Innate Immunity Part I October 3, Dan Stetson

Transcription

1 Innate Immunity Part I October 3, 2016 Dan Stetson stetson@uw.edu 441 Lecture #3 Slide 1 of 28

2 Three lectures on innate Immunity Part 1 (Today): Introduction and concepts Overview of main components and strategies of innate immune system Part 2 (Wednesday): Receptor systems and response pathways Modules of innate immunity Part 3 (Friday): More receptor systems Complement 441 Lecture #3 Slide 2 of 28

3 Our commensal microbes outnumber our own cells Skin: LOTS of bacteria & fungi Small Intestine: per ml ~10 13 human cells >10 14 bacteria Large Intestine: per ml *Nearly all of these bugs are good for us These numbers are likely an underestimate because we can t cultivate most of our own commensal bacteria 441 Lecture #3 Slide 3 of 28

4 On average, there are >50 million viruses per ml in coastal seawater 441 Lecture #3 Slide 4 of 28 Hennes & Suttle 1995 Limnology & Oceanography Stetson 40, /03/2016

5 Viral abundance in galactic terms viruses in the ocean each 100 nm (i.e m in length) = m m / 1000 m = km km / km (i.e. 1 light year) = 10 7 light years The nearest star is Proxima centari (4.2 ly) The Crab supernova is 4000 ly Our own galaxy the Milky Way is ~150,000 ly across They would stretch farther than the nearest 60 galaxies Point: There are lots of viruses on this planet Suttle 2005 Nature 437, Lecture #3 Slide 5 of 28

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9 The Four Classes of Human Pathogens The immune system detects and protects from all of these. How? 1. Generic forms of protection: barriers to pathogen entry 2. Specific immune cell types dedicated to defense against each 3. Innate immune receptors that distinguish broad classes of pathogens 4. Lymphocytes that provide specificity and reinforce innate immune cells 441 Lecture #3 Slide 9 of 28

10 Pathogens can occupy multiple niches 441 Lecture #3 Slide 10 of 28

11 Host versus microbe: a losing battle? The evolutionary history of all organisms has been strongly shaped by infection Bubonic plague in 1300 s: half of European population Spanish Flu of 1918: 500 million infected, ~100 million dead Microbes comprise the majority of the biomass on earth Microbes reproduce fast, we reproduce slowly E. coli: 20 minutes Virus: minutes to hours Humans: decades (they can adapt and change faster than us) We only have a limited number of genes to dedicate to immune defense 441 Lecture #3 Slide 11 of 28

12 The central questions How do we detect and respond to the vast array of microbes that we constantly encounter? How do we tailor the resulting immune response to the type of pathogen? (viruses, bacteria, fungi, parasites) specificity How do we eliminate pathogens and infected cells while sparing healthy tissues? self/non-self discrimination 441 Lecture #3 Slide 12 of 28

13 The basis of the immune response Innate Immunity Adaptive Immunity Only vertebrates have an adaptive immune system (T and B cells) Evolutionarily, the oldest part of the immune system All mammals, fish, insects, plants, even bacteria have an innate immune system The innate response is always ready to respond and the repertoire of pathogens it can respond to does not change Blocks pathogen entry Recognizes pathogens Kills pathogens to limit spread Removes pathogens 441 Lecture #3 Slide 13 of 28

14 Response to an infection Old view: Innate immunity is first line of defense; Adaptive immunity is only activated when innate immune functions are insufficient to contain pathogen. New view: Innate immune recognition is actually required for the adaptive immune response and immune memory: 1: Required for T and B cell activation by pathogens 2: Instructs the response that is most appropriate for each pathogen 441 Lecture #3 Slide 14 of 28

15 Epithelial barriers protect us from pathogens Physical cell-cell junctions prevent pathogens from entering our bodies Epithelial surfaces constantly being cleared by air or fluid Cilia (hair-like appendages) clear mucosal linings Normal flora- competes for nutrients with pathogens Damage: Cuts, burns, bite, loss of internal epithelial integrity **Often results in infection 441 Lecture #3 Slide 15 of 28

