BIOM 611G Medical Microbiology Innate Immune Response PDF

BIOM 611G, Medical Microbiology PCOM Georgia INNATE IMMUNE RESPONSE Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology...

BIOM 611G, Medical Microbiology PCOM Georgia INNATE IMMUNE RESPONSE Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology BMS1 & BMS2 Department of Biomedical Sciences December 04, 2024  Cellular and Molecular Immunology, 10th Ed., Abbas Chapter 4: Innate Immunity LECTURE OBJECTIVES Through the study of this content and recommended reading, the successful student will be able to: 1. Describe the innate defenses found in skin and mucous membranes. 2. Describe how the innate immune system recognizes microbes (include types of host PRRs and pathogen PAMPs, their cellular/extracellular distribution and function). 3. List the 3 major functions of the complement system and identify which biologically active fragments of complement carry out these functions. 4. Differentiate between the 3 initiation pathways (classical, alternative and lectin) of complement activation. 5. Describe the process of phagocytosis and killing, including the role of opsonins in the process. 6. Describe how complement components C3a and C5a play a role in inflammation and C3b is involved in opsonization. 7. Compare and contrast the roles of each cellular component of the innate immune system in combating infection. 8. List the steps of inflammation 9. Describe ways in which innate immunity stimulates or interacts with adaptive immunity. 2  Recognize presence of pathogen Recruit MAIN PURPOSE OF immune cells INNATE IMMUNE Remove/kill SYSTEM dead cells/foreign material/pathogens Regulate/activate adaptive immune system 3  Innate Immune System Components: An Overview Anatomic & Biochemical Bloodborne Components Barriers skin, oral mucosa, respiratory/intestinal Granulocytes, epithelium, mucus complement, macrophages, membranes, saliva, flushing anti-microbial peptides NK cells, action of tears/urine, stomach epithelial cells acid, microbiome Death of Halts infection pathogen via Lysis, Death of prior to entry enhancement of cytotoxicity pathogen phagocytosis 4  WHAT MAKES ST Describe UP THE VERY 1 LINE OF innate defenses found in skin and mucous IMMUNE membranes. DEFENSE? 5 PROTECTION VS PATHOGENS REQUIRES SEVERAL LAYERS OF DEFENSE Epithelial cells provide anatomical, chemical, and microbiological barriers to infection 6 Fig 2.5 Janeways’s Immnuobiology, 10ed. INNATE DEFENSES IN THE SKIN ▪ Physical barriers ▪ Thick keratin layer ▪ Tight junctions between keratinocytes ▪ Antimicrobial substances (AMPs) secreted by epithelial cells ▪ Defensins: lytic to microbes ▪ Abundant dendritic cells phagocytize microbes ▪ Commensal organisms ▪ Numerous cell types secrete cytokines and other inflammatory mediators ▪ Keratinocytes, Dendritic cells ▪ Mast cells, Endothelial cells Dark blue stain: dendritic cells in skin 7  INNATE DEFENSE AT MUCOUS MEMBRANES Respiratory epithelium Respiratory and GI epithelium Clinical context: Speculate on the potential consequences of the loss of ciliated epithelial cells following 8 a) influenza infection and b) increased thickness of mucous in cystic fibrosis. ST 1 LINE: PHYSICAL AND BIOCHEMICAL BARRIERS: A SUMMARY 9  Lipopolysaccharides Inflammatory ATP Inducers Urate crystals THE ‘HOW’ OF INNAT Sensor Macrophages Dendritic cells RECOGNITION: AN Cells Neutrophils OVERVIEW Inflammatory Cytokines Mediators Cytotoxicity Production of AMPs Target Induction of intracellular antiviral Tissues proteins Killing of infected cells 10 Adapted from Fig 1.6; Fig 1.10 Janeways’s Immnuobiology, 10ed.  