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Foundations of Disease > Exam 1: Innate Immunity & Phagocytes > Flashcards

Exam 1: Innate Immunity & Phagocytes Flashcards

1
Q

Innate Immune System

Definition

A

Set of host defense mechanisms that are always in place to provide early protection against microbial infections.

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2
Q

Innate Immunity

Functions

A
  1. Controlling infection and in some cases eliminating microbial pathogens prior to any symptom onset
  2. Facilitating the initiation and development of pathogen-specific adaptive immune responses
  3. Cooperating with adaptive immune defenses to effectively eliminate microbial pathogens
  4. Removes damaged tissues and promote repair
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3
Q

External Defenses

A

Physical and Mechanical Barriers:

  • Stratified squamous epithelium
  • Mucus layer
  • Mucocilliary escalator
  • Peristalsis
  • Normal Flora

Chemical and Biochemical Barriers:

  • Sweat and sebaceous secretions
    • Lactic acid
    • Fatty acids
    • Waxes
    • Alcohols
  • Gastric acid
  • Digestive enzymes
  • Bile salts
  • Lysozyme
  • Lactoferrin
  • Transferrin
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4
Q

Internal Defenses

A

Cellular Components:

  • Neutrophils
  • Monocytes/macrophages
  • Natural killer cells

Soluble Components:

  • Complement system
  • Cytokines
  • Chemokines
  • Acute phase proteins
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5
Q

Innate Immunity

Recognition

A
  • Recognize repeating patterns of molecular structure that are common to certain classes of pathogens ⇒ PAMPs
  • Recognize tissue damage associated molecules ⇒ DAMPs
  • Structures are not expressed by host cells and signal the presence of non-self or foreign antigens or injury
  • Shows coarse specificity
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6
Q

Pathogen Associated Molecular Patterns

(PAMPs)

A
  • Conserved molecular structures common to classes of pathogens
  • Often part of essential structures with limited variability
  • Recognized by cells of the innate immune system
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7
Q

Damage Associated Molecular Pattern Molecules

(DAMPs)

A
  • Molecules generated or released following tissue damage
    • Induced by microbial infection
    • Induced during a non-infectious inflammatory response where cells are damaged or stressed
      • Trauma
      • Burns
      • Chemical toxic exposure
      • Ischemia/reperfusion injury
  • Released during necrotic death but not apoptotic death
  • Recognized by the innate immune system
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8
Q

Pattern Recognition Receptors

(PRR)

A

Innate immune system receptors for PAMPs and DAMPs

  • Germ-line encoded (no somatic recombination)
  • Limited repertoire compared to T/B cell receptors
  • Are not clonally distributed
  • Present on all cells of the same lineage
    • I.E. all macrophages have a certain type regardless of location
  • Families of PRR’s exist to respond to specific treats i.e. extracellular, cytosolic, and endosomal classes
    • Cell-associated PRR:
      • Toll-like receptors
      • Scavenger receptors
    • Soluble recognition molecules:
      • Collectins
        • Collagen-containing carbohydrate binding proteins
      • Complement
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9
Q

Toll-Like Receptors

A
  • Prototypical PRR
  • On cytoplasmic and endosomal membranes
  • After binding ligand will dimerize to transduce a signal
  • Have relatively conserved cytoplasmic tails
    • Activate common adaptor proteins
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10
Q

Toll-like Receptor

Activation

A

Functions through two common adaptor proteins:

  • MyD88
    • Activates NF-𝛋B transcription factors
    • Turns on genes associated with:
      • Proinflammatory response
      • Cytokine response
      • Stimulation of adaptive immunity
  • TRIF
    • Activates IRF transcription factors
    • Turns on Type 1 Interferon genes
    • Important in viral infections
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11
Q

Activated PRR

Functions

A
  1. Phagocytosis and killing of the organism
  2. Recruitement of immune cells to the site of infection
  3. Production of effector molecules that:
    • Limit pathogen growth
    • Recruit and activate additional immune cells to the site of infection (T/B cells)
    • Influence the development of the adaptive immune response
  4. Tissue repair and remodeling
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12
Q

Innate Immunity

Defense Against Extracellular Bacteria

A
  1. Phagocytes
  2. IFN-γ
  3. Complement
  4. Inflammation
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13
Q

Neutrophils

(PMNs)

A
  • Short-lived cell
  • Predominant WBC of peripheral blood
  • Contains numerous granules which fall into two categories:
    • Primary (Azurophilic) granules: contain myeloperoxidase and cationic proteins
    • Secondary (specific) granules: contain lysozyme and lactoferrin
  • First cells to arrive at an inflammatory focus (~6-12 hrs)
  • Major phagocytic cell
  • Major defense against pyogenic bacteria:
    • Staphylococcus
    • Streptococcus
    • Neisseria
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14
Q

