Innate Immunity
Threats can be external or internal with infectious disease accounting for 1/3 of all deaths, however most microorganisms do not cause disease. Some microorganisms cause disease in certain scenarios and some are commensal. Some organisms are also antigentically unstable.
Crucial for...
First 4-6 days
Antigenically unstable organisms
Children
Initiation of adaptive response
Mechanical barriers..
Skin, UI, GI, airways
Prevent adhesion
Unfavourable pH enviornments
Commensal organisms
Consitutive secretion of microbicides
Mucus
Defensis
Lysozymes
histines
Tears
All cells are capable of some level of innate immunity
Soluable factors in body fluids
Inflammation
RSHP
Dilation of arterioles, venules and capilaries❤
Increased permablity and blood flow
Immune cell migration into imflammatory focus
Specilised cells embedded into tissues
Not in CNS (can be lethal)
Physical protection
Meningial membranes
Trauma via mechanical damage is the biggest threat
Complex and unqiue nerve connections that have little capacity for regneration
Threat, recognition, communication, elimination, resolution ♻
Recognition: cells and solutable factors.
Communication depends on the threat
Elimination can involve many systems
Resolution can involve a memory response
Extracelluar threats
Recognition
Invariant structures
PAMPS
Pathogen survival
DAMPS
Host survival
Gram +
Lipotechoic acid
Endogenous threats
Intracelluar components
Heat shock proteins
Phosphatidyl serine
ECM components
Uric acid
Chromatin
Gram -
LPS
Both
N formylated proteins
Fungi
Chitin
Viruses
dsRNA
Parasties
Soluable antigen glycosol residues
Protazoa
GPI linked mannose rich glycans
PRRS #
There are over 1000 DAMPS and PAMPS expressed on both immune and non immune cells.
Multiple types
Can recognise more than one PAMP/ DAMP
Germline
Involved in...
Signalling
Endocytotic events
Cell activation
Ligand uptake
Proinflammatory
Rare epigentic events otherwise change via serious gene pool changes
Cytoplasmic
Collectins
Secreted
NOD like
Membrane
TLR
Horseshoe- leucine rich repeats and cysteine repeats ligand binding
TLR signalling
1-13 common structure/ different substrates
3 dsRNA
Inner surface beta sheet
L sidechain specificity
LPS
Structure
Essential -ve OM
One of the most potent IS activators
Ld50 mice = 150ug
Symptoms
Hypertension
Loss of circulating leucocytes
Depression of myocardial function
'Timebomb' .. intestinal E.coli 1kg
Macrophages
TNFa
IL6
TLR4
Binds LPS
Signalling levels differ between cell type
Cofactors needed
LPB (LPS binding protein) binds to LPS and presents to macrophages via CD14.
Binding to CD14 makes system more sensitive to low levels of LPS ....
...BP1 is also present to protect against high concs of LPS.
This is swamped if LPS is at very high levels ⚠
Binding induces TLR multimer formation. Adaptor proteins then coordinate signal transduction.
MyD88
TRIF
Activates kinase
Nuclear translocation of IRF3
NfKb
IRAK
❌ Inhibitor IkB
Releases NfkB #
Activation in macrophages increases TNFa
Effects in mins/hrs
Slower
Animals and plants
Post translation mechanisms allow for complex control
Ubiquination
phosphorylation
Consitutivey active in cancers
Protective against apoptosis??
N formyl peptide (GPCRs) (FPRS)
N terminal loops ligand recognition
Transmembrane domains often form rings
Molecules interact with G protein's inner face
Ligands include..
N formyl petides
HIV1 env proteins
MHC binding proteins
Altered self
Prions
Amyloid B 1-42
Multiple ligands with no common sequence / ovbious structure similarties
Ensures that immune cells, defence molecules and cogulating factors reach the damage site
Inflammatory mediators
Coagulation factors
ROI/ RON
Purines (ATP)
Contact system
Complement factors
Coordination
Cytokines #
5-20KD
Communication between IR cells
Usually produced and act locally
Immunomodulators
Produced by any cell type
Auto/ paracrine
Stimulatory/ inhibitory
Redundancy
Interleukins 1-38, 39?
Produced by T cells
Interferons
A/B type 2
Viral
Y
Chemokines/ chemotaxis
Helper produce different subsets
Can be anti inflammatory
CNS
Skin constitutively expressed
Mainly macrophages