Describe how the innate immune WHAT DOES THE system recognizes microbes. INNATE IMMUNE Include the following: SYSTEM types of host PRRs/ ACTUALLY ‘SEE’ IN pathogen PAMPs ORDER TO cellular/ extracellular distribution and ACTIVATE? function 11  THE INNATE IMMUNE SYSTEM RECOGNIZES MICROBES NON-SPECIFICALLY Pathogens have unique molecules not found on mammalian cells Collectively referred to as PAMPs – Pathogen Associated Molecular Patterns 12 http://www.youtube.com/watch?v=4rEgaOW7Exk&feature=share&list=PLAB2FC119A2CA3C PAMPS ARE RECOGNIZED VIA PATTERN RECOGNITION RECEPTORS (PRR) Most cells of the body have receptors for PAMPs, referred to as PRRs Pattern Recognition Receptors 13 RECOGNITION OF THE ENEMY BY THE INNATE IMMUNE SYSTEM Interaction of PRRs with PAMPS Types of PRRs 14 CELLULAR LOCATION OF PRRS AND PAMPS Extracellular PAMPs Plasma membrane- bound PRRs Endosomal membrane-bound PAMPs in PRRs endosome PAMPs in cytoplasm Cytoplasmic PRRs 15 TYPES AND CELLULAR LOCATIONS OF Membrane-Bound (Plasma) PRRs Membrane-Bound Cytoplasmic/cytosolic (Endosomal) ▪ Toll Like Receptors (TLRs) ▪ Inflammasomes ▪ LPS, lipopeptides, peptidoglycan, ▪ TLRs ▪ Ex: NLRP members 1, 3 and 4 flagellin, etc ▪ CpG DNA, ss or ds ▪ DAMPs (damage associated molecular ▪ Signal the nucleus to secrete RNA patterns) and PAMPs cytokines/IFN ▪ Nucleic acids of digested microbes ▪ Uric acid crystals, DNA (of dead cells) ▪ Scavenger Receptor (SR) ▪ Promote inflammation ▪ Phagocytosis of bacteria ▪ RIG-I-like receptors (RLRs) ▪ C-type lectin receptors (CLRs) ▪ Viral dsRNA ▪ Recognize terminal mannose residues ▪ Mannose-binding lectin (MBL) ▪ Cytosolic DNA sensor (CDS) ▪ Microbial dsDNA ▪ Macrophage mannose receptor ▪ Phagocytosis of bacteria ▪ N-formyl methionine receptor ▪ Bacterial proteins 16 100+ different types of invariant receptors called PRRs have been identified. (PRR) TLRS PLAY IMPORTANT ROLES IN IMMUNE FUNCTION 17 TLR SIGNALING RESULTS IN GENE ACTIVATION 1. Cytokine and chemokine production ▪ TNFα, IL-1, IL-12, type I interferons, IL-8, IL-6 (and others) 2. Transition from innate to adaptive immune response 3. Activation of antigen presenting cells (APCs) ▪ Processes pathogens into specific pathogen-derived antigens and presents them via MHC I or II to T-cells ▪ T-cell responds only when presented with both signals ▪ Cytokine signaling cascade begins ▪ Different effector cytokines in response to different pathogens 4. Most important signal >> Tcell differentiation and regulation 18 CLINICAL CORRELATION: DISORDERS LINKED TO DEFICIENCIES IN TLRs OR THEIR PATHWAYS Early-onset, invasive Streptococcus pneumoniae 1. infections or (less frequently) Staphylococcus aureus or other pyogenic infections ▪ Recessive mutations in genes encoding adaptor molecules ▪ Susceptibility decreases after first few years of life 2. Susceptibility to herpes simplex encephalitis ▪ In patients with a deficiency in TLR-3 or Unc93b (an adaptor protein associated with TLR-3, -7, -8, and -9) 19 (PRR) INFLAMMASOMES ▪ Multiprotein complexes that assemble in the cytosol of cells in response to microbes (PAMPs) or changes associated with cell injury (DAMPs) ▪ Activation leads to ▪ Inflammatory form of programmed cell death of macrophages and DCs (pyroptosis) ▪ Characterized by swelling of