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MICR3305 > 5 - Induced Responses of Innate Immunity > Flashcards

5 - Induced Responses of Innate Immunity Flashcards

1
Q

The innate immune system recognises microbial elements that are often essential for survival of microbes

A
  • Ensures that the targets of innate immunity cannot be discarded by microbes in an effort to evade recognition by the host
  • Host cell pattern recognition receptors (PRRs) recognise pathogen associated molecular patterns (PAMPs)
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2
Q

Examples of target of innate immunity that is indispensable for microbes

A
  • Double stranded viral RNA (essential intermediate in life cycle of viruses)
  • LPS and lipoteichoic acids
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3
Q

Cellular locations of pattern recognition receptors of the innate immune system

A

Extracellular, Cytosolic and endosomal

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4
Q

Toll like receptors

A
  • Family of PRRs expressed on many cell types that recognise products of a wide variety of microbes and molecules released by dying cells
  • 9 different functional TLRs in humans (TLR1-TLR9)
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5
Q

Examples of bacterial products that bind to TLRs

A

LPS (gram -‘ve) and lipoteichoic acid (game +’ve)

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6
Q

Examples of nucleic acids that bind to TLRs

A
  • dsRNA
  • ssRNA
  • Unmethylated CpG dinucleotides
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7
Q

How is ssRNA distinguished from host/self ssRNA

A

By their location within endosomes and by high guanosine and uridine content

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8
Q

End result of TLR recognition of microbial ligands

A
  • Expression of genes whose products are important for inflammatory and antiviral responses
  • Ligand induced TLR dimerisation brings the TIR domains of the cytoplasmic tails of each protein close to one another
  • Leads to recruitment of TIR domain containing adaptor proteins which facilitate the recruitment and activation of various protein kinases
  • Leads to activation of different transcription factors
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9
Q

Major transcription factors that are activated by TLR signaling pathways

A
  • Nuclear factor kB(NF-kB)
  • Activation protein 1 (AP-1)
  • Interferon response factor 3 (IRF3)
  • IRF7
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10
Q

C type lectin receptors

A

Cellular receptors that recognise carbohydrates on the surface of microbes facilitate the phagocytosis of the microbes and the secretion of cytokines that promote inflammation and subsequent adaptive immune responses

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11
Q

Where are c type lectin receptors found

A
  • Integral membrane proteins found on the surfaces of macrophages, DCs, and some tissue cells
  • Other lectins are soluble proteins in the blood and extracellular fluids
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12
Q

Types of plasma membrane C type lectins with specificities for different carbohydrates

A
  • Mannose
  • Glucose
  • N-actylglucosamine (GlcNAc)
  • β-glucans
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13
Q

Inflammatory response

A
  • Bacteria trigger macrophages to release cytokines and chemokines which cause vasodilation
  • Leukocytes move to periphery of blood vessel as a result of increased expression of adhesion molecules by endothelium
  • Leukocytes extravasate at site of infection
  • Neutrophils engulf and kill the microbes
  • Blood clotting occurs
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14
Q

When do blood monocytes differentiate into tissue macrophages

A
  • During inflammation
  • Monocyte binds adhesion molecules on vascular endothelium near site of infection and receives chemokine signal
  • Monocyte migrates into tissue
  • Monocyte differentiates into macrophage
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15
Q

Adhesion molecules that control immune cell movement

A
  • Selectins
  • Integrins
  • Immunoglobulin superfamily
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16
Q

Selectins

A
  • Bind carbohydrates
  • Initiate leukocyte-endothelial interaction
  • e.g. P selectin
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17
Q

Integrins

A
  • Located on phagocyte
  • Bind to cell adhesion molecules and extracellular matrix
  • Strong adhesion
  • E.g. LFA-1
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18
Q

Immunoglobulin superfamily

A
  • Various roles in cell adhesion
  • Ligand for integrins
  • e.g. ICAM-1
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19
Q

Multistep process of neutrophils leaving blood and migrating to sites of infection

A
  • Rolling adhesion, tight binding, diapedesis, and migration
  • Binding of a chemokine such as CXCL8 (IL-8) to its receptor on the neutrophil
    triggers activation of integrin LFA-1
  • Inflammatory cytokines such as TNF-⍺ are also necessary to induce expression of adhesion molecules such as ICAM-1,
    ligand for the integrin, on vascular endothelium
  • Tight binding between ICAM-1 and integrin arrests
    rolling and allows neutrophil to squeeze between endothelial cells that form blood vessel wall
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20
Q

Phagocytosis

A
  • Phagocyte receptors bind to PAMPs and opsonins including antibody molecules and complement proteins
  • Ingested foreign particles are enclosed within phagosome that breaks away from plasma membrane
  • Phagosome fused with lysosome to create phagolysosome that contain antimicrobial molecules
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21
Q

What antimicrobial molecules do phagolysosomes contain

A
  • Reactive Oxygen Species (ROS)
  • Nitric oxide
  • Proteolytic enzymes
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22
Q

Important cytokines and chemokines secreted by dendritic cells and macrophages in response to bacterial products

