Innate Immune Responses Flashcards

1
Q

What does innate immunity involve?

A
  • Antimicrobial peptides
  • Phagocytosis
  • NK cells
  • Interferons
  • Complement system
  • Acute inflammatory response
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2
Q

What are the host defences in order?

A
  • Anatomical and chemical barriers- skin, mucus, antimicrobial peptides in mucus
  • Intrinsic immunity
  • Innate immunity
  • Aquired immunity
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3
Q

Outline intrinsic immunity

A

Always present in uninflected cells
• Apoptosis, autophagy, RNA silencing, antiviral proteins
• Cellular proteins that inhibit viral replication (TRIM, APOBEC3, Tethering)

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4
Q

What are permissive and non-permissive cells?

A

Whether they allow viral infection within themselves

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5
Q

Which cellular proteins inhibit viral replication?

A

TRIM
APOBEC3
Tetherin

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6
Q

What are the soluble mechanisms of innate immunity?

A

• Antimicrobial enzymes (lysozymes) and Antimicrobial proteins (defensins, cathelicidins, histatins)
—> present in skin (from keratinocytes and epithelial cells) and in cell granules
• Complement, cytokines, acute phase proteins

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7
Q

Outline defensins

A

• Small cationic (+ve) antimicrobial peptides
• Kill bacteria, fungi, some viruses
• Insert into negatively charged membrane to create holes
• Widely expressed (leukocytes and epithelium), intracellular and secreted
• Two structural families
- α-Defensins- constitutively expressed
- β-Defensins- Some induced (by lipopolysaccharide LPS)

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8
Q

Outline innate cellular responses

A

Respond to threat or communicate to other cells
• must distinguish infectious agents from commensals, self-antigens and environmental antigens- present auto/allergy
• Pattern recognition receptors (PRRs) recognise pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs)

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9
Q

Outline antigen recognition

A

Innate:
• about 1000 molecules can be recognised, <100 types of receptor
• germ-line encoded so limited diversity

Adaptive:
• recognises specific epitopes
• >10^7 molecules recognised, 2 receptor types- TCR and antibody
• Somatic recombination so huge diversity

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10
Q

Outline pattern recognition receptors PRRs

A
Soluble molecules:
• pentrexins (eg CRP)
• collectins (eg mannose binding lectin)
• ficolins
• complement proteins- recognise lipopolysaccharides (LPS) or terminal sugars on microbial cell wall

Cell-associated molecules:
• cell surface (C-type lectins, TLR 2,4,5, scavenger receptors on phagocytes)
• endosome/phagosome (some TLRs- 3,7,8,9- recognise nucleus acids not wall)
• cytosolic (NOD-like receptors NLRs, RIG-like receptors, c-GAS)- sense DNA in cytoplasm- damage

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11
Q

Outline the function of Toll-like receptors TLRs

A

Major group of PRR

Ligand engages TLR

  • > association of protein kinases to adaptor proteins
  • > activation of transcription factors
  • > respiratory burst, cytokines, chemokines, MMPs, antimicrobial peptides, expression of costimulatory molecules (APCs)
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12
Q

Give examples of TLRs

A
Plasma membrane:
• TLR2- bacterial lipopeptides and lipoproptein
• TLR4- bacterial LPS
• TLR5- bacterial flagellin
—> IRF, NFκB (B cell activation)

Endosomal:
• TLR3- viral dsDNA
• TLR7+8- viral ssRNA nucleotide analogues
• TLR9- bacterial unmethylated CpG DNA
—> IRF (interferon regulatory factor)/NFκB

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13
Q

Outline the classes of PRR

A

• NOD-like receptors (NLRs)

  • NOD1/2 recognise peptidoglycans in bacterial cell wall to prevent escape from phagosome
  • NLRP3 forms part of inflammasome and recognises bacterial products and DAMPs (ATP, ROS)
  • RIG-like receptors- recognise viral RNA (RIG1, MDAS)
  • Cytosolic DNA sensors- recognise microbial DNA in cytoplasm (c-GAS/STING pathway)
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14
Q

What are the cells of innate immunity and what do they do?