cells, loss of plasma membrane integrity, and release of inflammatory cytokines ▪ Generation of active forms of inflammatory cytokines ▪ IL-1β and IL-18 20 CLINICAL CORRELATION: DISORDERS LINKED TO DEFICIENCIES IN INFLAMMASOMES OR THEIR PATHWAYS 1.Gout ▪ Metabolic arthritis, pain ▪ Uric acid (MSU crystal deposition) 2. Contact dermatitis ▪ Urticaria (hives) 3. Familial cold auto inflammatory syndrome ▪ NLRP3 mutated >> overactive ▪ Intermittent episodes cold-induced fever, joint pain, urticaria, other signs/symptoms of systemic inflammation 4. Systemic juvenile idiopathic arthritis 21 SECRETED AND CIRCULATING PRRs-1 ▪ Mediate direct microbial killing, act as helper proteins for transmembrane receptors, and act as enhancers of phagocytosis (opsonins) by innate and adaptive immune effector cells. ▪ Antimicrobial Peptides ▪ Function 1: protection of skin and mucosal membranes ▪ Function 2: killing of phagocytosed organisms ▪ Secreted onto epithelial surfaces at site of injury creating a microbicidal shield that damages microorganisms prior to attachment and invasion ▪ Microbicidal against a broad range of bacteria, fungi, chlamydiae, parasites, and enveloped viruses ▪ Form pores through the outer membranes of a microbe, which disrupts the membrane integrity and leads to death. 22 SECRETED AND CIRCULATING PRRs-2 ▪ Antimicrobial Peptides: Defensins ▪ Function: disrupt bacteria, fungi, parasites, and some enveloped viruses by forming multimeric pores in the membranes of these pathogens ▪ alpha-defensins: contained in the azurophilic granules of neutrophils and are also synthesized by Paneth cells at the base of intestinal crypts ▪ beta-defensins: expressed on all epithelial surfaces, including those of the airways, urinary and gastrointestinal tracts, mouth, cornea and conjunctivae, and skin ▪ Antimicrobial Peptides: Cathelicidin ▪ Released from neutrophils, macrophages and epithelial cells and exhibits a broad range of antimicrobial activities ▪ Stimulated by induction of cytochrome P450 converting VitD to active form 🡪 certain human infections (eg, tuberculosis) may be more prevalent among populations with inadequate plasma levels of vitamin D 23 SECRETED AND CIRCULATING PRRs-3 ▪ Collectin: Mannose-binding protein/lectin ▪ Bind carbs expressed on bacterial and viral surfaces ▪ Results in chemotaxis, MBL activation of Cp, macrophage activation 🡪 Deficiency increases duration of infections ▪ Collectin: Pulmonary surfactant proteins A and D ▪ Plays role in innate defense against group B streptococci ▪ Results in chemotaxis, alternative activation of Cp, macrophage activation 🡪 Deficiency in A leads to increased susceptibility to infection 🡪 Polymorphisms linked to increased susceptibility to RSV 24 SECRETED AND CIRCULATING PRRs-4 ▪ Complement Proteins ▪ Set of over 20 different protein molecules always found in the blood and tissue ▪ Circulate in the plasma (predominantly synthesized in the liver) ▪ Present at a lower concentration in other body fluids as well as in the intracellular space ▪ Synthesized locally (many cell types) in combination with filtration from plasma ▪ C-reactive protein (CRP) ▪ Produced by hepatocytes in response to cytokines (IL-6) ▪ Reacts with phosphorylcholine in wall of some streptococci ▪ Activates complement and phagocytosis ▪ Rises 1000-fold in 24h 🡪 Indicator of inflammation 25  List the 3 major functions of the complement system and identify which complement components carry out these functions. Describe WHAT IS how complement components C3a and C5a play a role in inflammation COMPLEMENT, and C3b is involved in opsonization. REALLY? Describe how complement components C3a and C5a play a role in inflammation and C3b is involved in opsonization. 