Human Microbiome Module 1 Part I PDF
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This document is an introduction to the human microbiome and the role of normal flora. It includes information on the types of bacteria and viruses, and how they affect the human body. It also includes class objectives and an overview of why the topic is important.
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Human Microbiome!!!!! WHY DO WE CARE? HUMAN MICROBIOME It’s estimated we have over 100 trillion bacteria in, & on us, outnumbering the number of our cells Bacterial genes account for more than 100x the human genome The microbiome may weigh as much as 5 lbs! Gut microbiome: Hel...
Human Microbiome!!!!! WHY DO WE CARE? HUMAN MICROBIOME It’s estimated we have over 100 trillion bacteria in, & on us, outnumbering the number of our cells Bacterial genes account for more than 100x the human genome The microbiome may weigh as much as 5 lbs! Gut microbiome: Helps digest food Helps regulate immune system Protect against disease causing bacteria Produce vitamins B12, thiamine & riboflavin, & vitamin K (blood coagulation) Gut-brain axis ~10 QUINTILLION virus particles on the planet!!! They outnumber bacteria 10-1 in most ecosystems!!!! The Virome CLASS OBJECTIVES Define vocab words & use them appropriately Identify the normal microbiota and where it colonizes Define opportunistic vs. strict pathogens (DITKI) List examples of the role of the normal microbiota (“flora”) Understand what happens during dysbiosis and the consequences of Compare & contrast probiotic & prebiotic Define tissue tropism & identify what is required for it Learn the 6 steps required for the establishment of infectious diseases Be able to apply some of today’s material to clinical settings Vocab words THE MICROBIOTA Core Microbiome- Species that are present at a specific site in 95% or more of individuals With some transient e.g., Streptococcus pneumoniae- not a large component of normal microbiome, but present during certain infections Colonization required Secondary microbiome- small numbers of many species that may not be widely shared by individuals Taxonomic diversity of a population is great, but the functional properties are highly conserved (functional redundancy) in microbiomes associated with health “Normal” flora depends on pathogenicity & virulence & host response Usually a mutualistic relationship NORMAL MICROBIOTA Common Locations: Skin: moist areas especially, such as the groin and between the toes Respiratory tract: nose and oropharynx Digestive tract: mouth and large intestine Urinary tract: anterior parts of the urethra Genital system: vagina Less common locations: Rest of respiratory & digestive tract Urinary bladder Uterus Diagnostically Significant Locations: Blood Cerebrospinal Fluid (CSF) Synovial fluid Deep tissues ROLE OF NORMAL FLORA 1. Keeping out invaders (aka “dibs”) Can inhibit newcomers with bacteriocins 2. Role in human nutrition & metabolism? Synthesize Vitamin K & B vitamins 3. Good & bad conversion of ingested compounds Bacteria can make carcinogenic heterocyclic amines (cooked meat) less toxic Cyclamate (artificial sweetener) is converted to carcinogen cycohexamine by bacterial sulfatases ROLE OF NORMAL MICROBIOTA 4. Immune stimulation Normal microbiota can stimulate antibodies (like immunoglobulin A aka IgA) Can provide their own “immunity” (nude mice & bacteroides) 5. Common source of infection If a normal microbiota ends up in a place they’re not supposed to be i.e. E.coli from GI tract causing UTI FREQUENT TYPES OF NORMAL BACTERIAL MICROBIOTA Effect of antibiotics on gut microbiota. Fecal samples were collected from 4 patients treated with antibiotics: Patient A, moxifloxacin Patient B, penicillin + clindamycin Patient C, cefazolin followed by ampicillin/sulbactam Patient D, amoxicillin Fecal samples collected before, during (e.g., 3_D is day 3 of therapy), & after therapy were used to assess total microbiota. Changes are noted both during therapy & after therapy is discontinued. A, Total microbiota (16S rRNA