Review of The Innate Immune System

Question 1

What is the innate immune response?

Answer 1

Innate immunity involves recognition of broadly conserved features of different classes of pathogens

Question 2

What makes up the innate immune response?

Answer 2

1. Phagocytosis
2. The Inflammatory Response
3. Cytokines, Interferons and Antimicrobial peptides (AMPs)
4. Complement  complement system, enhances antibodies
5. Intrinsic Defences – “the hostile cell”  cells themselves can be hostile to the replication of pathogens
6. NK cells

Question 3

What is the purpose of the inflammatory response?

How is it performed?

Answer 3

A generic defence mechanism whose purpose is to localize and eliminate injurious agents and to remove damaged tissue components

Enhanced permeability and extravasation

Neutrophil recruitment

Enhanced cell adhesion

Enhance clotting

• A generic defence mechanism whose purpose is to localize and eliminate injurious agents and to remove damaged tissue components
• Enhanced permeability and extravasation  increase the permeability of the epithelia.
• Neutrophil recruitment
• Enhanced cell adhesion  make cells much more sticky
• Enhance clotting  to create an environment that is very resistant to pathogen spread.
• Stops the pathogen from leaving the site of infection
• Helps to remove the pathogen
• It will attempt to repair any damaged tissue  by a type of macrophages
• Macrophages mainly clear the area and recruit other cells
• Macrophage sending out chemokines and cytokines
• You get breakdown in the capillary so more neutrophils and macrophages can come in

Question 4

What are cytokines and chemokines?

What does IL-1/6,8,12 and TNF alpha do?

Answer 4

• Glycoprotein hormones that affect the immune response.
• Cytokines- Act to modify the behaviour of cells in the immune response.
• 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.
• IL-1/6- only one produced by macrophages and keratinocytes instead of macrophages and dendritic cells (activates lymphocytes).
• IL-8 (acts on phagocytes to chemoattract neutrophils).
• IL-12 (acts naïve t-cells to cause pro-inflammatory immune response and further cytokine secretion).
• TNF-a (acts on vascular endothelium to express adhesion molecules- E/P- selectins- to change cell-cell junctions with increased fluid loss).

Question 5

How do Phagocytes know what to eat?

Answer 5

• Material to be “eaten” is recognised in a number of ways:
• By detecting phosphatidylserine on exterior membrane surface (cells undergoing apoptosis)
• By Scavenger receptors  specific receptor
• By some Toll-Like Receptors (TLRs)  play a very little role in recognising with pathogens are to be eaten.
• By passive sampling  done mainly by neutrophils. At the site of infection, neutrophils destroy stuff at random
• Many pathogens trigger apoptosis
• As cells break down, PS goes on the outside rather than in.
• Macrophages will have a receptor that recognises this and will then phagocytose this

Question 6

Describe PRRs

What are the 3 types?

Answer 6

• Host factors that specifically recognise a particular type of PAMP
• They are germ-line encoded  so you will always express the same thing no matter which tissue
• 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
• Secreted – they act to tag circulating pathogens for elimination  e.g. the complement system

Question 7

Describe the complement system

Answer 7

• Predates development of the adaptive response.
• Complement proteins act as secreted Pattern recognition receptors (PRRs) and can be activated by a range of PAMPs and can also be activated by “altered self”.
• The use as an effector mechanism for the latter is therefore an adaptation grafted onto the original purposes of complement as a vital part of innate immunity.
• Functions through opsonisation, recruitment of phagocytic cells/vasoactive function, created pores in target membranes (membrane-attack complex).

Question 8

What are the 3 complement protein pathways?

Answer 8

1. Triggering protein in the classical system is C1q
2. Lectin pathway can recognise foreign glycosylation
3. Alternative pathway  any pathogen surface that is not of host origin

Question 9

What are interferons?

Answer 9

• Secreted factors (type I and type III)
• Induced by viral infection
• Offer cross-protection
• Widely distributed in evolution, from fish upwards, but species-specific
• Polypeptide hormones
• Major anti-viral immune responses
• Not expressed in tissues
• They are non-specific
• Polypeptide hormones- major anti-viral innate immune responses.
• Induced by viral infection- not expressed in tissues most of the time. Recognise PAMPs.
• Especially useful against “hit and run viruses” i.e. norovirus, which is gone before it does much damage and controlled by INFs. Lacking INF will be killed by norovirus.
• Secreted factors (type I and III). Non-specific to any virus.
• Widely distributed in evolution, from fish upwards, but species-specific.
• No antiviral response in first infected cells, apoptosis will release virions to infect neighbouring cells. This is prevented by interferons released by the primary infected cell and binds to neighbouring cells, causing them to go into anti-viral state. Much less effective to invade these cells. Produces defensins.
• INF works signal transduction to induce transcriptional upregulation of anti-viral response genes (>400). E.g. increases levels of inactivated Protein Kinase R (PKRi), which become activated (PKRa) when viral dsRNA is introduced into the cell. This switches of ribosome function, causing translational arrest so virus cannot replicate.

Question 10

What are antimicrobial peptides?

Answer 10

• Short secreted peptides that form defence against bacteria.
• Disrupt cell wall by forming pores, leading to lysis.
• Some induced by bacterial infection and offer broad protection.

Question 11

Describe the intrinsic defences against hostile cells

Answer 11

• Intrinsic defences- biochemical mechanisms.
• Apoptosis
• Restriction factors/Intrinsic Immunity.
• Epigenetic silencing.
• RNA silencing.
• Autophagy/Xenophagy.
• Ebola and Sendai virus (SeV) are common RNA viruses. SeV lethal in mice.
• Markers of apoptosis- stain with annexin V will show cell has phosphatidylserine on cell surface- go green. Will go green upon infection with SeV, so apoptosis.
• Ebola seems no apoptosis is triggered. Once stained with FLICA, some apoptosis but still little.
• SeV has higher markers of PARP and caspase 3 (production) than Ebola.
• Ebola blocks apoptosis, undermining host immune defences.

Question 12

What are natural killers and what do they do?

Answer 12

White blood cells- lymphocyte-like but larger with granular cytoplasm
Kill tumours and virally infected cells.

Question 13

How are NK cells activated?

Answer 13

Recognise via “loss of self” mechanism.

Selectivity is conferred by LOSS of “self” MHC molecules on target cell surfaces, AND up-regulation of activating ligands

Uninfected cells present MHC class 1 and peptide to NK cell and is not killed.

Infected cells down regulate MHC class 1 as pathogen thinks this will prevent presentation of peptide.

NK cells recognise absence of inhibitory signal of MHC class 1 and release perforins and engage death receptors.