16 Physical barrier: Epithelial cells First line of defense Most common portals of microbe entry: Skin Respiratory tract Gastrointestinal tract Reproductive tract Epithelial layer provides a physical and chemical barrier 441 Lecture #3 Slide 16 of 28

17 Importance of mechanical barrier: Cystic Fibrosis A genetic disease affecting about 30,000 people in the US Most CF patients die in their mid 20s or 30s from lung failure Defective chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) leads to abnormally thick mucous Patients cannot clear mucous efficiently Leads to chronic bacterial infection in the airway 441 Lecture #3 Slide 17 of 28

18 Infection occurs when pathogens breach the barriers Just under the barriers, sentinel cells survey for infection 441 Lecture #3 Slide 18 of 28

19 Phagocytes: the next line of defense Macrophages- continuously produced from monocytes. Make up ~15% of all tissue cells and monitor for pathogens. Found in large numbers in: Intestines Lung (Alveolar Macs) Liver (Kupffer cell) Spleen (clear old RBCs) Neutrophils (PMNs, polys)- Most abundant leukocytes Short lived (few days) Found in blood, but not in tissues at the steady state Macrophages and neutrophils are responsible for inflammation pain redness heat swelling 441 Lecture #3 Slide 19 of 28

20 Phagocytosis couples pathogen detection and destruction 441 Lecture #3 Slide 20 of 28

21 Movies demonstrating chemotaxis and phagocytosis Neutrophil chemotaxing towards bacterium Neutrophil phagocytosis Lecture #3 Slide 21 of 28

22 Phagocytosis of microbes also generates ROI and NO Reactive oxygen intermediates (ROIs) and Nitric Oxide (NO) are very toxic to ingested microbes Generated in phagolysosome NADPH oxidase- generates ROIs from molecular oxygen: Called the respiratory burst due to transient increase in O 2 consumption O 2- - superoxide anion Other free radicals H 2 O 2 - hydrogen peroxide made from O 2 - by superoxide dismutase H 2 O 2 in the presence of Fe 2+ can become: Hypochlorite: OCl - (BLEACH) Hydroxyl radical- OH. Inducible nitric oxide synthase 2 (inos2)- generates NO from arginine 441 Lecture #3 Slide 22 of 28

23 Importance of respiratory burst Chronic granulomatous disease (CGD)- Immunodeficiency due to inability to produce ROIs. Can t get rid of microbe so continuous recruitment of Macrophages and T lymphocytes surround microbe (granuloma) Mutation in any of the subunits of the NADPH oxidase complex Treatment: Broad spectrum antibiotics have improved survival in CGD Nitro Blue Tetrazolium (NBT) (oxidation state sensitive dye) Normal Carrier CGD patient 441 Lecture #3 Slide 23 of 28

24 Macrophage-derived cytokines and chemokines coordinate innate and adaptive immunity 441 Lecture #3 Slide 24 of 28

25 Inflammatory response Pain, redness, heat, and swelling all serve a purpose Cytokines cause increase in vascular diameter leading to increased local blood flow (heat and redness) Results in slower blood flow so cells can stick and enter Also induce adhesion molecule expression or activation Cells enter tissue by squeezing between endothelial cells (extravasation) Inflammation also results in vascular permeabilization Exit of fluid from blood into tissue to cause swelling and pain Generation of the peptide bradykinin induces pain Pain immobilizes, allows wound healing 441 Lecture #3 Slide 25 of 28

26 Recruitment of immune cells to sites of inflammation TNF and IL-1 act on endothelium to make them sticky Macs and endothelial cells also make chemokines to attract more cells N-formylmethionine-containing peptides can attract cells as well Lecture #3 Slide 26 of 28

27 Too much inflammation can be very bad: septic shock Incidence: 2 nd leading cause of death in Intensive Care Units 10 th leading cause of death overall High Mortality: Sepsis: 20% Severe sepsis: 40% Septic shock: 60% 441 Lecture #3 Slide 27 of 28

28 Summary: Part 1 The innate immune system: Uses barriers to block pathogen entry Uses sentinel cells to detect the presence of infection Orchestrates inflammation and recruitment of specialized cells to neutralize pathogens 441 Lecture #3 Slide 28 of 28