Review of Innate Immunity Flashcards
What is the specificity like for the two immune systems?
Adaptive immunity – involves very specific recognition of infectious agent (usually sees a protein = antigen)
Innate immunity – no specific antigen recognition
Innate immunity involves recognition of broadly conserved features of different classes of pathogens called PAMPs
What are PAMPs and some examples?
Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)
Molecules present only on pathogens and not on host cells
Essential for survival of pathogens
Invariant structures shared by entire class of pathogen e.g. gram-ve, gram+ve etc.
Gram-negative bacteria; lipopolysaccharides (LPSs) found in outer membrane
Gram-positive bacteria; teichoic acid, lipoteichoic acid, peptidoglycan found in outer membrane
Bacterial flagellin
Abnormal protein glycosylation
Abnormal nucleic acids - viruses
What are PRRs and the different classifications of PRRs?
Host factors that specifically recognise a particular type of PAMP
They are germ-line encoded meaning they are encoded in every cellular body
There are several classes of PRR, but functionally they are either:
- Extracellular – they recognise PAMPs outside of a cell and trigger a co-ordinated response to the pathogen
- Intracellular (cytoplasmic) – they recognise PAMPs inside a cell and act to co-ordinate a response to the pathogen (mostly for viruses)
- Secreted – they act to tag circulating pathogens for elimination
What are the basic components of innate immunity?
The inflammatory response Phagocytes - Monocytes/granulocytes/neutrophils Complement Cytokines, chemokines and anti-microbial peptides (AMPs) Natural Killer cells
What happens during the inflammatory response?
A generic defence mechanism whose purpose is to localize and eliminate injurious agents and to remove damaged tissue components
You get (in a loose general order):
- Enhanced permeability and extravasation
- Neutrophil recruitment
- Enhanced cell adhesion
- Enhance clotting
Triggered by the release of pro-inflammatory cytokines and chemokines at the site of infection
How are phagocytes able to recognise what to eat?
Material to be “eaten” is recognised in a number of ways:
- By detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis) - By detecting “atypical sugars” (e.g. mannose, fucose, b-glucan) on cell surfaces - By Scavenger receptors - By “passive sampling”- take up little goblets of extracellular fluid and turn over the membrane of the entire cell in 10 minutes - By detecting complement proteins bound to the pathogen surface
What are the roles of macrophages and dendritic cells in immunity?
Phagocytosis; material is destroyed in lysosomes
Infections can trigger macrophage activation - activated macrophages produce cytokines and chemokines to stimulate both innate and adaptive immune responses – this triggers the inflammatory response and can promote a local anti-microbial state
Peptides from broken down pathogens can be presented through MHC and promote the development or recall of an adaptive T cell response
- Mostly dendritic cells, macrophages do the same although they can promote the development of a new immune response they can trigger recall however
What is the Complement system?
Complement proteins act as secreted Pattern recognition receptors (PRRs), made by the liver, and can be activated by a range of PAMPs, and can also be activated by “altered self”
Originally thought to be a biochemically complex antibody-dependent effector mechanism leading to:
- Opsonisation
- Recruitment of phagocytic cells, vasoactive function
- Punches holes in target membranes (MAC)
How can the complement system be activated?
If you bind an antibody to an antigen you activate the classical complement system
The classical complement system can also be activated by LPS on the pathogens bound by C1q as well as abnormal phospholipids recognised by pentraxins
Atypical glycosylation can be recognised by menos(?) binding lectins and ficolins triggering the leptin pathways
Lack of host control factors can trigger the alternative pathway
What are the 3 types of PRRs, their ligands and outcome?
-Toll-like receptors (TLRs) (surface and endosomal)
-LPS (together with CD14)
lipoproteins
Unmethylated CpG
Flagellin
ds RNA; ss RNA (in endosomes)
-inflammation: cytokine release (TNF, IL-1, IL-12)
enhanced killing: reactive oxygen species, NO)
-NOD-like receptors (NLRs) (cytoplasm)
-Peptidoglycan from Gram positive and negative bacteria
Some viral DNA and RNA (indirect?)
-inflammation: cytokine release (IL-1, IL-8)
- RIG-like receptors (RIG-I and MDA5) (cytoplasmic)
- Viral dsRNA and 5’-triphospho RNA
- type I interferon production
What is the difference between cytokines and chemokines?
Glycoprotein hormones that affect the immune response
Cytokines
- Act to modify the behaviour of cells in the immune response
- Most of these are called interleukins (eg. IL-1)
Chemokines
- Act as chemotactic factors – i.e. they create concentration gradients which attract (or occasionally repel) specific cell types to a site of production/infection
What are interferons and what do they do?
Interferons; the main anti-viral cytokines
Secreted factors (type I and type III)
Type III protects epithelial cells like lungs while Type I protects other surfaces like blood vessels
Induced by viral infection
Offer cross-protection, so the interferon turned on during an influenza infection will work against polio
Widely distributed in evolution, from fish upwards, but species-specific
How does the interferon system work?
So here we have a virus invading the cell
The virus will replicate quite easily and so the cell will die
The process of the cell dying will release many new virions
These viruses will now attempt to invade the neighbouring cells but, if the interferon system works correctly, whilst the cell is making lots of new virus copies the cell detects the PAMPS using PRRs
It will up-regulate the synthesis of interferon
Interferon is secreted from these cells and they will bind to the receptor in neighbouring cells and that will transcriptionally activate production of about 400 antiviral gene products
What happens when the interferon binds to its receptor?
So interferon binds to its receptor on the target cell and triggers the JAK-STAT pathway which upregulated many gene products including one called protein kinase R (PKR) which is inactive usually
When the virus invades the cell and that viruses make dsRNA
The dsRNA is a cofactor for the activation of PKR and that consequences are translation arrest
What are AMPs?
Anti-microbial peptides (AMPs) e.. Defensins
For bacteria mostly
Secreted short peptides (18-45 amino acids)
Usually work by disrupting cell wall leading to lysis
Some are directly induced by bacterial infection
Offer broad protection