Mononuclear Phagocytes

A

Monocytes/Macrophages

  • Large, long-lived cells
  • Monocytes in blood ⇒ macrophages in tissue
  • Assume different names depending on which tissue they reside in
  • Resident macrophages found at sites of filtration where microorganisms can be removed
  • Circulating monocytes move from blood into tissue in response to infection and inflammation
    • Arrives after neutrophils (~12-24 h)
    • Can become “activated” ⇒ potent effector cells
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15
Q

Resident Macrophages

A
  • Clean up and maintain homeostasis of tissues
  • Filter fluids to remove microorganisms
  • Functions as gaurds in tissues
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16
Q

M1 Macrophages

A

“Classically activated or Inflammatory Macrophages”

  • Recruited from the blood into tissue in response to infection and inflammation
  • Usually arrive later than neutrophils
  • Development induced by:
    • IFN-γ
    • TNF
    • LPS
  • Activation results in:
    • Increased production of mediators
      • ROI
      • RNI
      • Proinflammatory cytokines
    • Upregulation of MHC II to promote T-cell activation
17
Q

M2 Macrophages

A

“Alternatively-activated macrophages”

  • Development induced by IL-4 and IL-10
  • Not actively antimicrobial
  • Secretes:
    • TGF-β
    • IL-10
    • Other growth factors
  • Functions:
    • Downregulates the inflammatory response
    • Promotes wound repair and fibrosis
18
Q

Dendritic Cells

A
  • Located in peripheral tissues
  • Phagocytic capabilities
  • Antigen presenting cells
  • Helps to activate T-cells and initiate the adaptive immune response
19
Q

Phagocyte Activation

A

Mediated by receptors

20
Q

Phagocyte

Attachment

A
  • Dependent on cell-surface receptors
  • Mediate attachment of organism to phagocytes
  • Examples:
    • MBP : collectin receptors
    • Scavenger receptors
    • IgG : Fc receptors (FcR)
    • Receptors for complement components
      • C3b: deposited on bacterial cell surfaces via alternative pathway
        • Binds to CR-1 on phagocytes
      • Mac1 receptors can bind iC3b or C4b
21
Q

Phagocytosis

A
  • Attach via cell-surface receptors
  • Engulfs organism into a phagosome
    • Becomes increasingly acidic
  • Fuses with cytoplasmic granules to form phagolysosome
  • Granule contents discharged around ingested microbe
  • Subsequent intracellular response includes:
    • Oxygen-independent mechanisms
    • Oxygen-dependent pathways
22
Q

Oxygen-Dependent

Antimicrobial Mechanisms

A

Occurs in macrophages and neutrophils:

  • Respiratory Burst ⇒ vigorous burst of oxygen consumption following activation
  • NADPH oxidase ⇒ reactive oxygen intermediates (ROI)
    • Superoxide anion (O2-)
    • Hydrogen peroxide (H2O2)
    • Singlet oxygen (O2)
    • Hydroxyl radicals (OH-​)
  • ROI are potent anti-microbials
    • Causes local damage to host
    • System is down-regulated quickly

Neutrophils only:

  • Neutrophils also have myeloperoxidase
    • Hydrogen peroxide + Cl- ⇒ OCl- or hypochlorite anion
23
Q

Reactive Nitrogen Intermediates

(RNI)

A
  • Occurs as part of the respiratory burst
  • Nitric oxide (NO) produced from arginine and oxygen by nitric oxide synthase
  • NO reacts with oxygen radical to produce peroxynitrite and reactive nitrogen intermediates (RNI)
  • Peroxynitrite causes damage to cell walls and viral capsules
24
Q

Oxygen-Independent

Antimicrobial Mechanisms

A
  • Defensins
    • Damage bacterial plasma membranes
  • Cationic proteins
    • Insert into plasma membrane and cause cell lysis
  • Cathepsin G
    • Serine protease that breaks down peptides
  • Lysozyme
    • Disrupts PG in bacterial cell walls
  • Bactericidal permeability increasing (BPI) proteins
    • Forms pores in bacterial outer membrane
  • Proteolytic enzymes
  • Lactoferrins
  • DNAses
  • Acid hydrolases
25
Q

LPS Effects

A

Surface receptors on phagocytes binds microbial components on gram negative bacteria:

  1. Lipopolysaccharide (LPS) binds serum LPS-binding protein ⇒ LPS+LPS-BP complex
  2. LPS+LPS-BP complex binds the CD14 receptors on surface of monocytes/macrophages
  3. LPS-CD14 receptor complex interacts with cell-surface Toll-like receptor-4 (TLR-4) leading to cell activation
  4. Stimulates cytokine synthesis and release:
    • TNF-α
    • IL-1
    • IL-6
    • IL-8
    • IL-12
  5. Cytokines important for:
    • Recruitment of effector cells
    • Lymphocyte activation & differentiation
26
Q

Interferon-γ

A

Type II Interferon

  • Secreted by NK cells early ⇒ innate immune response
  • Secreted by T cells late ⇒ adaptive immune response
  • Effects:
    • Recruitment and activation of macrophages
      • Phagocytize and kill microbial pathogens
      • Secrete additional cytokines, chemokines, and antimicrobial products
    • Stimulation of adaptive immune responses
    • Influence the nature of that response
  • Example:
    • Tuberulosis lives within modified vacuoles of macrophages
    • Macrophages can be induced by IFN-γ to kill intracellular pathogens
27
Q

