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L3 – What to Attack?
The immune system must distinguish pathogenic infectious agents from
commensals, self-antigens and environmental antigens
...

• PAMPs are particular molecular patterns that are typically associated
with infectious agents
...
PAMPs are not found in the host
...
DAMPs play a role in
sterile injury, where an immune response occurs in the absence of any
infectious agent (for example, bruising)
...

Polymorphism describes the variation in genes from one individual to
another and PRRs show very low polymorphism
...
They can
be subdivided into at least 5 distinct families on the basis of their
structure (Toll-like receptors, nod-like receptors, C-type lectin
receptors, RIG-like helicase receptors and scavengers)
...
MHCs can be responsible for the rejection of tissue
transplants between genetically different individuals
...
There are a
lot of different variants of MHCs and each variant can bind many
different peptide sequences
...
There are about 12 MHCs that are expressed, these are
what we call the classical MHCs
...
MHC class I and II are classical MHCs
...
3
sub-groups of MHC class I: HLA-DP, DQ and DR
...

T-cell receptor (TCR) – found on surface of T lymphocytes and are
highly specific
...

Antibody/B-cell receptor (BCR) – found on the surface of Blymphocytes as well as in soluble forms and is highly specific
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Genetic recombination of BCR genes creates huge diversity
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Soluble PRRs
• Direct attack of microorganism by soluble PRR molecules through
multivalent bidning
• Enhancement of phagocytosis of PRR-bound PAMPs
• Proteolytic cascade resulting in lysis of microorganism
Cell-associated PRRs
• Found on all cells of the immune system, both innate and adaptive
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As a consequence,
intracellular DAMPs are released, which then go on to engage the immune
system and promote inflammation
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An apoptotic death is under strict control and cells
destined for apoptosis express cell surface molecules (e
...

phosphatidylserine) that mark the cells for apoptosis and removal by
phagocytosis
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Consequence of PAMP-mediated stimulation
Cytokines are a diverse group of proteins that have pleiotropic effects; they
are able to activate other cells, induce differentiation and enhance
microbicidal activity
...
Chemokines, by definition, include amongst
their activity the ability to attract cells to the site of the infection, although that
is not their only role
...
Cytokines can cause cell
contraction of the blood vessel endothelium and often cause cells to release
other cytokines
...
The Toll-receptor was first
identified in drosophila affected with fungal affections, where the gene
encoding this receptor had been mutated and no longer protected the
drosophila
...

The Toll-like receptors recognise PAMPs and trigger a biochemical cascade,
following which transcription factors are activated and inflammatory cytokines
are synthesised
...

• TL2 recognises bacterial lipopeptides and lipoproteins
• TLR4 recognises bacterial lipopolysaccharide
• TLR5 recognises bacterial flagellin
In addition, there are several TLRs found on the surface of endosomal
compartments
...

• TLR3 recognises viral dsRNA
• TLR7 and TLR8 recognise viral ssRNA/nucleotide analogues
• TLR9 recognises bacterial unmethylated CpG DNA
...
α-interferon and βinterferon are also important activators of NK cells, where killing activity is
enhanced up to a 100-fold
...
They have multiple Nterminal leucine rich repeats arranged in a horseshoe crescent-shaped
solenoid structure that acts as the PAMP-binding domain
...
The
adaptors propagate a signal downstream, resulting in the activation of nuclear
factor κB (NFκB) and interferon-regulated factor (IRF) family transcription
factors
...
Following stimulation of a TLR, the IKK (IκB kinase)
complex phosphorylates IκB, resulting in the release of NFκB
...
NFκB can now localise to the nucleus where
it binds to regulatory regions on the DNA and initiates transcription of

inflammatory cytokines, such as interferons, IL-1, TNF and chemokines
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