Innate immune system (Week 3) Flashcards
epidermis
several layers of tightly packed epithelial cells
Dermis
connective tissue, blood vessels, hair, oil and sweat glands AND tissue-resident immune cells
3 barriers to infection
- Mechanical
- Chemical
- Microbiome
What secretes anitmicrobial molecules?
epithelial cells
Antimicrobial proteins
enzymes or binding proteins that inhibit or kill bacterial or fungal pathogens
ie. lysozyme
Lysozyme
enzyme cleaves peptidoglycan in bacterial cell wall
Antimicrobial peptides (AMPs)
disrupt pathogen membranes to enter and exert toxic effects
ie. defensins
Defensins
- antimicrobial peptides
- kill bacteria but also maintain good
bacteria (commensal microbes)
and prevent viral infection - electrostatic attraction and transmembrane electric field bring the defensin into the lipid bilayer
- defensin peptides form a pore
Extracellular pathogens
- populate spaces between cells and are accessible to secreted, soluble molecules (e.g. antibodies)
- what pAPCs uptake, process
and present on MHC Class II
Intracellular pathogens
- replicate inside of our cells
- containing infection means sacrificing our infected cells
- presented on MHC Class I
to mediate cell killing
Pattern Recognition Receptors (PRRs)
- essential for innate immune cells to detect pathogens
- bind pathogen-associated molecular patterns (PAMPs)
- located both on the plasma membrane and in endosomes and lysosomes
Damage-associated molecular patterns (DAMPs)
- ie. alarmins
- released by our own cells and tissues
- bind PRRs to alert immune cells
Toll-like Receptors (TLRs)
- PRRs
- membrane proteins (extracellular and intracellular) that have leucine-rich repeats (LRRs) that create the curves
- Exist as single domains that
dimerize in presence of PAMPs or DAMPs
What do plasma membrane TLRs recognize?
extracellular pathogenic material
What do endo/lysosomal TLRs recognize?
components released during
degradation of pathogen
What do TLRs do?
activate a transcription factor, Nuclear Factor kappa B (NFkB), important for turning on key activating/inflammatory genes in immune cells
C-Type Lectin Receptors
PRRs specific to extracellular carbohydrates on pathogens
NOD-like Receptors
- nucleotide oligomerization
domain - PRRs important for intracellular PAMPs and DAMPs
NLR Inflammasomes
- Some NLRs assemble into
complexes that turn on proteases to create strong inflammatory responses
(induce pro-inflammatory cytokine
expression) - kill activated macrophages to induce inflammation (release of pro-inflammatory cytokines
Pyroptosis
- Releases Cytokines from Macrophages
- programmed cell death that leads to inflammation through pores being formed in the plasma membrane
Cytokine secretion by macrophages
- secrete proinflammatory cytokines from Interleukin (IL) and Tumour Necrosis Factor (TNF) cytokine families
- These direct various aspects of
inflammation and cell recruitment - IL-12 and IL-18 also drive adaptive immune responses and IL-10 = anti-inflammatory
What do Type 1 Interferons do?
- important for immune responses
- Increase MHC Class I (improve
killing) expression, regulate
macrophages and T cells
How do Type 1 interferons work?
- signalling is antiviral
- block viral assembly, protein translation, degrade viral dsRNA, inhibit virus gene transcription and mRNA translation
How do neutrophils enter blood?
- by extravasation: leaving the bloodstream
- interact with endothelial cells
and “roll” - Cytokines promote adhesion molecule expression on blood
endothelium - Chemokines promote
neutrophil migration
Neutrophil phagocytosis
- bacteria is phagocytosed by neutrophil
- phagosome fuses with granules inside neutrophil
- pH of phagosome rises, activates antimicrobial response and bacteria is killed
- pH of phagosome decreases, fusion with lysosomes allows acid hydrolases to degrade the bacteria completely
- neutrophil dies by apoptosis and is phagocytosed by macrophage
Phagocytic receptors
- CLRs and scavengers
- on macrophages
- pathogen or dying/dead cell binds and gets engulfed/degraded/presented
Steps of NETosis
- signals from PRRs activate neutrophils
- phagosome NADPH oxidase (PHOX) is induced and intracellular membranes start to breakdown
- granule enzymes neutrophil elastase (NE) and myeloperoxidase (MPO) enter the nucleus and modify histones; chromatin decondenses
- Plasma membrane ruptures and the cytoplasm and nucleoplasm are expelled, forming NETs
- Cell dies
Phagocytosis and Respiratory burst
- Pathogens are killed by oxidative attack with reactive oxygen species (ROS) and reactive nitrogen species (RNS)
- respiratory burst is when phagocytes increase oxygen uptake seven-fold to produce more ROS
Granulomas
- can form without respiratory burst
- If phagosomes don’t appropriately increase their pH, they can’t break down pathogens
- infection cannot be cleared, macrophages get imprisoned in granulomas
How NK cells kill infected cells?
- virus infects cells and triggers interferon response
- type 1 interferon drives proliferation of NK cells
- type 1 interferon drives differentiation of NK cells into cytotoxic effector cells
- effector NK cells kill virus-infected cells by inducing apoptosis
NK cells and Macrophage interactions
- macrophages activated by viral infection secrete cytokines that recruit NK cells
- NK cell and macrophage conjugate
- synapse delivers IL-15, with IL-12 it activates NK cell - NK cells proliferate and differentiate into effector NK cells secreting interferon-y (IFN-y)
- Interferon-y binds its receptor on the macrophage, increasing phagocytosis and cytokine secretion
NK and dendritic cell interactions
- interactions direct the immune response
- DCs activate NK cells
- if NK cells outnumber DCs = NK cells kill pathogen infected cells including DCs
- if DCs outnumber NKs = NKs induce
motility of DCs
How does innate immunity activate adaptive immunity?
- Dendritic cells get activated by
PAMPs binding their PRRs - Induces DCs to uptake pathogens,
present antigen and travel to the
lymph node to activate adaptive
immune cells