gene) B, Metabolically active microbiota (16S rRNA transcripts) WHAT HAPPENS WHEN THE NORMAL MICROFLORA IS DISRUPTED? Dysbiosis! Linked to: Anxiety, depression, schizophrenia (~90% of serotonin made in the digestive tract) Obesity (twin studies- obese twins have lower bacterial diversity & higher levels of enzymes) Type 1 diabetes- less diverse gut microbiome Celiac disease (not every patient with the genetic predisposition develop Etc. DID YOU KNOW… 1/3 OF YOUR FECES IS BACTERIA?! PROBIOTIC VS. PREBIOTIC Prebiotic- Food ingredient that supports the growth of one of more members of the microbiota Come from types of carbs (mostly fiber) that humans can’t digest Beneficial bacteria in your gut eat this fiber Probiotic- live organism that, when ingested, is believed to provide benefit to the host Commonly gram-positive bacteria (e.g., Bifidobacterium, Lactobacillus ) & yeasts (e.g., Saccharomyces ) Found in ingestible capsules & as food supplements (e.g., yogurt, kefir, kombucha) TEST YOUR KNOWLEDGE #1 What is a role of the normal microbiota? Keeping out invaders Role in human nutrition & metabolism Conversion of ingested compounds (good AND bad) Immune stimulation Common source of infection TISSUE TROPISM OF INFECTIOUS AGENTS Tissue Tropism= site preferences Hepatitis viruses=liver, cholera bacillus=small intestine HIV=any site, Staphylococcus=any site Tissue tropism affected by 1. Site of entry e.g., Gonococcus Pharyngeal gonorrhea Opthalmia Gonococcal arthritis 2. Affinity for host receptors (i.e. ACE2 with SARS-CoV-2 virus spike protein) 3. Temperature of organ (i.e. outside of feet cooler than internal organs = athlete’s feet fungal infection) BACTERIAL COLONIZATION Must resist host defenses Must compete successfully with other microbial species Take advantage of host features like fibronectin on epithelial cells Fibronectin has high preference for Gram+ In poor health/hospitalization, decrease fibronectin=increase Gram- infection (like Gram- pneumonia) Table 2-1 MMD ESTABLISHMENT OF INFECTIOUS DISEASES 1. Encounter: The agent meets the host 2. Entry: The agent enters the host 3. Spread: The agent spreads from the site of entry 4. Multiplication: The agent multiplies in the host 5. Damage: The agent, the host response, or both cause tissue damage 6. Outcome: The agent or the host wins out, or they learn to coexist **each of these events requires breach of host defenses 1. ENCOUNTER Fetus is mostly sterile environment (some pathogens can cross placenta “congenital infections” – HIV, CMV, rubella) First encounter at parturition Exo (aka birth), prepared with mother’s antibodies via blood Exo & colostrum Exo Exogenously vs. Endogenously Acquired Diseases Endo Exo=external Exo environment/others Endo= agents already in or on body 2. ENTRY Ingress of microorganisms into body cavities from outside environment Inhalation- cholera, whooping cough, Covid Ingestion- cholera, traveler’s diarrhea, food-poisoning Penetration of microorganisms into deeper tissue after crossing epithelial barrier Insect bites- malaria, plague, African sleeping sickness, Chagas disease, elephantiasis Cuts & wounds- staph infections (MRSA), subacute bacterial endocarditis (strep viridans) Depends on inoculum size & number of invading organisms Organ transplants & blood transfusions- HIV, HBV, Creutzfeldt-Jacob disease “Burrowing” of hook worms 3. SPREAD Lateral propagation- travel to contiguous tissue (e.g. infected papercut on your finger that spreads to your hand) Dissemination- travel to distant sites (e.g. via blood or CSF) Things that affect spread: Anatomical Factors e.g. bacterial abscess in lung, if it ruptures inwards bronchial tree affected (pneumonia), if it ruptures outward into pleural cavity (pleurisy) Fluid dynamics e.g. spread in fluids like blood, CSF, synovial fluid, lymph, etc. 4. MULTIPLICATION # of microorganisms present must >threshold Incubation period- time needed for infectious agents to overcome host’s early defenses Environmental factors affect multiplication- i.e. temp, pH, osmotic pressure Must evade host defenses: Constitutive