26  Complement Proteins 30+ different plasma proteins produced by liver (mainly) Play Role in Various Processes Present at a lower concentration in Recognition of other body fluids + microbial pathogens intracellular space Heat-labile; activity Detection/removal of damaged &/or Three Pathways augments apoptotic cells bactericidal activity Clearance of of sera immune complexes Classical Lectin Alternative Tissue regeneration Essential for early & angiogenesis defense & Instructing adaptive Effector arm of immunity humoral immunity 27  THE Cp SYSTEM PROCEEDS IN DISTINCT PHASES TO ELIMINATE MICROBES Effector Arm 28 Fig 2.13 Janeways’s Immnuobiology, 10ed. AN OVERVIEW OF COMPLEMENT (CP) ▪ Divided into 3 major pathways, each have common goal ▪ C3 activation 🡪 inflammation + opsonization and enhanced phagocytosis + lysis 29 FIGURE 4.12 Pathways of complement activation. PRR Locations: Cell surface membrane-bound Endosomal membrane-bound Cytoplasmic Extracellular (secreted; soluble) Collectins MBL Pulmonary surfactant proteins A & D AMPs Defensins PRRs CRP Cathelicidin Secreted; soluble Overall Function of PRRs 1. Trigger phagocytosis Complement 2. Induce complement cascade 3. Induce cell surface display of Proteins co-stimulatory molecules 4. Trigger pro-inflammatory cytokine and chemokine production 30 ACUTE PHASE RESPONSE IS IMPORTANT PART OF INNATE RESPONSE ▪Acute Phase Response coined with discovery of C-reactive protein (CRP) in serum of patients during the acute phase of pneumococcal pneumonia J Exp Med. 1930;52(4):561 ▪ During acute phase response, usual levels of various proteins maintained by homeostatic mechanisms substantially change ▪ Acute phase response accompanies both acute and chronic inflammatory states and is associated with a wide variety of disorders, including ▪ infection, trauma, infarction ▪ inflammatory arthritis's and other systemic autoimmune and inflammatory diseases ▪ various neoplasms ▪ An increase in the concentration of serum proteins (APR) accompanies inflammation and tissue injury 31  ACUTE PHASE REACTANTS (APR) Class of proteins whose plasma concentrations increases (positive acute-phase proteins) or decreases (negative acute-phase proteins) by at least 25% in response to inflammatory cytokines ▪ Positive acute-phase proteins ▪ Ex: ceruloplasmin, several components of the complement cascade, CRP, serum amyloid, fibrinogen, haptoglobin IL-1β, IL-6, and TNF-α , IFNγ ▪ Negative acute-phase reactants ▪ Ex: albumin, transferrin, and transthyretin ▪ Effects of APR: fever, anemia of chronic inflammation AND ▪ Behavioral: anorexia, somnolence, lethargy ▪ Neuroendocrine: increased production of corticotrophin-releasing hormone; muscle wasting: cachexia; impaired growth in children; altered serum concentrations of various cations, including iron, copper, and zinc; and secondary amyloidosis ▪ Can be fatal: septic shock 32 INTERFERONS (IFNS) ▪ A class of small protein and glycoprotein cytokines produced by T cells, fibroblasts, and other cells in response to tumor cells, viral infection and other biologic and synthetic stimuli. ▪ Bind to specific receptors on cell membranes ▪ Effects include enhancing the phagocytic