Review of innate immune system Flashcards
Adaptive immune response is too slow to protect us from some new pathogens
Infected on day 0 by microbe
Adaptive immune response from de novo starts day 5, antibodies take time to accumulate to high levels
Cytotoxic T cells take time to peak and don’t begin until day 3-4
If pathogen replicates slowly, peak replication at 8-10 days, you will be able to respond somewhat with T cells and antibodies because they’re occurring at about same time the pathogen is replicating
If you get infected by pathogens that replicate more quickly e.g influenza, peaks at 2 days or so, before T cells and antibodies can kick in
Innate immunity keeps pathogen under control, but many pathogens eventually do need adaptive immune response to kick in
What experiment was done in mice to show that both adaptive and innate immune responses are needed to resolve infection?
Two experiments done, mouse models of infection by influenza virus
Mice groups – one lacking B and T cells
Other lacking innate immune response
Mice deficient in B and T cells eventually dies – can make innate immune response but can’t make adaptive immune response. Takes long to die but dies.
Mice with intact adaptive immune response but lack innate immune response, these mice die quickly, faster than mice that can’t make B and T cells
How does the specifity differ between adaptive and innate immunity?
Adaptive immune system - involves specific recognition of infectious agent, makes molecule response to particular epitopes (bit of protein that is pathogen specific)
Innate immunity - no specific antigen recognition. involves recognition of broadly conserved features of different classes of pathogen.
e.g if you are a gram negative bacteria (E.coli) have a common origin and certain features conserved across the class
What molcule is pattern recognition done 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 pathogens e.g Gram negative bacteria
examples:
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 pattern recognition receptors / PRRs?
What three types of PRRs are there?
Host factors that specifically recognise a particular type of PAMP
Germ-line encoded – unlike antibodies and T cells which are rearranged semantically , there is no rearrangement
Several classes of PRR, but functionally they are either:
Extracellular – 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
Secreted – they act to tag circulating pathogens for elimination – macrophages and phagocytes will decorate it in complements and get rid of it
What is the inflammatory response in innate immunity?
What cells are recruited to the site of infection?
A generic defence mechanism whose purpose is to localise and eliminate injurious agents and to remove damaged tissue components
Enhanced permeability and extravasation
Neutrophil recruitment – major phagocytic cells, get recruited to site of infection by seeing chemokine gradients generated at the sight of infection
Enhanced cell adhesion – stick to tissues where infection is ongoing
Enhance clotting – cut off blood supply if pathogen is restricted to a site
Triggered by the release of pro-inflammatory cytokines and chemokines at the sight of infection – cytokines are pro-inflammatory and chemokines create chemical concentration gradient down which particular cell types can migrate
What cells are phagocytes?
What do they need to know?
Dendritic cells, macrophages, neutrophils.
Need to know when they’re infected in order to produce chemokines and cytokines
Molecular recognition events are distinct and use different PRRs
therefore don’t say TOL like receptors are there to make chemokines and cytokines + are involved in phagocytes recognising and eating because they are different types of receptors
Macrophages and dendritic cells have three distinct roles 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 – triggers inflammatory response and can promote a local anti-microbial state
APC- Peptides from broken down pathogens can be presented through MHC and promote the development or recall of an adaptive T cell response.
Macrophages can present antigens and trigger recall of something you’ve seen before.
How is material to be eaten by phagocytes recognised?
By detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis) - phosphatidylserine is normally meant to face into cytoplasm, when cells start to lose integrity (cells undergoing apoptosis) ability of cell to maintain asymmetry of its phospholipid bilayer breaks down, phosphatidyl serine ends up facing outside of the cell – signal for macrophages to eat it
By detecting atypical sugars (e.g mannose, fructose, B-glucan) on cell surfaces
By scavenger receptors
By “passive sampling”- take up little goblets of extracellular fluid, turn over their membrane of the entire cell in about 10 mins, don’t know what it is but are capable of destroying it
By detecting complement proteins bound to the pathogen surface – complement receptors on surfaces of macrophages which detect pathogens that have complement bound, take them up and destroy them
What is the complement system?
