MIMM-314 -- Lecture 3 -- 2011 08/01/2012 1 January 11, 2011 MIMM-314 R.G.E.Palfree 1 IMMUNOLOGY Year 2011 version Dr. Roger Palfree’s Lecture 3 Receptors Macrophage cytokines Lymphoid Tissues Trafficking From infection to Antigen Presentation (somewhat integrated and not necessarily in that order) Made available via www.rogerpalfree.com January 11, 2011 MIMM-314 R.G.E.Palfree 2 Innate Immune System Receptors Cell surface proteins, soluble proteins in body fluids, and also cytoplasmic proteins which sense viral infection. Commonly have several binding sites with different ligand specificities. Frequently polymeric, with several binding sites for the same ligand. Recognize (bind with functional avidity to) microbes, via multivalent binding to so-called “pathogen-associated molecular patterns” (PAMPs).
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MIMM-314 -- Lecture 3 -- 2011 08/01/2012
1
January 11, 2011 MIMM-314 R.G.E.Palfree 1
IMMUNOLOGY
Year 2011 version
Dr. Roger Palfree’s Lecture 3
� Receptors
� Macrophage cytokines
� Lymphoid Tissues
� Trafficking
� From infection to Antigen Presentation
(somewhat integrated and not necessarily in that order)
Made available via www.rogerpalfree.com
January 11, 2011 MIMM-314 R.G.E.Palfree 2
Innate Immune System Receptors
Cell surface proteins, soluble proteins in body fluids, and
also cytoplasmic proteins which sense viral infection.
Commonly have several binding sites with different ligand
specificities.
Frequently polymeric, with several binding sites for the
same ligand.
Recognize (bind with functional avidity to) microbes, via
multivalent binding to so-called “pathogen-associated
molecular patterns” (PAMPs).
MIMM-314 -- Lecture 3 -- 2011 08/01/2012
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January 11, 2011 MIMM-314 R.G.E.Palfree 3
Soluble receptors for common types of foreign material
C1q(a complement
protein)
MBL(mannan-
binding lectin)
SP-A, SP-D
Ficolins
CRP(C-reactive
protein)
Noted for binding IgM, IgG in immune complexes. C1q
may also bind directly to some microbial surfaces in the
absence of antibody. (Like MBL but not a lectin).
Binds patterns of certain carbohydrates (e.g. mannose,
fucose, GlcNAc). Associates with MASPs (serine
proteases which can activate the complement cascade)
Pulmonary surfactant proteins (collectins like MBL)
opsonize microbes for alveolar macrophage.
Like collectins, but not lectins. Bind patterns of acetyl
groups (may be on carbohydrate or other molecules).
Associate with MASPs.
Pentraxin which binds PAMP via phosphocholine. Also
triggers complement by binding C1q collagen domain.
January 11, 2011 MIMM-314 R.G.E.Palfree 4
Phagocyte Membrane Receptors
Note that macrophage, in their janitorial role, have receptors for
many molecules found normally in the body.
They particularly recognize molecular surfaces associated
normally intracellular molecules (phosphatidyl-serine), or
molecules altered by abnormal conformation, degradation, or
chemical modification (e.g. oxidation).
Opsonizing protiens like Antibodies, Complement and Collectins
are similarly recognized by phagocyte receptors. Some more
specialized than others.
Phagocytes also have receptors for foreign material.
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Membrane receptors for common types of foreign material
Mannose Receptor Family
MR (CD206)
DEC205 (CD205)
Scavenger receptors
Toll-like receptors (TLR)
f-MLP receptor (7tm-GPCR)
Have multiple C-type lectin-like Carbohydrate
Binding Domains (also called CTLDs).
DEC205 is a Dendritic Cell C-type multi-lectin
receptor
Diverse ligands include negatively-charged
polymers. Includes lipoteichoic acid found in
Gram positive bacterial wall.
Whereas the above are important for uptake
of foreign material, TLR family members are
important for signalling the presence of
foreign material. More on these later.
Signal: formyl-methionine at pptd N-terminal
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A pretty picture from Taylor et al., 2005, Trends in Immunology 26: 104.
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Toll-Like Receptors
Anecdote (1980):
Biologist, Christiane Nusslein-Volhard was so delighted
with a Drosophila mutant which helped in explaining
embryogenesis in the fruit fly, that she exclaimed “Toll !”,
which is German slang for “fantastic !”.
The Toll-1 Receptor and 8 others serve critical functions in
Drosophila development.
Nusslein-Volhard received a Nobel prize in 1995 for this
work.
January 11, 2011 MIMM-314 R.G.E.Palfree 8
Toll-Like Receptors and Defense
Fungal infection causes expression of antimicrobial peptides
(AMPs) in Drosophila.
These AMP genes have binding sites for a transcription
activator called “dorsal” (promotes transcription of specific
genes).
Activation of dorsal is caused by signals through the Toll
receptor.
Mutations in the Toll signalling pathway reduced the insect’s
survival after fungal infection.
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Toll-Like Receptors in Mouse and Human
Several Toll-like receptor (TLR) genes were found in mouse.
Mice which have mutant TLR-4 genes:
are hyporesponsive (do not respond well) to LPS and are
unable to survive infection with gram-negative bacteria.
TLR-2 knockout mice:
have an impaired response to gram-positive bacterial cell
wall and to peptidoglycan from S. aureus.
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Receptor
TLR-1
TLR-2
TLR-3
TLR-4
TLR-5
TLR-6
TLR-9
Known Agonist
Lipopeptide
Several, including lipoteichoic acid,
peptidoglycan, zymosan, lipoprotein, and
HSP70 (released by damaged cells)
dsRNA
LPS, Hyaluronic acid fragments, HSP60,70
Flagellin
zymosan
unmethylated CpG DNA
7th edition Immunobiology updates this with discussion of hetero and homodimers
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Some TLRs are on the cell surface.
TLR-1, TLR-2, TLR-4, TLR-5, TLR-6
Some are in the endosomal compartment and
make contact with agonist in the phagolysozome
in phagocytic cells
TLR-3, TLR-7, TLR-8, TLR-9
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TLR Signalling through TIR domains and adapters
I will not ask
questions on the
details of the
signalling pathways.
Main points are
covered in text slides.
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Signalling is through the cytoplasmic TIR domains
(Toll-IL-1 Receptor Domains) which affect signalling
cascades via TIR Adapters (e.g. MyD88).
TLR-4 activates 2 pathways:
• A pathway through MyD88 which activates NFκκκκB,
which is like the Drosophila dorsal transcription
factor, and results in cytokine (esp. TNFαααα)
production.
• A so-called MyD88-independent pathway resulting
in induction of nitric oxide synthase (iNOS) and
type 1 Interferons (IFNαααα/ββββ).
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Lipopolysaccharide (LPS)
is detected via TLR-4 in a 3
step process:
1. LPS is bound by LPS-
Binding Protein (LBP) in
the fluid.
2. The LPS-LBP complex
passes LPS to CD14 on
the phagocyte.
3. The LPS-CD14
complex interacts with
TLR-4.
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TLR and Antimicrobial Peptides (AMPs)
As Toll activation triggers AMP production in the fruit fly,
TLR activation is often associated with AMP production.
Bronchial epithelial cells responding to dsRNA via TLR3
produce cytokines and beta-Defensins 2 and 3.
Tracheobronchial cells responding to LPS via TLR-2 and
TLR-4 produce beta-Defensin 2.
It works the other way too:
mouse beta-defensin 2 has been found to activate
dendritic cells via TLR-4
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There are different varieties of Dendritic Cell
Their expression of TLRs differs, and they respond