An introduction to innate immunity - unfinished

Question 1

name some components of innate immunity

Answer 1

non-specific, no antigen recognition

Physical barriers
Skin, mucosal surfaces

Chemical barriers
pH, secreted factors-tears e.g.,

Phagocytes
Monocytes/granulocytes

Inflammation; acute phase response

Complement

Cytokines/chemokines

Question 2

specific/adaptive immunity

Answer 2

Involves very specific recognition of precipitating agent

T lymphocytes
B lymphocytes (antibody)
Cytokines

Question 3

Neutrophils

Answer 3

Large cells (10-20 microns); only live about 2-3 days

90% of granulocytes are neutrophils

Neutral staining cytoplasmic granules containing enzymes
e.g. lysozyme

Phagocytic, kill bacteria by microbicidal mechanisms

Most important cell in non-viral infections

Question 4

Eosinophils

Answer 4

Contain prominent granules, which stain red with eosin
Granules contain a crystalline core cytotoxic for parasites; EOSINOPHIL BASIC PROTEIN
Important in immunity to helminth infections
Phagocytic, though this is not a major function

Question 5

Basophils

Answer 5

<0.2% white blood cells, only go into tissues during inflammation
When stimulated, release substances that promote inflammation
Important in allergy
Not thought to phagocytose

Question 6

Monocytes

Answer 6

in blood 1-2 days
Mononuclear leukocytes
Phagocytic
APC

Question 7

Macrophages

Answer 7

APC
MCs in tissues = macrophages
Up to 10x larger than MCs
can live months or years
Characteristics of macrophages depend on tissue e.g. Kupffer cells in liver, microglia of brain
Phagocytic (like neutrophils and eosinophils), adherent

Question 8

what maintains immune response after innate?

Answer 8

Adaptive seems to be important in maintaining the immune response after the innate

Question 9

Recognition receptors on innate cells - 2 categories

Answer 9

Specificity from host molecule
- IgG, complement components, chemokines

Inherent specificity (pattern recognition) - those that have an inherent specificity for a pattern, looking for conserved patterns on bacteria or virus

• germline-encoded receptors for conserved molecular patterns
• detects foreign invaders or aged/damaged host cells (apoptotic)

Question 10

Opsonic receptor vs non-opsonic receptor

Answer 10

opsonic - – recognises host molecule to cause phagocytosis – the phagocytic capabilities are enhanced by IgG or complement bound to that bacterial or viral organism

non-opsonic - recognises pattern conserved molecules

Question 11

Fc Receptors

Answer 11

Receptors for the Fc region of Ig
Expressed on many cell types
FcγR, αR, εR
Results in internalisation of Ab coated Ag
On Mφ results in activation and production of reactive oxygen species

Question 12

Complement receptors

Answer 12

CR1-5
Diverse structures
CR1, CR3 (CR4) bind C3 cleavage products which are bound to pathogens, Immune complexes or other complement activators
Endocytic and activatory

Question 13

Chemokine receptors

Answer 13

7 transmembrane receptors
Common family of membrane proteins
G-protein coupled
Recognise host chemokines and also microbial formyl-met peptides (starting sequence in protein synth)
Result in cell migration

Question 14

General properties of pathogen-associated molecular patterns

Answer 14

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

Question 15

Pattern recognition receptors

-examples?

Answer 15

Mannose receptors
Scavenger receptors
Toll-like receptors (TLRs) (surface and endosomal)
NOD-like receptors (NLRs) (cytoplasm)
RIG-like receptors (RIG-1 and MDA5) (cytoplasmic)
7-transmembrane receptors (G-protein-coupled)

Question 16

Lectin receptors

Answer 16

Eg Mannose receptor

Lectins bind carbohydrates

MR recognises terminal mannose and fucose (not present in human molecules)

MR is membrane bound cf soluble Mannan Binding Lectin in complement

Results in phagocytosis

Question 17

Scavenger receptors

Answer 17

Membrane bound PRRs
Bind to apoptotic cells/modified self molecules and responsible for ‘clearing up’ after an immune response.
After e.g. viral infection where you’ve had a lot of cellular debris
Also bind bacterial cell walls
Recognise lipoproteins (lps)
Can mediate endocytosis
Main role is fine tuning TLR signalling (eg SR-A and TLR4 and TLR2 and CD36 in S.aureus and M.tb recognition).