What does it lead to?
Biochemically complex antibody-dependent effector mechanism
Complement system acts as secreted PRRs and can be activated by range of PAMPs and by ‘altered self’
Leads to:
Opsonisation – binds and coats pathogen, pathogen can’t go anywhere and is harmless
Recruitment of phagocytic cells, vasoactive function – if you have complement bound it can do recruitment
Punches holes in target membranes (MAC)
What can the complement system see and what pathway does it activate?
Antibody binding to antigen on surface of complement system activates classical pathway.
Classical system also activated by LPS on target of pathogen which binds to C1q
Atypical glycosylation on pathogen surface can be recognised by proteins, mannose binding lectins MBL and ficolins. Triggers complements through lectin pathway.
Cells contain complement control factors on surface membrane, stopping complement from non-specifically attacking host cells
Lack of host control factors is seen as a non-self and activates complements through alternative pathway
Pamps are recognised by a distinct group of PRRs
TLR, NOD-like receptors, RIG-like receptors
Describe TLR
Expressed either on surface of macrophages and dendritic cells
Or expressed in the endosomes, so that their ligand binding domain faces into the endosome
9 in humans, different TLR see different types of PAMP
e.g TLR2 sees LPS
When phagocytosing proteins that are inside endosomes (viral proteins) you can strip off protein coat from outside of virus to unmask RNA or DNA (CPG)
CPG seen by TLR9
Ds RNA seen by TLR3
Specialist receptors for pathogens
Describe NOD-like receptors (PRRs)
If pathogen enters into cytoplasm without going through endosome need to sense that
NOD-like receptors can see bacteria cell walls from intracellular bacteria
Can see viral DNA and RNA
ligand: peptidoglycan from gram positive and negative bacteria, some viral DNA/RNA
Describe RIG like receptors
Main cytoplasmic receptors
Signal viral infection
Bind to viral dsRNA, never made by the host
Or binds to 5’-triphospho RNA , RNA that is improperly capped, foreign not host
outcome: type 1 interferon production
What do cytokines do?
Act to modify the behaviour of cells in immune response
Most of these are called interluekins but not all
Describe how the interferon system works
No antibodies
No prior knowledge of infection
Cell gets infected, virus replicates, makes lots of new viruses
Viruses will attempt to spread
First they try to kill the cell they’ve infected
Viral progeny will then try and infect new cells in its environment
If the interferon system works properly, the first cell will release interferon (which is made when a cell senses it is infected)
Interferon secreted and binds to receptors in neighbouring cells
Triggers transcriptional response which turns on transcription and subsequent translation of many antiviral genes
when virus attempts to replicate in secondary cells, if they’re in antiviral states as a result of receiving a signal from the first infected cell, cell is now not permissive for replication
NK cells are activated by loss of self
What is the mechanism by which NK cells detect target cells?
Sensitivity conferred by loss of self MHC molecules on target cell surfaces and up regulation of activating ligands.
MHC class 1, molecule that presents peptides that trigger cytotoxic t cell attack, is on the surface of every cell in the body
NK cells have mechanism for recognising MHC class 1
If you take an uninfected cell, which presents rapid self-peptides, NK cells have receptor on their surface of MHC class 1, if they detect it they do nothing
Doesn’t attack cells expressing MHC class 1
Many pathogens don’t have MHC class 1 because it is presenting peptides from the pathogen to T cells and triggering an adaptive immune response
Pathogens, particularly viruses and some bacteria work hard to downregulate MHC class 1 on cells they wish to infect
So MHC class 1 receptor on NK cell doesn’t detect MHC on target cell - infected cell or tumour cell. Seen as non-self.
By this mechanism NK cells recognise that cells shouldn’t be there, engage them, and induce cell death with granules of proteases
Compare innate and adaptive immunity
