W11 Innate immunity

Question 1

Sites of Microbe Entry

Answer 1

Conjunctiva
Arthropod
Capillary
Scratch, injury
Skin
Anus
Urinogenital tract
Alimentary tract
Respiratory Tract

Question 2

The Inflammatory Response

Answer 2

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 3

Cytokines

Answer 3

Act to modify the behaviour of cells in the immune response

Most of these are called interleukins (eg. IL-1)

Question 4

Chemokines

Answer 4

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 5

IL-1

Answer 5

Main producer = Macrophages + keratinocytes

Acts upon = lymphocytes + liver

Effect = Enhances response
Induces acute-phase protein secretion

Question 6

IL-6

Answer 6

Main producer = Macrophages + dendritic cells

Acts upon = lymphocytes + liver

Effect = Enhances response
Induces acute-phase protein secretion

Question 7

CXCL8 (IL-8)

Answer 7

Main producer:
Macrophages + dendritic cells

Acts upon:
Phagocytes

Effect:
Chemoattractant for neutrophils

Question 8

IL-12

Answer 8

Main producer:
Macrophages + dendritic cells

Acts upon:
Naive T cells

Effect:
Diverts immune response to type 1, proinflammatory, cytokine secretion

Question 9

TNF - alpha

Answer 9

Main producer:
Macrophages + dendritic cells

Acts upon:
Vascular endothelium

Effect:
Induces changes in vascular endothelium (expression of cell-adhesion molecules (E- + P- selectin), changes in cell-cell junctions w/increased fluid loss

Question 10

How do macrophages “see” microbes?

Answer 10

Passive sampling
Scavenger receptors
Engulfing apoptotic cells

Question 11

Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)

Answer 11

Pattern recognition is through Pathogen-associated Molecular Patterns (PAMPs)

Question 12

Examples of Pathogen-associated Molecular Patterns (PAMPs)

Answer 12

Gram-negative bacteria; lipopolysaccharides (LPSs) found in outer membrane

Gram-positive bacteria; teichoic acid, lipoteichoic acid, peptidoglycan found in outer membrane

Question 13

Other PAMPs include

Answer 13

Bacterial flagellin
Abnormal protein glycosylation
Abnormal nucleic acids - viruses

Question 14

Pattern recognition receptors (PRRs)

Answer 14

Host factors that specifically recognise a particular type of PAMP
They are germ-line encoded

Question 15

There are several classes of PRR, but functionally they are either

Answer 15

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

Question 16

Lectin receptors

Answer 16

Ligand:
terminal mannose and fucose

Outcome:
phagocytosis

Question 17

Scavenger receptors

Answer 17

Ligand:
bacterial cell walls
modified low-density lipoproteins

Outcome:
phagocytosis

Question 18

Toll-like receptors (TLRs) (surface and endosomal)

Answer 18

Ligand:
LPS (together with CD14)
lipoproteins
unmethylated CpG
flagellin
ds RNA; ss RNA (in endosomes)

Outcome:
inflammation: cytokine release (TNF, IL-1, IL-12)
enhanced killing: reactive oxygen species, NO)

Question 19

NOD-like receptors (NLRs) (cytoplasm)

Answer 19

Ligand:
peptidoglycan from Gram positive and negative bacteria
some viral DNA and RNA (indirect?)

Outcome:

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

Question 20

RIG-like receptors (RIG-1 and MDA5) (cytoplasmic)

Answer 20

Ligand:
dsRNA and 5’-triphospho RNA

Outcome:

type I interferon production

Question 21

Complement

Answer 21

A system of secreted proteins made in the liver that recognise PAMPs on the surface of microbes and “decorate” or “tag” them. The microbes are then cleared by phagocytosis, “opsonised” or they have holes punched in them

Question 22

Three ways of activating complement:

Answer 22

i) . Recognition of LPS and other PAMPs by the C1q component of “classical” pathway
(ii) . Non-host glycosylation is recognised by MBP and other lectins to activate the “lectin” pathway
(iii) . Membranes that are recognised as “non-self” activate the “alternative” pathway

Complement activation involves a proteolytic cascade

Question 23

Natural Killer (NK) cells (Large granular lymphocytes)

Answer 23

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

Question 24

Natural Killer (NK) cells are activated by loss-of-self

Answer 24

NK cells possess the ability to recognise and lyse virally infected cells and certain tumour cells.
Selectivity is conferred by LOSS of “self” MHC molecules on target cell surfaces, AND up-regulation of activating ligands

Question 25

Cell death

Answer 25

(i). Perforin +
cytotoxic granules
(ii). Engagement of
death receptors

Question 26

CMV has four gene products which

Answer 26

which reduce the expression of Class 1 MHC molecules and two class I MHC homologues (UL18 & M144), that give a negative signal to NK cells

Question 27

NK cells bind

Answer 27

cells bind HLA-E which carries in its groove a peptide from the leader sequence of classical class I MHC molecules

Question 28

Leader sequence found on

Answer 28

This same peptide sequence is found on the leader sequence of human hCMV. Thus, whilst MHC class I molecules are down regulated in hCMV infected cells, HLA-E is up regulated

Question 29

There are many inherited defects associated with Innate Immunity

Answer 29

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

Complement – non-core defects linked to suspectibility 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)