Question 18

PAMPs & DAMPs

Answer 18

Pattern recognition and Damage recognition
PAMPs such as TLR ligands
DAMPs such as ‘alarmins’, inc defensins, HMGB-1, ATP etc.

Question 19

Toll-like receptors

Answer 19

Discovered in Drosophila sp, important in development but also in defence
Pattern recognition molecules for bacterial and viral ligands
Most Mammalian Sp: 10-15
Stimulate cytokine release

Question 20

Other Intracellular receptors

Answer 20

Recognise intracellular bacteria and viruses

NOD-like receptors (nucleotide binding and oligomerization domain)- bind dsRNA and also peptidoglycan

RIG-1- (retinoic acid inducible gene-1) like helicases (RLH)- recognise dsRNA intermediate of viral replication (also MDA-5)

Some NLRs can form the inflammasome.

Question 21

Inflammasome

Answer 21

A multiprotein oligomer complex which assembles in the cytoplasm after PAMP/DAMP detection. Can lead to activation of Caspases inc Caspase 1 which cleaves precursors to IL-1 and also IL-18

Composed of several intracellular PRRs including NOD-like receptor and can be triggered by PAMPs and DAMPs (DAMPs leading to ‘sterile’ inflammation.).

Leads to pyroptosis; Inflammatory cell death.

Linked to autoimmunity (MS, diabetes) and inflammation such as atherosclerosis. May simply be an exaggerated response to host-derived factors.

Question 22

Natural Killer cells

Large granular lymphocytes

Answer 22

4% white blood cells

Collection of cells playing role between innate & specific immunity

Lymphocyte-like but larger with granular cytoplasm

Kill certain tumour & virally infected cells

Activated by FcR and KIR

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

Question 23

Treat cancer using LAK cells

Answer 23

Lymphokine activated killer cells
Take peripheral blood, separate the white cells out
Give them IL-2 to activate the cells that have the IL-2 receptor, the reason it will have IL-2 receptor because its been partially activated by tumour they’ve seen the tumour
This generates LAK or NK cells which you reinfuse the patient with
These can kill tumou

Question 24

NKT cells

Answer 24

Express NK and T cell markers, NK1.1 and TCR

Restricted TCR α-chain usage

Intermediate TCR expression.

Recognises through CD1d (non-classical MHC1)

Produces Th1 and Th2 cytokines

Recognises lipids, glycolipids, hydrophobic peptides.
α-galactosylceramide and anti-tumour effect.

Question 25

γδ T cells

Answer 25

Makes up ~10% peripheral blood MNC but up to 70% of mucosal T cells

Some express CD8 and CD4, most double negative

Restricted through MHC molecules as αβ

Some γδ T cells are restricted through other molecules such as α3 butyrophilin

γδ T cells can recognise a number of bacterial antigens

Can also recognise small aliphatic molecules (isoprenoid pyrophosphates and amines) which may represent a pattern recognition system

γ chain consists of V, J and C regions

δ chain consists of V, D, J and C regions

The effect of extensive junctional diversity increases the γδ TCR repertoire to ~1019 possible receptors BUT Vγ9Vδ2 all seem to recognise IPP

Question 26

Dendritic cells

Answer 26

Irregularly-shaped cells in most tissues

In tissues, DC may be myeloid or lymphoid derived
DCs when immature capture and engulf Ag, pass to LYMPHOID TISSUES where they mature and effectively present antigen to T cells

Question 27

Danger signals” are required…

Answer 27

to produce immunity

Question 28

Th1 / Th2 polarisation

Answer 28

Th1
Key cytokine in polarising immune response is IL-12p70 produced by dendritic cells
IL-12p70 produced in response to DCs detecting intracellular infection
e.g. signalling through endosomally located TLR3 in response to dsRNA in apoptotic cell body
IFN-α produced by pDCs also polarises for Th1

Th2
IL-4 directs CD4 T cells to promote B cell proliferation
In response to DC detecting an extracellular infection
e.g. signalling through cell surface bound TLR5 in response to flagellin