activity of macrophages, inducing enzymes, suppressing cell proliferation, inhibiting viral proliferation, and augmenting the cytotoxic activity of T lymphocytes. ▪ Type 1 IFN: IFNa and IFNb trigger AVP (antiviral protein) production in neighboring uninfected cells which blocks viral replication in the cell ▪ Activates NK cells to kill virus infected cells ▪ Produced by leukocytes ▪ IFNg: Activate defense cells for phagocytosis (e.g. macrophages) ▪ Produced by lymphocytes ▪ Weak antiviral cytokine compared with the type I IFNs 33 INNATE CHEMICAL DEFENSES: TYPE 1 INTERFERON How did the infected cell “know” it was infected? How did it sense the intracellular presence of the virus? Interferon also enters blood and induces “flu-like” symptoms of muscle and joint pain. 34 CYTOKINES CAN HAVE A WIDE SPECTRUM OF BIOLOGICAL ACTIVITY 35 CYTOKINES OF IMMUNITY-1 INNATE IL-8: (neutrophil chemotactic factor) Macrophages, endothelial and epithelial cells; Induces neutrophil migration to infection site. 36 CYTOKINES OF IMMUNITY-2 INNATE 37 Note that IFNg and TGFb are cytokines of both innate and adaptive immunity. IF 1ST LINE OF Compare and contrast the roles of each cellular DEFENSE IS component of the innate immune system in BREACHED, combating infection. WHAT DOES Describe THE 2ND LINE the process of OF DEFENSE phagocytosis and killing, including the role of DO? opsonins in the process. 38  CELLS OF THE IMMUNE SYSTEM A. Phagocytes C. Lymphocytes 1. Neutrophils 1. Natural Killer cells (NK cells) (polymorphonuclear 2. *T-lymphocytes (T cells) phagocyte/ PMN) 3. *B-Lymphocytes (B cells) 2. Macrophages (mononuclear phagocytes) 3. Dendritic cells (DC) D. Antigen presenting cells (APCs) 1. Macrophages (pAPC) 2. Dendritic cells (pAPC) B. Granulocytes 1. Neutrophils 3. *Follicular dendritic cells (FDC) 2. Basophils 4. *B-Lymphocytes (B cells) (pAPC) 3. Eosinophils *Not component of innate immunity and will be discussed in later lectures. 4. Mast cells 39 Fig 1.3 Janeways’s Immnuobiology, 10ed. A. PHAGOCYTES 1. Neutrophils (polymorphonuclear phagocyte/ PMN) 2. Macrophages (mononuclear phagocytes) 3. Dendritic cells (DC) 40  PHAGOCYTES PERFORM PHAGOCYTOSIS Cells with a primary function to ingest and destroy microbes and get rid of damaged tissues ▪ Imagine stepping outside barefoot and getting a splinter in your foot. ▪ Why don’t you get sick from the bacteria covering the splinter? http://www.cellsalive.com/mac.htm ▪ Neutrophil phagocytosing a bacteria (video is sped up) ▪ The immune cell locates the bacteria using chemotaxis. Mayer-Scholl A, Hurwitz R, Brinkmann https://www.youtube.com/watch?v=Z_mXDvZQ6dU V, Schmid M, Jungblut P, et al. (2005) Neutrophil engulfing Bacillus anthracis 41 PHAGOCYTOSIS AND INTRACELLULAR KILLING: ANBinding 1. OVERVIEW of phagocyte to microbe 2. Formation of phagosome; microbes are ingested into phagosomes 3. Phagosomes fuse with lysosomes 4. Formation of reactive oxygen and reactive nitrogen compounds 5. Microbes are killed by enzymes and toxic substances produced in the phagolysosomes ▪ Phagocytes produce or mediate production of: ▪ Toxic oxygen radicals ▪ Peroxides ▪ Nitric oxide (NO) ROS= reactive oxygen species 42 iNOS = inducible nitric oxide synthase 43  1. NEUTROPHIL ▪ aka polymorphonuclear leukocytes (PMNs) ▪ Lobulated nucleus ▪ Most important cell in defense against extracellular bacteria ▪ ~60% of WBCs ▪ Production stimulated by G-CSF ▪ Phagocyte: killing and degradation of