defenses ComplEment Phagocytosis Induced defenses Humoral immunity Cellular immunity 5. DAMAGE Type & intensity of damage depends on the tissues & organs affected Not always caused directly by pathogen, but as a consequence of host immune response i.e. cytokine storm Direct tissue damage usually caused by toxins (i.e. botulinum), cell death Endotoxin (remember “LPS” for later) damage depends on amount. Little=fever, Lot=shock & intravascular coagulation 6. OUTCOME Depends on what happens at all of the above stages Think of a bad paper cut: Was there an endogenous encounter? Did the pathogen gain entry via the cut? Did the pathogen spread to contiguous or distant tissue? Did the pathogen multiply? Did the pathogen cause damage? * Did the pathogen subvert normal immune responses at every step?* =Infectious Disease TEST YOUR KNOWLEDGE #2 What are the six things needed for establishing a viral infection? 1. Encounter 2. Entry 3. Spread 4. Multiplication 5. Damage 6. Outcome TEST YOUR KNOWLEDGE #3 A 22-year-old female patient presents to your gynecologist office for her annual physical. She confides in you that she recently had unprotected sex with a person she met on (insert whatever hip dating site exists now). After reminding her of the dangers of unprotected sex, you take some vaginal and blood samples to test for various sexually transmitted infections. Her vaginal culture comes back positive for a large quantity of N. gonorrhoeae, however she isn’t reporting any symptoms like abdominal pain, foul smelling vaginal discharge or fever. At what stage of the establishment of infectious disease would you suspect your patient is currently in? ALSO A SCIENTIST Elisabeth Bik, PhD - Utrecht University for undergrad & PhD (Netherlands( PhD worked on developing vaccines for new class of Vibrio cholerae causing epidemics in Bangladesh & India Moved to Stanford & studied how the human oral microbiota is distinct from the gut microbiota https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941673/ Studied dolphin microbiome & its distinction from other mammals & sea dependent uBiome where she sequenced human microbiomes Started “Microbiome Digest” a blog on daily microbiome research & Scientific Integrity: has identified over 400 published papers with figure manipulation Follow her on TWITTER: @MicrobiomDigest (for fun bio games) Basic Characteristics of Pathogens WHY DO WE CARE? BASIC CHARACTERISTICS OF PATHOGENS As future physicians, we care about pathogens because pathogens cause disease & you will be treating diseases According to the CDC, more than 2.8 million antibiotic-resistant infections occur in the U.S. each year, and more than 35,000 people die as a result. In addition, 223,900 cases of Clostridioides difficile occurred in 2017 and at least 12,800 people died (CDC, 20202). 2019 Antibiotic Resistance Threat Report (CDC, 2019) lists 21 bacteria & fungi that pose threats to the US (urgent, serious, concerning, watch-list G4 Swine Flu WHY DO WE CARE? BASIC CHARACTERISTICS OF PATHOGENS https://www.cdc.gov/respiratory- viruses/data/index.html https://nextstrain.org/ncov/gisaid/global https://nextstrain.org/ncov/ https://covariants.org https://www.fda.gov/food/whole- genome-sequencing-wgs- program/genometrakr-network https://nextstrain.org/monkeypox/hmpx v1?p=full https://www.ncbi.nlm.nih.gov/pathogens/ CLASS OBJECTIVES Identify the three domains of life and what they compose Compare & contrast prokaryotes & eukaryotes (including cell walls) Understand pros and cons of being prokaryotic and be able to identify ways in which they adapt and survive Hint: RON Identify basic differences amongst different types of bacteria (gram+ vs. gram- vs. acid fast) Define fungi & distinguish how fungi differ from viruses & bacteria Define what a parasite is and their basic organizational structure Be able to identify how viruses are classified PHYLOGENETIC TREE OF LIFE PROKARYOTES VS. EUKARYOTES Bacteria Animals, Plants, Fungi, etc. *Archaea-single-celled, asexual replication, morphologically similar to bacteria, but genes and