Introduction to innate immunity Flashcards
Describe innate immunity
Physical barriers
Chemical barriers
Phagocytes
Inflammation, acute phase response
Complement
Cytokine/chemokines
Describe adaptive immunity
T lymphocytes
B lymphocytes
Cytokines
Describe the specificity of the innate immune response
Non specific
No antigen recognition
Describe the specificity of the adaptive immune response
Involves very specific recognition of precipitating agent
Compare innate and adaptive immunity
Cells - macrophages, neutrophils, DCs (innate); lymphocytes (adaptive)
Speed - fast (innate); slow (adaptive)
Memory - none (innate); yes (adaptive)
Specificity - low (innate); very very very high (adaptive)
Receptors - host molecule, pattern recognition (innate); Ig, TCR (adaptive)
Strategy of recognition - small no of ligands, highly conserved, widely distributed, receptors evolved by natural selection (innate); every possible antigen, receptors generated randomly within individual, cannot be passed to offspring (adaptive)
Describe neutrophils
Large cells 10-20 microns
Neutral staining cytoplasmic granules containing enzymes e.g. lysozyme
Only live for 2-3 days
90% of granulocytes are neutrophils
Phagocytic - kill bacteria by microbicidal mechanisms
Most important cell in non-viral infections
Describe eosinophils
Contain prominent granules which stain red with eosin
Granules contain a crystalline core cytotoxic for parasites (eosinophil basic protein)
Important in immunity for helminth infections
Phagocytic but this is not a major function
Describe basophils
< 0.2% of WBCs are basophils
Only go into tissues during inflammation
When stimulated they release substances that promote inflammation
Important in allergy
Not thought to phagocytose
Describe monocytes
In the blood for 1-2 days
Phagocytic
They are mononuclear leukocytes
Describe macrophages
Monocytes in tissues are macrophages
Up to 10x larger than monocytes
Can live for months-years
Phagocytic
Adherent
Characteristics depend on the tissue
How do innate cells recognise foreign molecules?
Two ways:
1) Get their specificity from host molecules e.g. IgG, complement components, chemokines
2) Inherent specificity (pattern recognition) e.g. germline encoded receptors for conserved molecular patterns which detect foreign invaders or aged/damaged host cells (apoptotic)
What are examples of opsonic receptors?
FcR
CR3
What are examples of non-opsonic patter-recognition receptors?
Lectin receptors
Scavenger receptor
TLRs
What is the ligand for Fc receptors and the outcome of its binding?
Ig ligand
Outcome = phagocytosis
What is the ligand for complement receptors and the outcome of its binding?
Complement components
Outcome = phagocytosis
What is the ligand for 7-transmembrane receptors (G-protein-coupled) and the outcome of its binding?
Chemokines e.g. IL-8
Complement fragments e.g. C5a
Lipid mediators e.g. prostaglandins, leukotrienes
Outcome = Migration into tissues
What are the types of Fc receptors?
Fc gamma R
Fc alpha R
Fc epsilon R
What does binding to Fc receptors result in?
Internalisation of antibody coated antigen
What do Fc receptors on macrophages result in?
Activation and production of ROS
What are some types of complement receptors?
CR1-5
CR1
CR3
CR4
What do complement receptors bind?
Cleavage products which are bound to pathogens, immune complexes of other complement activators
They can be endocytic and activatory
Describe chemokine receptors
7 transmembrane receptors
Common family of membrane proteins
G-protein coupled
What do chemokine receptors do?
Recognise host chemokines and also microbial formyl-met peptides (starting sequence in protein synth)
Result in cell migration
What are the general properties of PAMPs?
Present only on pathogens and not on host cells
Essential for survival of pathogens
Invariant structures shared by entire class of pathogens
Name the types of pattern recognition receptors
Mannose receptors
Scavenger receptors
TLRs
NOD-like receptors (NLRs)
RIG-like receptors
7-transmembrane receptors
What is the ligand and outcome for mannose receptors?
Terminal mannose and fucose
Outcome = phagocytosis
What is the ligand and outcome for TLRs?
LPS with CD14
Lipoproteins
Unmethylated CpG
Flagellin
dsRNA, ssRNA in endosomes
Outcome = inflammation, cytokine release (TNF, IL-1, IL-12), enhanced killing, ROS & NO
What is the ligand and outcome of NLRs?
Peptidoglycan from gram positive and negative bacteria
Some viral DNA and RNA
Outcome = inflammation, cytokine release (IL-1, IL-8)
What is the ligand and outcome of RIG-like receptors?
dsRNA and 5/-triphospho RNA
Outcome = type 1 IFN production
What is the ligand and outcome of 7-transmembrane receptors?
Formyl-methionine peptides
Outcome = migration into tissues
Give an example of a lectin receptor
Mannose receptor
What do lectins bind?
Carbohydrates
Describe mannose receptor
Recognises terminal mannose and fucose which ae not present in human molecules
It is a membrane bound soluble form of Mannan Binding Lectin in complement
Results in phagocytosis
Describe scavenger receptors
Membrane bound PRRs
Bind to apoptotic cells/modified self molecules
Responsible for clearing up after an immune response
Also bind bacterial cell walls
Recognise lipoproteins
What is the main role of scavenger receptors?