phagocytosed material ▪ Also kill via neutrophil extracellular traps (NETs) ▪ Express FcR for IgG and CRs ▪ Mediates earliest phase of inflammation ▪ Function for 1-2 days once in tissue hCAP18- human cationic antimicrobial protein ▪ Activated function: phagocytosis and bactericidal mechanisms First responders ▪ Abundant in pus (typically dead since short lived and when Short-lived they kill, they typically die themselves) Form pus 44 http://vimeo.com/70326148; http://www.youtube.com/watch?v=fpOxgAU5fFQ CLINICAL CORRELATION: ABNORMAL NEUTROPHIL COUNT (+/-) ▪ Neutrophilia ▪ Elevated number of neutrophils in blood often indicative of bacterial infection ▪ Neutropenia ▪ Reduction of neutrophils in blood ▪ Gram (-) aerobic bacteria (eg, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) most common ▪ Gram (+) cocci, Staphylococcus species and Streptococcus viridans most common ▪ Candida species are the most common fungi 45 2. MACROPHAGES ▪ aka mononuclear phagocyte ▪ Phagocyte: killing and degradation of phagocytosed material ▪ Tissue resident cells derived from circulating monocytes which have large horseshoe nucleus ▪ Specialized phenotype depending on tissue/organ ▪ Express many types of receptors: PRRs, FcRs, CRs ▪ Professional APC (pAPC): constitutively expresses MHC Class II ▪ Secrete: TNFa (activate vascular endothelium, inc. vascular permeability), IL-1 (activate endothelium), IL-6 (lymphocyte activation; inc. antibody production), IL-8 (recruit neutrophils), IL-12, chemokines + ▪ Activated function: phagocytosis, wound healing, killing of tumor cells, cytokine secretion, inflammation (recruit neutrophils), antigen presentation (pAPC), granuloma formation  REMEMBER: MACROPHAGES ARE DERIVED FROM MONOCYTES 47 Macrophages located in submucosal tissue first encounter pathogens and then are reinforced by neutrophils.  3. DENDRITIC CELLS (DC) ▪ Phagocyte ▪ Professional APC (pAPC): constitutively expresses MHC Class II ▪ Essential for activating naïve T cells ▪ Long-lived, similar to macrophages ▪ Classical DCs ▪ Skin, mucosa, organ parenchyma ▪ Plasmacytoid ▪ early responders to viral infections) ▪ Interstitial DCs ▪ populate organs such as heart, lungs, liver, intestines ▪ Secrete: ▪ Activated function: phagocytosis, killing of tumor cells, cytokine secretion, inflammation, antigen presentation (pAPC)  ACTIVATED MACROPHAGES AND DENDRITIC CELLS PRODUCE CYTOKINES AND CHEMOKINES Effector Functions 1. Migration into tissues 2. Killing of microbe 3. Inflammation, enhanced adaptive immunity 49 4. Tissue repair B. GRANULOCYTES 1. Neutrophils (polymorphonuclear phagocyte/ PMN) 2. Mast cells 3. Basophils 4. Eosinophils 50 2 & 3. MAST CELLS AND BASOPHILS ▪ Mast: present in tissue (skin and mucosal epithelia) ▪ Basophil: present in blood (can enter tissue) ▪ High affinity FcR for IgE ▪ Binding of IgE leads to degranuation >> histamine release (inflammation) 51 ▪ Important against helminths, allergic diseases, inflammation  4. EOSINOPHILS ▪ Blood granulocytes BM derived ▪ U-shaped nucleus ▪ Low #s in blood; can be present in peripheral tissues ▪ FcR for IgG and IgE ▪ Azurophilic granules = primary granules ▪ Contain acid hydrolases, myeloperoxidase, lysozyme ▪ Activated function: mediates killing of helminths (parasitic worms) & other parasites; allergic responses 52  1. Mast cell or basophil sensitized with IgE Allergen ▪ IgE is secreted by plasma cells following Ag (allergen) activation of B cell ▪ IgE attaches