metabolic pathways more similar to eukarya THE PROS OF BEING PROKARYOTIC… Lack of membrane bound nucleus means transcription & translation can be coupled… occurring faster Binary fission is simpler & faster than mitosis Small & space saving High metabolic rates- grow quickly (some double once every 20 minutes) Being small allows microbes to have high metabolic rates = surface-to-volume ratio ↑ as size of cells ↓ Rate of biochemical reactions is limited by diffusion; smaller the cells = diffusion less limiting DID YOU KNOW? THERE ARE 10-100 TRILLION BACTERIA IN THE LARGE INTESTINE… ONLY 7.6 BILLION PEOPLE ON EARTH CONS OF BEING FREE LIVING With the exception of yeast (has a nucleus=eukaryotic), most unicellular organisms are prokaryotes 3 demands of free-living microbes: R- Resistance – survive damaging agents O- Occupancy – habitability of environment N- Nutrition – intermittent availability of food GOAL: ADAPT & SURVIVE (EFFICIENTLY) TEST YOUR KNOWLEDGE #1 What are 3 differences between prokaryotes & eukaryotes? Eukaryotes have nucleus, Prokaryotes do not Prokaryotic DNA is circular, Eukaryotic is linear No membrane bound organelles in prokaryotes Prokaryotes reproduce binary fission, eukaryotes reproduce mitosis/meiosis Prokaryotes are smaller, eukaryotes are bigger Prokaryotes 70S ribosome, Eukaryotes 80S ribosome Prokaryotes are haploid, eukaryotes are diploid (or more!) RESISTANCE Avoid host detection Develop resistance to environmental threats (i.e. temp, pH, radiation, antibiotics, etc.) Antibiotic resistant bacteria MECHANISMS OF SURVIVAL Cell wall- protect cytoplasmic membrane Outer membrane- protect cell wall Bacteria protect their cytoplasmic membrane: Gram-positive Gram-negative Acid-fast GRAM POSITIVE VS. GRAM NEGATIVE Peptidoglycan Ability of bacteria to retain purple dye & iodine after alcohol challenge (Gram+), if not counterstained with safranin (Gram-) Remember LPS from last class? = Lipopolysaccharide PEPTIDOGLYCAN NAM NAG Protects against osmotic pressure Murein/peptidoglycan shape determines bacterial shape: Rods (bacilli) Spheres (cocci) Helices (spirilla) Some antibiotics work by inhibiting synthesis of murein/peptidoglycan: penicillins, cephalosporins, & carbapenems (β-lactams) OUTER MEMBRANE & LIPOPOLYSACCHARIDE (LPS) Lipid A (endotoxin)- anchors LPS to outer membrane. Elicits fever in host Core polysaccharide- composed of short series of sugars O-antigen- hydrophilic carbohydrate chains that exclude hydrophobic compounds Hydrophilic compounds can enter cells via specialized porin channels & passive diffusion Larger molecules (B12, iron) translocated in PERIPLASMIC SPACE Compartment between two membranes Contains thin murein layer & gel-like solution for facilitating nutrition Contains degradation enzymes to make impermeable molecules smaller, & binding proteins for transport Can inactivate β-lactamases, so Gram- bacteria more resistant ACID FAST Not Gram+ nor Gram- Cell walls contain waxes Special stain needed OCCUPANCY Habitability of environment (not external agents like antibiotics) Develop mechanisms to evade common behavior of environment Movement For example, developing biofilm to prevent being washed away from gastrointestinal wall OCCUPANCY & MOVEMENT: CAPSULES, FLAGELLA, & PILI Capsule- slimy outer coating to prevent phagocytosis Flagella- long, helical filaments for motility (one or more!) Bacterial chemotaxis- movement towards substances that attract, & away from those that repel Swimming- all counterclockwise Tumbling- some counterclockwise, come clockwise Pili (fimbriae)- attachment of cells to other surfaces NUTRITION Is nutrition available for the bacteria? For example: roughly 20x/day ileocecal valve move nutrient rich contents from small intestine into cecum, intestinal bacteria feed on this, but what happens when the nutrients are gone?! CYTOPLASMIC MEMBRANE & TRANSPORT Contains permeases to facilitate entry of most metabolites Facilitated diffusion- substance carried across the membrane down a concentration gradient. Uptake driven by intracellular use Active transport- movement