A
  • Macrophages
  • Dendritic cells
  • Polymorphonuclear leukocytes (neutrophils, eosinophils, basophils)
  • mast cells
  • NK cells (borderline innate/adaptive)

—> Phagocytosis, inflammation, cytotoxicity

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15
Q

Outline phagocytosis

A

• Neutrophils first to respond, then monocytes enter tissue and become macrophages

  1. Chemotaxis/scavenger molecule recognition of pathogen
  2. Adherence via PAMP recognition
  3. Cell activation via PRR
  4. Phagocytosis initiation- encloses pathogen
  5. Phagosome formation
  6. Phagolysosome formation- joining to lysosome
  7. Enzymes, pH, killing of bacteria (respiratory burst-> O2 dependent killing- ROS and RNS generated)
  8. Release of degradation products
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16
Q

What is opsonization?

A
  • Complement or antibody coating of a microbe to make phagocytosis more efficient
  • Antibodies (with Fc) bound to microbes bind to FcR on phagocytes
  • Complement (can be activated by antibodies)-> more opsonization and chemotaxis and increased vascular permeability-> influx of phagocytes
17
Q

What are the microbicidal mechanisms of phagocytic cells?

A
  1. Reactive oxygen intermediates:
    H2O2-> HOCl + •OH chloramines (damage bacterial cell wall)
  2. Nitric oxide:
    O2-> NO• -> •ONOO peroxide nitrile radical
    - Inhibited by L-NMMA arginine analogue
  3. Oxygen-independent mechanisms (enzymes):
    • Damage microbial membranes
    -Cathepsin G
    -bacterial permeability increasing protein BPI)
    • Split mucopeptide in bacterial cell wall (crystal lattice structure)
    -lysozome
    • Complex with iron
    -lactoferrin
    • Digestion or killed organisms
    -proteolytic enzymes
    -other hydrolysis enzymes
18
Q

Describe natural killer cells

A
  • Large granular lymphocytes
  • 5-10% of circulating leukocytes
  • Destroy abnormal host cells (infected, tumour, stressed)
  • Granules contain killing molecules
  • Makes interferon-γ in response to signals
19
Q

Describe the activation of NK cells

A

• Missing self- lack of MHC class 1 which usually inhibits NK response from activated receptors
- tumours- lymphoma, melanoma
- infection- adenovirus, CMV
• Activators- many activators can cause response despite MHC class 1 presence- eg viral haemagglutinins/antibody coated cells

20
Q

Describe the mechanisms of NK cell killing

A

• Granules contain perforin and granzymes

  • perforin punches holes (pores) in target cell
  • granzymes enter through pore and digest cell
  • OR endocytosis and perforin-assisted release from vesicle

• Fas ligand pathway to apoptosis

  • FasL binds Fas (both on membranes) and activates FADD
  • FADD-> Procaspase-8-> Caspase-8-> Caspase-3inactive-> Caspase-3-> APOPTOSIS
21
Q

Outline dendritic cells and the difference between immature and mature DCs

A

Link between innate and adaptive
• Immature DCs pick things up by endocytosis/phagocytosis
• Mature in inflamed tissues following antigen capture and cytokine signals
• Mature DCs migrate to lymph nodes and present antigenic peptides to T cells
• DCs are professional APCs- at birth they are only cell able to APC

Immature DCs

  • high antigen uptake- highly phagocytic
  • low surface MHC class II
  • low costimulatory molecules (needed to activate T cells)
  • CCR7+, CCR1,2,5,6+ chemokine Rs

Mature DCs

  • low antigen uptake- poorly phagocytic
  • high surface MHC
  • high costimulatory molecules
  • CCR7+++