyloid (accumulates in Alzheimer’s disease) • ROS as a DAMP occurs where theres high levels of intracellular ROS o under normal circumstances ROS contained in a vacuole in phagocyte intracellular o ROS gets high in a process of f rustrated phagocytosis - where a phagocyte tries to eat big chunk of something (like abestus fiber) so the cell throws ROS at it (abestus) and nothing happens and this is sensed by the cell and leads development of the innate response and mechanisms in orde r to try to clear the contamination of products MAMPs and DAMPs are the “sensees”, what are the sensors? • PRM - pattern recognition molecules o Soluble PRMs § Collectins (eg: surfactant, mannose -binding lectin), Ficolins o Cell signaling PRMS § Toll-like receptors (TLR), Nod-like receptors (NLR) o *PRMS & TLR & NLR area of research in her lab * Collectins • Assemble into multi-meric structures o Assembled into multimeric structures made up of subunits that multermerize into trimers that have ligand binding domains that are dimerized into large complexes • Bind microbial carbohydrates o They float around blood and look for carbohydrates that are specific to the microbial cell surface then collectins link to the complement system for destruction of microbe o collectin is a soluble factor that is floating around in the serum and looks for microbial patterns in order to generate innate immune response to these factors • Link to the complement system for destruction of microbe (see next week’s lecture) Cell-signaling PRMs Membrane-associated • TLR o PRM involved in sensing microbial or danger associated patterns and initiating a defence responses How they do that: o TLR stick through plasma membrane have exterior domain which binds to the MAMPS then they stick into the cytoplasm and have a domain that can connect them to different signalling pathways to generate a response in the cell Cytoplasmic • NLR o NLR are completely found within the cytosol TLRs and NLRs • History of the discovery of these PRMs • The MAMPs/DAMPs they recognize How they tell the cell that they have recognized a MAMP/DAMP • Signal transduction and activation of gene expression Christiane Nuesslein -Volhard: discovery of Drosophila Toll • Identified a protein she called “Toll” meaning “COOL” in German • Helps the Drosophila embryo to differentiate its top from its bottom Nicolas Gay: Toll and inner part of the Human IL -1 receptor is similar • Searching for proteins similar to Toll • Shows cytoplasmic domain of Toll related to that of hIL -1R (now called a TIR domain for Toll IL-1 Receptor) o IL1 is an important receptor for triggering information when it binds its cytokine IL1 • Why does a protein involved in human inflammation look like one involved in fly neural tube development? Bruno Lemaitre and Jules Hoffmann: Drosophila use Toll to defend from infection with fungus • Infected Toll-deficient adult flies with Aspergillus fumigates • All flies died after 2-3 days • Flies use Toll to defend from fungi • Thus, in Drosophila, Toll seems to be involved in embryonic development and adult immunity Ruslan Medzhitov & Charles Janeway: discovery of human Toll • Argued that an ancient immune defence system   based on the Toll signalling   might exist in humans • Searched for human  proteins that totally resemble  Drosophila Toll • also report similarity to plant proteins o they discovered the existence of TLR in mammals o the interior of the IL receptor is similar to the drosophila toll Fernando Rock & Fernando Bazan:  identification of five human “TLRs” • Identified 5 human Tolls,  which they called Toll like  receptors (TLRs)   • TLR4 same as Medzhitov’s  human Toll • 4 complete - 1 partial hTLR • 3 Drosophila TLRs • humans have a recognition system to protect themselves against different infections Bruce Beutler: TLR4 Activated by LPS • Normal mice die after being injected with
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