of molecules across cell membrane into a region of higher concentration, assisted by enzymes. Requires energy Group translocation- (phosphorylation-linked transport) energy dependent transports certain sugars, which are chemically altered in the process TEST YOUR KNOWLEDGE #2 What are some differences between Gram+ & Gram- bacteria? Gram+ have teichoic & lipoteichoic acid, thick peptidoglycan cell wall surrounding cell membrane, retain dye- iodine stain after alcohol wash Gram- have LPS outer membrane outside thin peptidoglycan cell wall that surrounds cell membrane, porin channels for transport, & periplasmic space, do not retain dye-iodine stain after alcohol wash, but retain saponin counterstain (red) WHAT ARE FUNGI AND HOW DO THEY DIFFER FROM BACTERIA? FUNGI (SINGULAR: FUNGUS) ARE A KINGDOM OF USUALLY MULTICELLULAR EUKARYOTIC ORGANISMS THAT ARE HETEROTROPHS (CANNOT MAKE THEIR OWN FOOD) AND HAVE IMPORTANT ROLES IN NUTRIENT CYCLING IN AN ECOSYSTEM. FUNGI REPRODUCE BOTH SEXUALLY AND ASEXUALLY BASICS OF FUNGI Eukaryotic (Nucleus, mitochondria, Golgi, and endoplasmic reticulum) Rigid cells walls made of chitin & glucan Cell membranes contain sterol Ergosterol (we have cholesterol) Can be targeted by antifungals Multiple forms Unicellular- e.g. “yeast” Multicellular- e.g. “mold” Dimorphic- species alternate between yeast & mold forms Depends on environmental (temp, pH, CO2) Reproduction- sexual, asexual, or both! Produce spores, budding, etc. PARASITES Parasite- an organism that lives on or in a host organism and gets its food from or at the expense of its host Two major groups: Protozoa*- amoebozoa, flagellates, ciliates, and apicomplexa *some argue about the term, but we’re going to call them protozoa Animalia: Helminths- nematodes, cestodes, trematodes Ectoparasites (Arthropods)- Mites, Lice, Fleas, Ticks, etc. Ectoparasites: lives outside the host (i.e. flea, tick, etc.) BUT WHAT ABOUT VIRUSES?! VIRUSES ARE NEITHER PRO NOR EUKARYOTIC BECAUSE THEY AREN’T “LIVING” THINGS CANNOT REPRODUCE BY THEMSELVES VIRUS CLASSIFICATION ALSO A SCIENTIST Dr. Syra Madad, DHSC, MS, MCP - Bachelor of Science degree in Psychology from the University of Maryland - Master of Science degree in Biotechnology with a concentration in Biodefense and Biosecurity - Doctoral degree in Health Science with a concentration in Global Health from Nova Southeastern University Senior Director, System-wide Special Pathogens Program at New York City Health + Hospitals Principal Investigator of NYC Health + Hospitals Center for Global Healthcare Preparedness to Special Pathogens Core Faculty in the National Emerging Special Pathogens Training and Education Center (NETEC) & Assistant Secretary for Preparedness and Response (ASPR) Assistant Professor in the Graduate Biotechnology/Biodefense Program at the University of Maryland Netflix’s “Pandemic: How to Prevent an Outbreak” NETFLIX’S “PANDEMIC” https://www.youtube.com/watch?v=fPs90HZbSVQ Dr. Syra Madad- https://www.youtube.com/watch?v=nchiJBYxCp8 (not on the exam) Host Pathogen Interactions Pt. 1 WHY DO WE CARE? HOST-PATHOGEN INTERACTIONS II Last class, we learned about normal microbiota, dysbiosis, & ESTABLISHMENT of infectious disease Today we’ll be discussing how the body fights back, aka immune system basics Don’t worry, this is an intro… we’ll cover this ad nauseum next semester CLASS OBJECTIVES Differentiate between innate & adaptive immunity Be able to describe components of the innate immune system & their function Be able to identify different immune cells based on job, role, and/or picture Be able to describe how the innate immune system activates the adaptive immune response Differentiate between the different lymphocytes of the adaptive immune response (how lymphocytes are activated & their roles) Be able to describe what antibodies are and what immunological memory is Distinguish between MHC class I & II Antigen- a foreign substance which induces an immune response, especially antibody production INNATE VS. ADAPTIVE IMMUNITY Innate Adaptive Cells of innate & adaptive immune system have