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IMM250 - TEST NOTES Lecture 5.doc

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University of Toronto St. George

When things go wrong… Diseases and infections caused by innate immune mutation or dysfunction Outline of the Lecture • When the innate immune system over-reacts: o Sepsis o SARS/H5N1 • Mutations in the innate immune system impacting on inflammation and infection: • Chronic granulomatous disease o Nod2 o NLRP3 o TLR signalling • Hygiene hypothesis Part 1: • When the innate immune system over-reacts: o septic shock o SARS o Avian Flu Sepsis • Sepsis is a serious medical condition characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence of a known or suspected infection. • The body may develop this inflammatory response to microbes in the blood, urine, lungs, skin, or other tissues. • High level of microbes present in blood • innitiates due to known or suspected infection in the body nd can be in any part of the body • instead of a local innate immune responce to control the infection, your whole body gets involved and produces mediators and produces septic shock Septic shock • Septic shock is a serious medical condition caused by decreased tissue perfusion and oxygen delivery as a result of infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death. Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with the infection as effectively as those of healthy adults. The mortality rate from septic shock is approximately 50% • sepsis leads to septic shock • because of this infection thas now turned systemic you now have increasedtissue perfusion so less blood flow is coming into that tissue and that tissue is deprived of oxygen, then you have multiple organ dysfunction • septic shock killed pope john paul the 2nd he had a urinary tract infection and his whole body responded to the infection Comparison With Other Major Diseases • incidence usually used as a static time and prevelance is an overview of a population and how many people have it • incidence gives you an idea how the infection is increasing in a population and prevelance tells you the total number of infections in a population over a time period • CHF conjestive heart failure • sepsis kills as many people as heart attack SARS • SARS- severe acute respiratory syndrome o Caused by a coronavirus o Resulted in a near “pandemic” (spread of an infectious disease world-wide) o Spread from China to 37 countries in weeks o One of the largest outbreaks was here in Toronto in 2003 • coronavirus looks like a crown • bats live with virus hapily and are a breeding ground for the virus • civets are cat like animals • • Transmission: o Bats thought to be reservoir (asymptomatic breeding ground) o Bats - civets – humans • Symptoms: o Flu-like (fever, sore throat, myalgia) but later, shortness of breath o Death due to lung failure o Mortality rate for outbreak was 10% Avian Flu • Caused by a bird-specific influenza virus called “H5N1” (these letters and numbers are derived from the surface proteins of the virus - “H” for hemagglutinin and “N” for neuraminidase) • number refers to number identifie so 5 referes to the fifth identified • Transmission: o Birds can be infected by the virus o Highly pathogenic for birds but can be passed to humans although inefficiently (for now!) • Symptoms: o Typical flu-like (fever, sore throat, myalgia) but later, shortness of breath, pneumonia- like symptoms o Death due to lung failure o Mortality rate could be as high as 60% of infected individuals • spread from china H5N1 infections Avian Flu - the new Spanish flu? • Spanish flu caused also by an avian influenza virus killed 50 million to 100 million people worldwide in 1918. • The worry with avian flu is that it could be as or more virulent - WHO projects 100 million deaths world-wide. These 3 diseases lead to a innate immune-mediated “cytokine storm” • Positive feed-back loop amplifies cytokine production - cytokine storm • TNF, IL-1, IL-6 and IL-8 are key mediators • in a ctokine storm theres a positive feed back loop that amplifies cytokine production, so similar to the complemente cascade have a mass of amplification of cytokines, one cytokine is turning on the production of another but its also feeding back and turning on production of more of the same cytokine so have a mass of production of cytokines and importantly in these diseases it moves from a local responce in a tissue to a whole tissue (SARS, AVIAN) being involved to a systemic responce (sepsis) • IL1b product of the inflamasome activation • IL8 chemokine that brings in neutrophils to the site of infection Initiation of septic shock • if you have a local responce, some of those bacterial products beacuse of the inefficient ability for the immune system to contain the infection the bacterial products like LPS, peptidylglycan, they start to circulate in the blood stream and start activting all the different cells that are present in the body, so endothelial cells, neutrophils, macrophages, monocytes, epithelil cells, all the cells in your system