to mast cell or basophils’s FcRe 2. Cross-linking of IgE following re-exposure to allergen🡪 ▪ Degranulation with release of histamine and other mediators into extracellular space ▪ Histamine causes increased vascular permeability and smooth muscle contraction 53 http://www.youtube.com/watch?v=eVBqMXMIFnM&NR=1 http://www.youtube.com/watch?v=NFTL51FvX4Q&feature=related C. LYMPHOCYTES 1. Natural Killer cells (NK cells) 2. *T-lymphocytes (T cells) 3. *B-Lymphocytes (B cells) * Not component of innate immunity and will be discussed in later lectures. 54 1. NATURAL KILLER (NK) CELLS ▪ Make up about 10% of lymphocytes in blood and lymphoid tissue ▪ Larger than T and B cells ▪ Cytoplasm contains granules ▪ Bridges innate and adaptive immunity ▪ Receptor: CD16 and CD56 ▪ Induced by: IL-12, IL-18, type I IFN ▪ Secrete: IFN-γ, perforin, granzyme ▪ Activated function: ▪ Kill infected, stressed or damaged and tumor cells 55  NK CELLS SERVE AS EARLY DEFENSE AGAINST INTRACELLULAR INFECTIONS ▪ Nonspecifically kill virus-infected, stressed and tumor cells ▪ 2 major functions 1. Lysis of target cells 2. Production of cytokines (IFN-g and TNF-a) ▪ Take action against the following: ▪ IgG-coated cells (antibody-dependent cell-mediated cytotoxicity (ADCC) ▪ Intracellular pathogens ▪ Viruses ▪ Bacteria, ex: Leishmania, Listeria monocytogenes ▪ Protozoa, ex: Toxoplasma, Trypanasoma 56 1. NK cells release granules to lyse target cells 2. NK cells secrete IFNg to activate macrophages 57  ACTIVATING AND INHIBITORY RECEPTORS OF NK CELLS NK cells interpret presence of class I MHC Intracellular molecules as markers of normal, healthy ITIMs self, and their absence is an indication of ITAMs infection or damage. NK cells will be inhibited by healthy cells Extracellular but will not receive inhibitory signals from infected or stressed cells. NK cells are likely to receive activating signals from the same infected cells through activating receptors. Net result will be activation of NK cell to secrete cytokines and kill infected or stressed cell. 58 D. ANTIGEN PRESENTING CELLS (APCS) 1. Macrophages (pAPC) 2. Dendritic cells (pAPC) 3. *Follicular dendritic cells (FDC) 4. *B-Lymphocytes (B cells) (pAPC) * Not component of innate immunity and will be discussed in later lectures. 59  THE PROCESS OF COORDINATED COMMUNICATION OF List DIFFERENT IMMUNE the steps of CELLS AND BLOOD inflammation. VESSELS THROUGH AN INTRICATE CASCADE OF MOLECULAR SIGNALS: INFLAMMATION 60  additional effector molecules Deliver and cells to the sites of infection ESSENTIAL ROLES OF physical barrier to prevent the Provide spread of pathogen INFLAMMATI ON Promote tissue repair 61  Inflammatory Inducers (infection or tissue damage) 🡪 Inflammatory Sensors (macrophages and mast INFLAMMATO cells/basophils), Inflammatory Mediators (cytokines, chemokines) 🡪 Systemic responses and cell/tissue changes RY RESPONSE ▪ Macrophages 🡪 TNFa, IL-1, IL-8, IL-12, chemokines + PATHWAY ▪ Mast cells (localized) and basophils (circulating) 🡪 histamine ▪ Histamine 🡪 local vasodilation and capillary permeability to improve the recruitment of leukocytes to the region ▪ Damaged cells also release chemotactic factors which attract leukocytes to the site of infection Side effects include ▪ Increased blood flow 🡪 redness and heat, while increased permeability releases fluids and causes swelling and tenderness ▪ +/- Loss of function ▪ Inflammation can be either acute or chronic 62 