common source- multipotent hematopoietic stem cell INNATE IMMUNE SYSTEM Early, generalized, first-line of defense Recognize microbes that are encountered by the host Prevent infection of the host by either eliminating the microbes or allowing them to exist on body surfaces as normal microbiota that is not harmful (and is often beneficial) Initiate adaptive immune responses and influence the nature of those responses based on the type of the invading microorganism Identifies “Non-Self” via pattern recognition receptors (PRRs) which recognize structures present in microbes but not in mammals known at Pathogen Associated Molecular Patterns (PAMPs) COMPONENTS OF THE INNATE IMMUNE SYSTEM: CELLULAR Skin, mucous membrane surfaces, nose hairs, flow of urine, coughing & sneezing- mechanical defenses Phagocytic cells (neutrophils, macrophages)- ingest & kill bacteria Pro-inflammatory cells (macrophages, mast cells, eosinophils, basophils, etc.)- induce host defenses & inflammation Antigen Presenting Cells (APCs) (dendritic cells, macrophages)- recognize, process & present antigen to lymphocytes; initiate adaptive immune response- Natural Killer Cells*- kill virus infected or damaged cells (like cancer cells) *also part of adaptive immune system Neutrophil extracellular traps (NETs)- complexes of DNA, histones, & granule proteins released by neutrophils that “catch” extracellular microbes CELLS OF THE INNATE IMMUNE SYSTEM COMPONENTS OF THE INNATE IMMUNE SYSTEM- HUMORAL Bile, gastric acid, (low pH) mucous, tears (lysozyme), normal microbiota bacteria & fungi, produce antimicrobial peptides- kill & digest microorganisms Complement- enhance phagocytosis/opsonization, induces inflammation, kills some organisms Cytokines- small secreted proteins released by cells that are involved in signaling (pro-inflammatory, anti- inflammatory, attract leukocytes) Chemokines- “chemoattractant cytokines” involved in signaling (pro-inflammatory, anti-inflammatory, attract leukocytes) COMPLEMENT- “COMPLEMENTS ANTIBODIES” Makes invading microorganisms susceptible to phagocytosis (opsonization) Promotes the inflammatory response Produces substances that are chemotactic for white blood cells Lyses some microorganisms directly (MAC) Classical- triggered by antigen-antibody complexes Alternative- triggered by bacterial lipopolysaccharides (LPS) Lectin- triggered by mannose containing polysaccharides Final product of all 3: membrane attack complex (MAC)-Binds to pathogen surface & makes membrane permeable to lyse cells *do not memorize this picture, you’ll freak out for no reason. *LPS can block MAC* TEST YOUR KNOWLEDGE #1 If LPS can block MAC, what type of pathogens would most likely be able to avoid being killed via the complement pathway? Gram Negative bacteria (because they contain LPS!) CONSEQUENCES OF RECOGNIZING ANTIGEN: INDUCED INNATE IMMUNITY Increased production of antimicrobial peptides- enhances the killing of microorganisms Secretion of numerous mediators of inflammation, such as cytokines, chemokines, etc. by pro- inflammatory cells; induces inflammation Activation of complement- enhance phagocytosis/opsonization, induces inflammation, kills some organisms Activation of clotting cascade Chemotactic attraction of phagocytic cells and lymphocytes to the site of infection Acute phase response- greatly increased production of many defense proteins and proinflammatory mediators Inflammation Brings more Erythema-increased antimicrobial cells blood supply and proteins to the site of infection INFLAMMATION IS Brings more CHARACTERIZED BY: Inflammation Edema- Increased vascular permeability antimicrobial cells & proteins to the site of infection 1. REDNESS (RUBOR) Infiltration of Chemotaxis infection site with 2. HEAT (CALOR) white blood cells 3. SWELLING (TUMOR) 4. PAIN (DOLOR) LEADS TO LOSS OF FUNCTION (FUNCTIO LAESA) TEST YOUR KNOWLEDGE #2 What immune cell type is pictured below? A. Eosinophil B. Macrophage C. Monocyte D. Neutrophil PURPOSE OF ADAPTIVE IMMUNE SYSTEM Steps in when innate immune system fails Makes up immunological memory- provides