L13 - Review of the Innate Immune System

Question 1

Why do we need an innate immune system?

Answer 1

the adaptive immune response is too slow to protect us from new pathogens.
Allows survival until adaptive immune response kicks in.

Question 2

What is the Innate immune system?

Answer 2

The unspecific Immune system, that is present from birth

Question 3

Describe the differences in specificity between adaptive and innate immunity?

Answer 3

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

Question 4

What are PAMPs?

Answer 4

Pathogen associated molecular patterns

Molecules present only on pathogens and not on host cells
Essential for survival of pathogens
Invariant structures shared by entire class of pathogens

Question 5

Give examples of PAMPs on Gram positive and negative bacteria as well as in general?

Answer 5

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

Question 6

What are PRRs?

Answer 6

Pattern Recognition Receptors

Host factors that specifically recognise a particular type of PAMP

They are germ-line encoded

Question 7

What are Extracellular PRRs?

Answer 7

Extracellular – they recognise PAMPs outside of a cell and trigger a co-ordinated response to the pathogen

Question 8

What are Intracellular PRRs?

Answer 8

Intracellular (cytoplasmic) – they recognise PAMPs inside a cell and act to co-ordinate a response to the pathogen

Question 9

What are Secreted PRRs?

Answer 9

Secreted – they act to tag circulating pathogens for elimination

Question 10

Briefly state some of the components of the Innate Immunity?

Answer 10

The inflammatory response
Phagocytes
Monocytes/granulocytes/neutrophils
Complement
Cytokines, chemokines and anti-microbial peptides (AMPs)
Natural Killer cells

Question 11

Describe the Inflammatory response as a component of Innate Immunity?

Answer 11

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
Triggered by the release of pro-inflammatory cytokines and chemokines at the site of infection

Question 12

Describe Phagocytosis as a component of Innate Immunity?

Answer 12

Phagocytes have to be able to recognise what to eat

Phagocytes need know when they are infected in order to produce cytokines and chemokines

The molecular recognition events are distinct – i.e. they use different pattern recognition receptors

Question 13

What are the roles of Macrophages and Dendritic cells?

Answer 13

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

Dendritic cells - Peptides from broken down pathogens can be presented through MHC and promote the development or recall of an adaptive T cell response

Question 14

How do Phagocytes know what to engulf?

Answer 14

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”

By detecting complement proteins bound to the pathogen surface

Question 15

Describe the complement system as a component of Innate Immunity?

Answer 15

Originally described as a heat-sensitive component of serum that could augment the ability of antibodies to inactivate antigen

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)

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”

Question 16

What PAMPs are recognised by Toll-like receptors, and what cytokines/chemokines are produced as a result?

Answer 16

PAMPs:
LPS (together with CD14)
lipoproteins
Unmethylated CpG
Flagellin
ds RNA; ss RNA (in endosomes)

Produce:
inflammation: cytokine release

(TNF, IL-1, IL-12)
enhanced killing: reactive oxygen species, NO)

Question 17

What PAMPs are recognised by Nod-like receptors, and what cytokines/chemokines are produced as a result?

Answer 17

PAMPs:
Peptidoglycan from Gram positive and negative bacteria
Some viral DNA and RNA (indirect?)

Produce:
inflammation: cytokine release (IL-1, IL-8)

Question 18

What PAMPs are recognised by RIG-like receptors, and what cytokines/chemokines are produced as a result?

Answer 18

PAMPs:
Viral dsRNA and 5’-triphospho RNA

Produce:
type I interferon production

Question 19

What are Cytokines and Chemokines?

Answer 19

They are both 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

Question 20

What are Interferons?

Answer 20

The main Anti-viral Cytokines

Secreted factors (type I and type III)

Type 3 protects epithelial surfaces and type 1 protects other surfaces

Induced by viral infection
Offer cross-protection
Widely distributed in evolution, from fish upwards, but species-specific

Question 21

What are Defensins?

Answer 21

Secreted short peptides (18-45 amino acids)

Usually work by disrupting cell wall leading to lysis

Some are induced by bacterial infection

Offer broad protection

Question 22

What are NK cells?

Answer 22

Natural killer cells

Make up 4% white blood cells

Lymphocyte-like but larger with granular cytoplasm

Kill certain tumour & virally infected cells

Target cell destruction is caused by cytotoxic molecules called granzymes & perforins
via surface contact

Question 23

How are NK cells activated?

Answer 23

Activated by loss-of-self.

NK cells have an MHC receptor that recognisesMHC class 1 peptide on the surface of uninfected cells. If it recognises this pepetide, it does nothing.

In an infected cell, MHC 1 peptide is lost.

If NK cells cannot detect the MHC 1 peptide, it engages the cell and induces cell death via perforins and cytotoxic granules

Question 24

State some diseases that are associated with defects in Innate Immunity?

Answer 24

Complement – core defects (e.g. C3) linked to development of autoimmune diseases such as lupus

Complement – non-core defects linked to suseptibility to specific types of pathogens such as Neisseria

Macrophage deficiencies - Chronic granulomatous disease (CGD); No oxidative burst for bacterial killing

Macrophage deficiencies – IRF8 mutations linked to susceptibility to TB

Aicardi–Goutières syndrome associated with constitutive production of inflammatory cytokines

Lack of interferon-responsiveness – sensitivity to viral infection (e.g. measles)