https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/63-defence-against-infectio/inflammation.html FACTORS AFFECTING NONSPECIFIC DEFENSES ▪ Age ▪ Steroid use ▪ Stress ▪ Nutritional Status ▪ Genetics 63  ST WHEN THE 1 2 LINES OF Describe DEFENSE ways in which innate AREN’T immunity stimulates SUFFICIENT…TH or interacts with RD adaptive immunity. E 3 LINE OF DEFENSE MUST BE ACTIVATED 64 65 3 PHASE RESPONSE TO INITIAL INFECTION 1. Innate Phase Relies on pathogen recognition by 2. Induced Innate Response germline-encoded 3. Adaptive Immune Response receptors 66 Fig 2.2 Janeways’s Immnuobiology, 10ed.  PHASES OF THE IMMUNE RESPONSE 67 Fig 1.7 Janeways’s Immnuobiology, 10ed.  OVERVIEW OF IMMUNE RESPONSES 68 WHICH IMMUNE COMPONENT PROVIDES PROTECTION DEPENDS ON SITE OF INFECTION & WHETHER INTRACELLULAR OR NOT 69  A 6-year-old child fell and sustained a skin wound which became infected with extracellular bacteria. Phagocytes recruited to the injured area included which of the QUESTION following: 1 A. B. Opsonins Mast cells C. Neutrophils D. T cells E. NK cells  A 25-year-old medical student becomes infected with the flu virus 3 days before the I&I midterm exam. Which innate defense mechanism does she hope is working well enough to kill infected cells QUESTION and speed her recovery? 2 A. Neutrophils B. CD8+ CTLs C. B cells D. NK cells E. Basophils ON YOUR OWN WHAT IS THE DIFFERENCE BETWEEN INNATE AND LO3. Compare and contrast between ADAPTIVE innate and adaptive IMMUNITY? immunity 73  BASIC TENANTS OF IMMUNITY INNATE Adaptive When does it develop? Are receptors antigen-specific? What do receptors recognize? What are receptors called? How long does it take to begin responding after exposure? How long after exposure until maximal response? Alternate names 74 Remove the black highlighting to see answers. BASIC TENANTS OF IMMUNITY INNATE Adaptive Acquired over a lifetime as adaptation to When does it develop? Everyone is born with this response infection/exposure Are receptors antigen-specific? No Yes Pathogen-Associate Molecular Each receptor recognizes it’s own antigen What do receptors recognize? Patterns (PAMPs) (1 cell/receptor/antigen) What are receptors called? Pattern Recognition Receptors (PRR) Bcell or Tcell Receptor (BCR/TCR) How long does it take to begin Immediately (minutes) Lag time: Begins day 4+ responding after exposure? How long after exposure until 7+ days for maximal response (‘maximal’ can maximal response? Immediately maximal response increase with subsequent exposure to same antigen) How long does response last? Days Days to weeks Alternate names Native immunity Acquired immunity 75 Components of blood Plasma Red blood cells (Erythrocytes) White blood cells (Leukocytes ) Platelets From Dr. McAfee’s Lecture 9/7/202 BLOOD CELLS: RECOGNIZE THEM! 77 ANTIGEN PRESENTING CELLS Which is a pAPC? 1. a 2. b 3. c 4. d GRANULOCYTES PHAGOCYTES 1. a1. 1. a 2. a 2. a 3. A 3. a 4. aa MYELOID-DERIVED LYMPHOID-DERIVED CELLS 1. a CELLS 1. a 2. a 2. a 3. a 3. a 4. a 5. a 6. a INNATE IMMUNE CELLS ADAPTIVE IMMUNE CELLS 1. a 1. a 2. a 2. a 3. a 3. a 4. a 5. a 6. a 7. a EARLY DEFENSE: QUESTIONS TO CONSIDER How do the different components of How does the innate immune system innate immunity function to combat recognize microbes? different kinds of microbes? EARLY DEFENSE: QUESTIONS TO CONSIDER How do innate immune reactions stimulate adaptive immune How do you detect deficiencies in innate immunity? responses? 83