An introduction to innate immunity Flashcards
List the components of the innate and adaptive immune system
Innate immunity
* Physical barriers
– Skin, mucosal surfaces
* Chemical barriers
– pH, secreted factors
* Phagocytes
– Monocytes/granulocytes
* Inflammation; acute phase response
* Complement
* Cytokines/chemokines
Specific/adaptive immunity
* T lymphocytes
* B lymphocytes (antibody)
* Cytokines
Compare specificity of the Innate immunity and the Adaptive immunity
Innate immunity
non-specific, no antigen recognition
Adaptive immunity
involves very specific recognition of the particular
pathogen,
Innate involves recognition, but not as specific as
adaptive immunity
Comparison of the key characteristics of the innate and adaptive immunity
Describe neutrophils
- 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
- constitute the majority of leukocytes in the blood stream
*have a characteristic multilobed nucleus
Neutrophils have a large arsenal of enzymes and antimicrobial proteins stored in two main types of granule: - the primary (azurophilic) granules are lysosomes
- the secondary granules contain lactoferrin and lysozyme
Describe Eosinophils
- 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,
The major function of eosinophils appears to be the secretion of various toxic granule constituents following activation
Describe Basophils
- <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
- Basophils and mast cells play a role in immunity against parasites
Describe Monocytes and Macrophages
Monocytes
* in blood 1-2 days
* Mononuclear leukocytes
* Phagocytic
Macrophages
* MCs in tissues = macrophages
* Up to 10x larger than MCs
* can live months or years mononuclear
* Characteristics of macrophages depend on tissue e.g. Kupffer cells in liver, microglia of brain
* Phagocytic, adherent
Recognition receptors on innate cells
- Specificity from host molecule
– e.g. IgG, complement components, chemokines - Inherent specificity (pattern recognition)
– germline-encoded receptors for conserved molecular patterns
– detects foreign invaders or aged/damaged host cells (apoptotic)
List Recognition receptors on innate cells:
specificity from host molecule and their outcomes
Describe Fc Receptors
- Receptors for the Fc region of Ig
- Expressed on many cell types
- FcgR, alphaR, eR
- Results in internalisation of Ab coated Ag
- On Macrophages results in activation and production of reactive oxygen species
Describe Complement receptors
- 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
Describe Chemokine receptors
- 7 transmembrane receptors
- Common family of membrane proteins
- G-protein coupled
- Recognise host chemokines and also microbial formyl-met peptides (starting sequence in protein synthesis)
- Result in cell migration
describe pathogen-associated molecular
patterns (PAMPs)
- Present only on pathogens and not on host cells
- Essential for survival of pathogens
- Invariant structures shared by entire class of
pathogens
the proteins which recognize them are PRRs
List Pattern recognition receptors, their ligand and outcome
Describe Lectin receptors
- 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
Describe Scavenger receptors
- Membrane bound PRRs
- Bind to apoptotic cells/modified self molecules and responsible for ‘clearing up’ after an immune response. May affect M1/M2
- 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).
Compare all classes of scavenger receptors
No real structural homology between classes. Class A-I
Class A have collagen domain or C-type lectin domain.
Class B have a CD36 domain
Class D LAMP domain Etc. Appear to all have clusters of cationic residues, centrally located. May account for binding to similar ligands. May be linked to FcRg ITAM
Endocytic receptors
give examples of PAMPs and DAMPs
- PAMPs such as TLR ligands
- DAMPs such as ‘alarmins’, inc defensins, HMGB-1, ATP etc.
Other Intracellular receptors than TLR
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.
Describe the Inflammasome
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.
Describe Natural Killer cells (Large granular lymphocytes)
- A group of lymphocytes that have the intrinsic ability to recognize and destroy some virally
infected cells and some tumor cells. - 4% white blood cells
- Collection of cells playing role between innate & specific immunity
- Kill certain tumour & virally infected cells
- Activated by FcR and KIR
- Target cell destruction is caused by cytotoxic molecules called granzymes & perforins
Describe natural killer T cells
- Express NK and T cell markers, NK1.1 and TCR
T cells: CD3 and have a unique ab TCR (expressing an invariant Va and Vb11
CD16 and CD56 are used to distinguish NK cells - Restricted TCR alpha-chain usage (Valpha24 in Hu, 14 in Mo)
- Intermediate TCR expression.
- Recognises through CD1d (non-classical MHC1)
- Produces Th1 and Th2 cytokines (IFNg and IL-4.)
- Recognises lipids, glycolipids, hydrophobic peptides.
- alpha-galactosylceramide and anti-tumour effect
Describe gd T cells
- 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 alphab
- Some gd T cells are restricted through other
molecules such as alpha3 butyrophilin - have a specific repertoire of TCRs biased towards
certain bacterial/viral antigens - Can also recognise small aliphatic molecules
(isoprenoid pyrophosphates and amines) which may represent a pattern recognition system - g chain consists of V, J and C regions
- d chain consists of V, D, J and C regions
- The effect of extensive junctional diversity increases the gd TCR repertoire to ~1019 possible receptors
BUT Vg9Vd2 all seem to recognise IPP
Describe DC targeted antigen delivery
- DC-SIGN; lectins designed to target tumour
Ag to DCs. Cross-presentation - DEC205- lectin receptor, anti-DEC205-ovalbumin complex endocytosed and antigen presented on Class1 and 2
- FcgR mediated uptake- Ab conjugated to tumour antigen (lymphoma anti-Id)
- Associated with cell mediated immunity
Can the innate receptor be used clinically?
gd T cells
- Have been shown to recognise non-peptide antigens
- Have been shown to have broad cytotoxicity against tumour cells both allogeneic and autologous
- Vg9Vd2 Recognise prenyl pyrophosphate ligands:
can be over expressed on tumour cells eg B-cell
lymphomas. - Zoledronic acid
- Now in trials.
TLR ant/agonists
DC vaccines
- HIV, Hep B & C peptides/native or transfected
viruses-more than one epitope. But also therapeutic vaccination. More useful in cancer. - Used to be non-matured
- TNF A
- Complex cytokine cocktails including TLR
agonists:
Poly I:C; Aldara
‘Virtually virally infected cell’
- Induce death in a TC which will correctly stimulate the DC which endocytoses it.
- TC will release signals which will activate/mature the DC.
- Correct presentation of the TC peptides by the
DC to the adaptive response.