Defense Against Viruses

A
  1. Production of cytokines
    • IFN-α and IFN-β by viral infected cells
    • TNF-α and IL-12 by macrophages
  2. NK cell activation
    • Killing of virally infected cells
  3. Development of the adaptive immune response with virus specific:
    • T-cells ⇒ kill virally infected cells
    • B-cells ⇒ secrete antibodies that can block viral entry into host cells
28
Q

Type I Interferons

Basics

A
  • Large family of structurally related cytokines
  • Mediate the early innate immune response to viral infections
  • Able to interfere with viral replication
  • Most significant are IFN-α and IFN-β
29
Q

Type I IFN

Induction

A
  • Viral nucleic aids bind to intracellular receptors linked to the production of transcription factors
    • TLR-3
    • RIG-1
  • Toll-like receptors can be found on endosomal membranes that recognize dsRNA and ssRNA
  • Cytoplasmic sensors recognize viral RNA
  • Stimulation of either causes activation of interferon regulatory transcription factors (IRFs)
  • Within several hours of a viral infection, host cells begin to produce and secrete IFN-α and/or IFN-β
30
Q

Type I IFN

Effector Functions

A
  1. Transcription Regulation
    • All Type I IFN’s bind to the same cell surface receptors
    • Signals host cell to activate or increase synthesis of a large set of proteins
    • Net result is an increased resistance to viral replication in all cells
    • Stimulation of effector mechanisms to kill virally infected cells
  2. Anti-viral Functions
    • IFN α/β induced proteins can directly inhibit one or more steps in the viral life cycle (entry, transcription, translation, assembly, release)
    • Promotes viral genome degradation inside host cell
      • Activates oligoadenylate synthetase
        • Polymerizes ATP into 2’,5’ linked oligomers
      • Activates endoribonuclease (RNase) to degrade viral RNA
    • Inhibits viral protein synthesis
      • Activates P1 kinase (ser/thr kinase)
        • Phosphorylates eIF-2
        • Leads to inhibition of all protein synthesis
  3. Immuno-regulatory functions
    • Increases MHC expression, viral antigen processing, and presentation to virus-specific T cells
    • Helps to initiate the adaptive immune response
    • Activates NK cells to kill virus infected host cells
31
Q

NK cells

Basics

A
  • Large granular lymphocytes
  • Distinct from T cells and B cells
  • Found in blood and spleen
    • Migrates into infected tissues in response to inflammatory cytokines
  • After recognition, able to kill various targets without need for additional activation
  • Function can be enhanced by:
    • IFN α/β initially produced in response to a viral infection
    • Cytokines produced by macrophages early in the course of many infections:
      • Interleukin-12 (IL-12)
      • Tumor necrosis factor-α (TNF-α)
32
Q

NK Cells

Recognition Methods

A

NK cells do not express an antigen specific receptor:

  1. Express a set of activating and inhibitory receptors
    • Cooperate to allow the recognition of many virally infected host cells and tumor cells
    • Example:
      • Viruses down-regulate MHC I receptors to evade T-cells
      • Lack of MHC class I causes activation of NK cells
  2. Express an IgG binding FC receptor (CD16) on surface
    • Facilitate Antibody Dependent Cellular Cytotoxicity (ADCC)
    • IgG binds to surface of virally infected cells
    • Facilitates NK cell recognition
33
Q

NK Cell

Cytotoxicity

A

Important in the early control of viral infections and mediate the killing of virus infected cells.

  1. Activation
    • Activating & Inhibitory Receptor imbalance
    • CD16
  2. Cytoplasmic granules are discharged onto the surface of virally infected cells
  3. Perforin ⇒ creates a pore in the plasma membrane of infected cells
  4. Allows entry of granzymes ⇒ activates apoptotic cascade
  5. Leads to host cell death

Also able to kill through the Fas:FasL pathway.

(Discussed later)

34
Q

NK Cell

Cytokine Production

A

Activated NK cells secrete cytokines including:

  • Interferon-γ
    • Important in the recruitment and activation of macrophages
    • Helps shape the cytokine profile secreted by TH cells
35
Q

Innate & Adaptive Immune System

Interactions

A

Cooperation between adaptive and innate immune systems can enhance the effectiveness of the overall response.

  • Antibody-dependent cellular cytotoxicity (ADCC)
    • NK cells bind Fc portion of IgG
    • Facilitates NK cell identification and killing of targets prior to the release of cytotoxic mediators
  • Opsonization
    • IgG or complement components (C3b) coat surface of pathogens
    • Phagocytes express Fc receptors for IgG and C3b receptors
    • Opsonized antigen phagocytized more readily
  • Classical pathway of complement activation
    • Mediated by IgM and IgG

Foundations of Disease (46 decks)

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