A
  • IL-1β
  • IL-6
  • CXCL8 (IL-8)
  • IL-12
  • TNF-⍺
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23
Q

Local effects of IL-1β

A
  • Activates vascular endothelium
  • Activates lymphocytes
  • Local tissue destruction
  • Increases access of effector cells
24
Q

Systemic effects of IL-1β

A
  • Fever
  • Production of IL-6
25
Q

Local effects of TNF-⍺

A
  • Activates vascular endothelium
  • Increases vascular permeability (leads to increased entry of IgG complement, and cells to tissues and increased fluid drainage to lymph nodes
26
Q

Systemic effects of TNF-⍺

A
  • Fever
  • Mobilisation of metabolites
  • Shock
27
Q

Local effects of IL-6

A
  • lymphocyte activation
  • Increased antibody production
28
Q

Systemic effects of IL-6

A
  • Fever
  • Induces acute phase protein production
29
Q

Local effects of CXCL8

A
  • Chemotactic factor that recruits neutrophils, basophils, and T cells to site of infection
30
Q

Local effects of IL-12

A
  • Activates NK cells
  • Induces the differentiation of CD4 T cells into Th1 cells
31
Q

Excess TNF production

A
  • Leads to sepsis
  • Macrophages activated in liver and spleen secrete TNF-⍺ into bloodstream
  • Systemic edema causing decreased blood volume, leading to collapse of vessels
  • Disseminated intravascular coagulation leading to wasting and multiple organ failure
  • Death
32
Q

Acute phase proteins

A

Produced by hepatocytes in response to cytokines produced by macrophages in the presence of bacteria (e.g. C reative protein and mannose binding lectin)

33
Q

C-reactive protein

A

Binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement

34
Q

Mannose binding lectin

A

Binds mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement

35
Q

What is the major way by which the innate immune system blocks viral infections

A

By inducing the expression of type 1 interferons

36
Q

Type 1 interferons

A
  • Large family of structurally related cytokines that mediate the early innate response to viral infections
  • Most important are IFN-α and IFN-β
37
Q

What produces IFN-α

A

Major source is plasmacytoid DCs but also produced by mononuclear phagocytes

38
Q

What produces IFN-β

A

Many cell types in response to viral infection

39
Q

Outcomes of interferons

A
  • Inhibition of viral protein synthesis
  • Degradation of viral RNA
  • Inhibition of viral gene expression and virion assembly
40
Q

Antiviral response

A
  1. Production of IFN-α, IFN-β, and IL-12 (1-5 days)
  2. NK-cell mediated killing of infected cells (1-6 days)
  3. T-cell mediated killing of infected cells (2-10+ days)
41
Q

NK cells

A
  • Cytotoxic cells that play important roles in innate immune responses, mainly against viruses and intracellular bacteria
  • Innate lymphoid cells (ILCs)
42
Q

How can NK cells be differentiated from T cells

A

As they do not express CD3, (T cell receptor)

43
Q

Why are NK cells referred to as lymphoid cells and not lymphocytes

A

Because they do not express clonally distributed diverse antigen receptors like T lymphocytes

44
Q

Functions of NK cells

A

Kill infected cells and to produce IFN-γ, which activates macrophages to destroy phagocytosed microbes (important for intracellular bacteria)

45
Q

How do NK cells kill other cells

A

Activated NK cells produce perforin, a protein that facilitates the entry of
granzymes into the cytosol of target cells, to initiate a sequence of signalling events that induce apoptosis

46
Q

Activating and inhibitory receptors of NK cells

A
  • Activating receptors recognise ligands on infected and injured cells, stimulating killing activity of NK cells
  • Inhibitory receptors recognise ligands on healthy normal cells, shutting off NK cell activity
47
Q

Antibody dependent cellular cytotoxicity (ADCC)

A
  • Anti-viral function of NK Cells
  • Antibodies bind to virus infected cells
  • NK cells bind to antibodies with CD16 receptor
  • NK cells release cytotoxic granules and antiviral cytokines to kill infected cells
48
Q

Two signal hypothesis of stimulation of adaptive immunity

A
  • Activation of lymphocytes requires two distinct signals
  • First signal is the antigen
  • Second is molecules produced during innate immune responses (e.g. complement, costimulator)
  • Ensures that adaptive response are induced when there is a dangerous infection and not harmless antigens (including self)
49
Q

Examples of two signal hypothesis

A
  • IL-12 stimulates the differentiation of naive CD4+ T cells to the Th1 subset
  • IL-6 promotes the production of antibodies by activated B cells
50
Q

What TLRs detect bacterial lipopeptides

A

TLR1, 2 and 6

51
Q

What TLRs detect bacterial peptidoglycan

A

TLR2

52
Q

What TLRs detect LPS

A

TLR4

53
Q

What TLRs detect bacterial flagellin

A

TLR5

54
Q

What TLRs detect dsDNA

A

TLR3

55
Q

What TLRs detect ssRNA

A

TLR7 and 8

56
Q

What TLRs detect CpG DNA

A

TLR 9

57
Q

TLR structure

A
  • Leucine rich repeat motifs
  • Cysteine rich flanking motif
  • TIR domain

MICR3305 (23 decks)

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