start to produce cytokines (cytokine storm) so you get a massive production of cytokines that are auto amplified as positive feedback loop producing more cytokines. and cytokines can start having effects like enhanceing the production of ROS, production of prostoglandins, production and amplication of the complementation cascade so all the systems are working together to produce a massive inflamatory responce also have increased expresion of adhesion proteins on endothelial cells throughout the body. then you start to have quagolation, you start to block the blood vessels the cells start to plug those blood vessels and you no longer purfuse the tissue with nutrients and oxygen, a lot of these mediators result in vascular instabilitiy, so you have endothelial cells that open up allowing leakage of the serum of the blood into the tissues and get vasodilation and more blood and more products come to the site • start to get quagolopothy, blood clots forming in many vesels, have high fever and leakage of capilaries, then multiple organs start to fail because of lack of nutrients and oxygen delivered to the sites SARS & Avian Flu • similar effect in lung tissue, virus is interacting with the epithelial cells of the lung which are amplifing cytokines and other mediators of the innate immune responce and also macrophages that are recurited to the site of the inflamtory responce are also producing cytokines and chemokines. • the whole lung tissue is often involved in the infection and what happenns is all the cytokines being dumped into the lung and have an influx of leukocytes and things into the lungs, dilation of the blood vessels and quagolation (blood clots that form) and tissue destruction because of this Why do people die? • Cytokine production leads to massive production of endogenous vasodilators. • Structural changes in the endothelium result in leakage of fluid causing subsequent tissue edema. • Plugging of select microvascular beds with neutrophils and clotting factors impair blood flow to organs. • Organ or lung-specific “ischemia” (restriction in blood supply). • Results in organ failure. • edema = swelling • ischemia - restriction in blood supply because of all the factors above Pathogenesis of SARS & Avian Flu - one hypothesis 1. Viruses infect alveoli 2. High levels of ROS are generated 3. ROS “oxidizes” a host lipid called PAPC 4. Ox-PAPC is recognized by mistake by TLR4! 5. Alveolar macrophage produces proinflammatory cytokines 6. Cytokine storm • dont need to know detail of PAPC • little pockets where gas exchange takes place between lung tissue and pockets of air that re forming in the lung area • virus infect tissue and • high level of ros transfers oxygen to papc molecule so it becomes oxidized • this ox-PAPC is LPS, this amplifies the inflamatory responce, in additon virus itself having this effect, our own host modified by high levels of ROS is starting to trigger TLR4 and result in hyperinflammation and more production of cytokines and enhances cytokine storm in the virus How are patients treated? • Dampen the “cytokine storm” – steroids (anti-inflammatory) • Get rid of clots - activated protein C • Vasopressors - constrict blood vessels • Type I interferons? (for SARS & Avian Flu) • bad side is that it dampens inflamation which can help you when your undergoing sepsis but its good for the infection because the virus and bacteria can start more of a foot hold and start to increase their infectious capasity • so cn dampen the inflamatory responce but can allow the virus to grow better in the infected host • have protein normally in our bodies and its efficient at getting rid of clots formed in blood vessels • it can help get rid of clots and help increase perfusion to the tissues that need to be perfused with nutrients and oxygen or else they will die • reduce dilation and blood flow • type 1 interferons are secreted by virally infected cells and actually help the spread of virus by telling nearby cells that theres a virus and then those cells become me resistant to the infection • helps resstrict the spread of the virus to the tissue Prevention? • “Tamiflu” - also for treatment – blocks viral propagation • But resistance of new viruses is likely • if overused by population then Part 2: • Mutations in the innate immune system: o chronic granulomatous disease o Crohn’s disease o NLRP3 mutations o TLR mutations Chronic granulmatous disease (CGD) • Mutations affecting NADPH oxidase (the enzyme that generates ROS) • Microbes cannot be killed • Patients have re-current infections and “granuloma” - tumor-like formations of immune cells surrounding un-digested microbes • caused by • so • and • bc mutation in enzyme CGD - histology of a granuloma • a cut granuloma • forms like a solid tumor in normal tissue and its made up of microbes that havent been able to be killed by innate immune sytem in the center of the tumor, surrounding this is neutophils that have been recruited to the site of infectionbut because they can not generate a high level of ROS in
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