Fine tuning TLR signalling
e.g. SR-A, TLR4, TLR2 and CD36 in S. aureus and M. tb recognition
Name the class A scavenger receptors
SR-A I
SR-A II
MARCO
CD163
Name the class B scavenger receptors
CD36
SR+BI
What do class A receptors have?
Collagen or C-type lectin domain
What do class B receptors have?
CD36 domain
What do class D receptors have?
LAMP domain
What do all of the scavenger receptors appear to have?
Clusters of cationic rsidues, centrally located
May account for binding to similar ligands
May be linked to FcR gamma ITAM
Describe TLRs
Pattern recognition molecules for bacterial and viral ligands
Stimulate cytokine release
What are the types of TLR?
TLR1 to -9
Ligand for TLR1
Modulin
Lipopeptides
Origin = gram positive bacteria
Ligand for TLR2
Lipopreoteins, peptidoglycan, lipteichoic acid; origin = gram positive bacteria
Mannuronic acid polymers; origin = pseudomonas aeruginosa
Modulin; origin = Staphylococcus
Lipoproteins, lipopeptides, lipoarabinomannan; origin = Mycobacteriae, Mycoplasmae
Heat-killed bacteria; origin = Listeria
Zymosan; origin = Yeast
Ligand for TLR3
dsRNA
Origin = virus
Ligand for TLR4
LPS; origin = gram-negative bacteria
Lipoteichoid acid, mannuronic acid polymers; origin = gram positive bacteria
Taxol; origin = plant
Hsp60, Hsp70, fibronectin; origin = Host
Ligand of TLR5
Flagellin
Origin = gram negative bacteria, gram positive bacteria
Ligand of TLR6
Modulin
Soluble tuberculosis factor
Outer surface protein A lipoprotein (OspA-L)
Origin = gram positive bacteria
Ligand of TLR7
ssRNA
Small antiviral compounds
Origin = virus
Ligand for TLR8
Small antiviral compounds
Ligand for TLR9
Unmethylated CpG-DNA
Origin = bacteria, virus
What do NLRs do?
Bind dsRNA and peptidoglycan
What do RIG-1-like helicases do?
Recognise dsRNA intermediate of viral replication
What can some NLRs form?
The inflammasome
What is the inflammasome?
A multiprotein oligomer complex which assembles in the cytoplasm after PAMP/DAMP detection
What does inflammasome formation lead to?
Can lead to activation of caspase including caspase-1 which cleaves precursors to IL-1 and IL-18
What is the inflammasome composed of?
Several intracellular PRRs including NLRs and can be triggered by PAMPs and DAMPs
What does inflammasome formation lead to?
Pyroptosis
Inflammatory cell death
What is the inflammasome linked to?
Autoimmunity (MS, diabetes)
Inflammation such as atherosclerosis
May be an exaggerated response to host-derived factors
What are some other innate cells?
NK cells
NKT cells
DCs
Gamma delta T cells
Innate lymphoid cells
Describe NK cells
Large granular lymphocytes
4% of WBCs are NK cells
Play a role between innate and specific immunity
What do NK cells do?
Kill certain tumour and virally infected cells
What are NK cells activated by?
FcR and KIR
How do NK cells destroy target cells?
Target cell destruction cause by cytotoxic molecules called granzymes and perforins
What are NKT cells?
Express NK and T cell markers
Intermediate TCR expression
Describe NKT cells
Restricted TCR alpha chain usage
Recognises through CD1d
Produces Th1 and Th2 cytokines
Recognises lipids, glycolipids, hydrophobic peptides
What effects do NKT cells have?
Alpha-galactosylceramide and anti-tumour effect
Describe gamma delta T cells
Make up 10% of peripheral blood mononuclear cells but up to 70% of mucosal T cells
Some express CD8 and CD4
Most are double negative
Restricted through MHC molecules as alpha beta
Some gamma delta T cells are restricted through other molecules such as alpha-3 butyrophilin
What do gamma delta T cells recognise?
A number of bacterial antigens
Small aliphatic molecules (isoprenoid pyrophosphates and amines) which may represent a pattern recognition system
What does the gamma chain consist of?
V, J and C regions
What does the delta chain consist of?
V, D, J and C regions
What are immune lymphoid cells?
A growing family of immune cells that have similar phenotypes and functions to T cells
However, they do not express acquired antigen receptors or undergo clonal selection/expansion like when stimulated like T cells do
Where are ILCs found?
At barrier/mucosal surfaces
e.g. intestine, lungs, skin etc.
Name group 1 ILCs
NK cells
ILC1
Name group 2 ILCs
ILC2
Name group 3 ILCs
LTi cell
NCR- ILC3
NCR+ ILC3
Describe ILC3
Main ILC in human non-inflamed gut
What does ILC3 do?
Produces IL-22 in response to endothelial signals e.g. IL-23
Produces induced antimicrobial response
DCs control this partly by production of IL-22BP
How are ILCs involved in Crohn’s Disease
The ILC3 population is replaced by the ILC1 population
Produces IFN-G and causes chronic inflammation
What are DCs?
Irregularly shaped cells in most tissues
May be myeloid or lymphoid derived in tissues
What DCs do?
When immature they capture and engulf Ag and pass to lymphoid tissues where they mature and present antigen to T cell
They direct polarisation of the immune system towards either Th1 or Th2 cells
