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IMS: Immunology > Innate Immunity > Flashcards

Innate Immunity 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 acidity
  • 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
  • Structures are not expressed by host cells and signal the presence of non-self or foreign antigens
  • 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 include:
      • Toll-like receptors
      • Scavenger receptors
    • Soluble recognition molecules include:
      • Collectins
        • Collagen-containing carbohydrate binding proteins
      • Complement
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9
Q

Toll-Like Receptors

A
  • Prototypical type of PRR
  • Set of receptors on cytoplasmic and endosomal membranes
  • After binding ligand will dimerize to transduce a signal
  • Have relatively conserved cytoplasmic tails which 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
  • 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 Immune

Defense Against Bacteria

(Extracellular Pathogens)

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 defense against pyogenic bacteria:
    • Staphylococcus
    • Streptococcus
    • Neisseria
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14
Q

Mononuclear Phagocytes

A

Monocytes/Macrophages

  • Larged long-lived cells
  • Monocytes in blood ⇒ macrophages in tissue
  • Assume different names depending on which tissue they reside in
  • Resident macrophages provide 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)
    • Due to ability to become “activated” they are more potent effector cells
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15
Q

Dendritic Cells

A
  • Located in peripheral tissues
  • Phagocytic capabilities
  • Antigen presenting cells
  • Helps to activate T-cells and initiate the adaptive immune response
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16
Q

Phagocytosis

A
  • Dependent on cell-surface receptors which mediate attachment of the organism to phagocytes
    • Examples:
      • Macrophage mannose receptors
      • Scavenger receptors
      • Receptors for antibodies
      • Receptors for complement components
        • C3b: can be deposited on bacterial cell surfaces following activation of complement by the alternative pathway in the early innate immune response to bacterial infection
          • Binds to CR-1 on phagocytes
        • Mac1 receptors can bind iC3b or C4b
  • Phagocytes engulf the organism and enclose it in a phagosome
    • Becomes increasingly acidic
  • Fuses with cytoplasmic granules to form phagolysosome
    • Granule contents discharged around ingested microbe
  • Subsequent intracellular response includes:
    • Oxygen independent
    • Oxygen-dependent pathways
17
Q

Oxygen-Independent

Antimicrobial Mechanisms

A
  • Defensins
  • Cationic proteins
  • Cathepsin G
  • Lysozyme
  • Bactericidal permeability increasing (BPI) proteins
  • Proteolytic enzymes
  • Lactoferrins
  • DNAses
  • Acid hydrolases
18
Q

Oxygen-Dependent

Antimicrobial Mechanisms

A

Occurs in macrophages and neutrophils

  • Respiratory Burst is a vigorous burst of oxygen consumption following activation
  • NADPH-dependent oxidases generate reactive oxygen intermediates (ROI)
    • Superoxide anion (O2-)
    • Hydrogen peroxide (H2O2)
    • Singlet oxygen (O2)
    • Hydroxyl radicals (OH-​)
  • ROI are potent anti-microbials
    • Can also cause local damage to host
    • So system is down-regulated quickly

Neutrophils only

  • Neutrophils also have myeloperoxidase
    • Use hydrogen peroxide and Cl- to produce a halogenating system (OCl- or hypochlorite anion) = bleach
19
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
20
Q

Macrophage

Gram-negative Response

A
  1. Lipopolysaccharide (LPS) of gram-negative bacteria binds to serum LPS-binding protein to form 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
21
Q

Interferon-γ

A

Type II Interferon

  • Secreted by NK cells early as part of the innate immune response
  • Secreted by T cells late as part of the adaptive immune response
  • Extremely important in the recruitment and activation of macrophages
    • To phagocytize and kill microbial pathogens
    • To secrete additional cytokines, chemokines, and antimicrobial products
  • Important in the stimulation of adaptive immune responses and 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
22
Q

Defense Against Viruses

A
  1. Initial production of cytokines including
    • IFN-α and IFN-β by viral infected cells
    • TNF-α and IL-12 by macrophages
  2. Subsequent NK cell activation and killing of virally infected cells
  3. Development of the adaptive immune response with virus specific:
    • T-cells that kill virally infected cells
    • B-cells that secrete antibodies that can block viral entry into host cells
23
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
24
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
  • Within several hours of a viral infection, host cells begin to produce and secrete IFN-α and/or IFN-β
25
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
26
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)
27
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 class 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
28
Q

NK Cell

Cytotoxicity

A

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

  1. After activation, NK cell cytoplasmic granules are discharged onto the surface of virally infected cells.
  2. Granule proteins (Perforin) create a pore in the plasma membrane of infected cells.
  3. Allows entry of granzymes which activates an apoptotic cascade.
  4. Leads to host cell death.

Also able to kill through the Fas:FasL pathway.

(Discussed later)

29
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
30
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 of IgG and C3b receptors
    • Opsonized antigen phagocytized more readily
  • Classical pathway of complement activation

IMS: Immunology (19 decks)

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