body with the ability to recognize & remember specific pathogens through their antigens Produces antibodies (Antibody-ody-odys: https://twitter.com/ravenscimaven/status/1376172066232225792?lang=en ) Humoral immune response- Antibodies recognize and bind to microbial epitopes: to prevent microbial spread by immobilization (agglutination) prevention of microbial attachment to host cells (neutralization) promotion of microbial phagocytosis and clearance (opsonization) targeting of microbial destruction by soluble molecules (complement) or by leukocytes Cell-mediated immunity- leukocytes destroy invading cells CELLS OF THE ADAPTIVE IMMUNE SYSTEM: LYMPHOCYTES CD8 “Cytotoxic” T cell- kill virus-infected & damaged cells CD4 “Helper” T cell- help cytotoxic T cells & B cells in their immune function B cells (plasma cells)- make antibodies Tregs- suppress/regulate immune response LYMPHOCYTE DEVELOPMENT, ACTIVATION, & ANTIGEN PRESENTATION Both T & B cells must go through stages of development to make sure they can distinguish “self” from “non-self” T-cells that wrongly identify “self” or identify self too-strongly are not selected- less than 2% of T-cells actually “graduate” and enter the periphery Cells become activated when presented with antigen When T cells are activated they divide & proliferate Helper (CD4) T cells- secrete cytokines & activate other cells (CD8 T cells & B cells) Cytotoxic (CD8) T cells- kill cells bearing the antigen (i.e virus infected or damaged cells) When B cells are activated they divide & proliferate & synthesize immunoglobulins B cells differentiate into plasma cells which secrete antibody IMMUNOGLOBULINS Immunoglobulin aka antibodies- glycoprotein molecules produced by plasma cells (white blood cells) Immunoglobulins are bound to B cells, while antibodies are secreted into blood & tissue INITIATION OF ADAPTIVE IMMUNE RESPONSES BY INNATE IMMUNITY AKA ANTIGEN PRESENTATION 1. Microbial antigen appears 2. Dendritic cell recognizes the microbial antigen via pattern recognition receptors 3. Dendritic cell takes up microbial antigen & migrates to lymph node & matures into an antigen presenting cell 4. Dendritic cell processes the antigen and loads it onto MHC class II molecules 5. Dendritic cell presents antigen + MHC class II molecule to CD4+ Helper T cells & activate them 6. Activated CD4+ T cells then activate B cells to differentiate into plasma cells to secrete antibody & eliminate the microbial antigen MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) Glycoproteins found on different cells and upregulated during innate immunity Used in antigen recognition to activate T cells in adaptive immunity MHC class I Presents endogenous antigens (from cytoplasm) Found on all nucleated cells Presents antigen to Cytotoxic (CD8) T cells MHC class II Presents exogenous antigens (extracellular) Found on antigen presenting cells (APCs) (dendritic cells, macrophages, B cells) Presents antigen to Helper (CD4) T cells IMMUNOLOGICAL MEMORY Immunological memory- once an infectious organism stimulates an adaptive response, subsequent encounters with that organism produce mild or even unapparent effects because of the rapid and enhanced action of antibodies or effector T cell Tolerance- responses to future exposures can be diminished TEST YOUR KNOWLEDGE #3 What are differences between MHC class I & class II? MHC class I Presents endogenous antigens (from cytoplasm) Found on all nucleated cells Presents antigen to Cytotoxic (CD8) T cells MHC class II Presents exogenous antigens (extracellular) Found on antigen presenting cells (APCs) Presents antigen to Helper (CD4) T cells ALSO A SCIENTIST Brigitte Askonas (1923-2013) -Biochemisty, PhD University of Cambridge “Mother Figure” or “Grand Dame of Immunology” Born to Jewish parents who converted to Catholism & fled Austria after Nazi takeover Studied B cells and determined their role in producing antibodies as part of the immune response, and macrophages and their role in antigen presentation “Good science gets recognition regardless of the sex of the scientist”