Sunrise Free Radical School
Inflammation and Immunity:
From Innate Oysters to Adaptive Humans
J. John Cohen
Department of Immunology
University of Colorado Medical School
john.cohen@uchsc.edu
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Cohen 1
Metchnikoff 1883
Metchnikoff watched the reaction to a thorn inserted into a
mollusk. Hemocytes (amoebocytes) arrived and tried to ingest
the foreign body; if they could not, they walled it off, gradually
converting into, or recruiting, fibroblasts. We do exactly the
same thing to foreign bodies.
Source: Wikipedia
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Cohen 2
Mouse macrophage
Oyster hemocyte
The similarity between an invertebrate phagocyte and our own is striking;
they also use many of the same mechanisms, including the production of
reactive oxygen species.
http://www.mdsg.umd.edu/oysters/oysblood.htm
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http://itgmv1.fzk.de/www/itg/diabate/images.html#fig5
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Cohen 3
silicone droplets
chromic catgut
Foreign body reactions in the human. The
suture material is not digestible by
macrophages, so it has been walled off by
fibroblasts.
Atlas of Granulomatous Diseases Yale Rosen, M.D.
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The clear (unstained) globules of silicone have
been released from a ruptured breast implant.
They also cannot be ingested, and this early
stage shows the accumulation of macrophages,
including one that has become a multinucleated
giant cell showing the “asteroid bodies”
characteristic of the foreign body reaction.
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Cohen 4
Toll Like Receptors
• The next slide shows a schematic that gives a feel for the multiple
Toll-like receptor (TLR) pathways.
• These receptors respond to foreign molecular patterns (PAMPs), so
they are referred to as PRRs.
• Recognized motifs include:
lipopolysaccharide (LPS) from Gram-negative cell walls,
peptidoglycans from the cell walls of both Gram-negative and –
positive bacteria,
viral double-stranded RNA, and
CpG-rich bacterial DNA.
• The result of the signals in all cases is a pro-inflammatory response
and the release of chemokines and cytokines.
Review: Beutler B. Inferences, questions and possibilities in Toll-like receptor
signaling. Nature. 2004 Jul 8;430(6996):257-63.
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Cohen 5
Ligands are
PAMPs
(pathogenassociated
molecular
patterns);
Receptors
are
PRRs
(patternrecognition
receptors)
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Cohen 6
The structure of two chemokines, HCC2 and, in the inset, eotaxin, shows
their overall similarity. Their receptors are 7-span transmembrane
structures which are, in general,
ion channels that result in cell
activation. Chemokines are low
molecular weight peptides whose
major role is in inflammation.
HCC2, a chemokine
CCR5, a chemokine receptor
Source: Aegis (CDC)
Source: Protein data base (PDB)
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Cohen 7
Oyster family
Human family
http://faculty.haas.berkeley.edu/arose/Asher1st2.htm
In ecology, there are r-strategists and K-strategists.
Oysters are r-strategists: they have huge numbers of progeny but invest relatively little in
the survival of any individual; their survival is statistical. So they have the simple innate
immune response, but cannot amplify it, nor do they adapt to specific challenges.
The human is a K-strategist; small litters, but a heavy investment in individual survival.
So we (jawed vertebrates) have added the adaptive immune response which vastly
increases our chances (remember the Bubble Boy, born without an adaptive immune
response and
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unable to live in the SFRBM
real world).
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Dendritic cell
iccosomes
Dendritic cells are the link between
innate and adaptive immunity.
They
are superb
phagocytes.
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David Hunt. Cell Systems Initiative, U. of Washington.
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Cohen 9
Dendritic Cells
• When dendritic cells are bathed in the cytokine and chemokine
products of the innate response, they change, and move from the
local area through the lymphatics to the draining lymph node (next
slide) as they mature into the best antigen-presenting cells.
• Iccosomes are clumps of stored antigen-antibody immune complexes,
which allow the dendritic cell to stimulate immunity for a long time.
• Dendritic cells enter the lymph node via the afferent lymphatics and
percolate through the substance of the node, positioning
themselves at the interface between T and B cell areas. There they
display their processed antigenic peptides on both MHC Class I
and Class II, so that it can be recognized by the best-fitting
receptors of both CD4 (helper) T cells (which see antigen on Class
II) and CD8 (killer) T cells (which see antigen on Class I).
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Cohen 10
chemokines
cytokines
PAMP
PRR
T
Immature dendritic
cell
Mature dendritic cell
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Cohen 11
Antigen is
picked up by
a dendritic cell
and taken to
the draining
lymph node,
where it is
presented to
T cells.
Artist: Helen Macfarlane
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Cohen 12
The peptides are
now on the cell
surface, presented
on MHC Class II
molecules
and cross-presented
on MHC Class I
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Cohen 13
LYMPH NODE
A: Germinal centres (B cells)
B: Zone of T, B, and DC contact
C: Paracortex (T cells)
D: Afferent lymphatics
E: Subcapsular sinus
F: Efferent lymphatic
F
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Cohen 14
A helper T cell
with the
correct
receptor
recognizes
peptide +
MHC
and becomes
activated
T Cell
Receptor
MHC
foreign
peptide
T Cell
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Dendritic
Cell
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Pique, Garcia, Wilson: Scripps
Cohen 16
Members of the helper cell family
• There are 3 cells in the helper family.
• Th1 cells are the activators of delayed hypersensitivity and
are sometimes thought of as “pro-inflammatory”. Their
characteristic cytokine, interferon-gamma, is strongly
chemotactic for macrophages.
• Th2 cells help B cells make antibody. Their cytokines oppose
Th1 development (Th1 cytokines oppose Th2 development,
so there is “sibling rivalry”). Thus Th2 are sometimes
thought of as anti-inflammatory.
• Newly recognized are the Tregs, whose cytokines shut down
both Th1 and Th2 responses. This is one of the hot areas
in immunology.
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APC
Th1
IL-2,
IFN-γ
APC
IL-10,
Treg
TGFβ
APC
IL-4, IL-5,
Th2IL-10
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Inflammation,
delayed
hypersensitivity
Downregulation of
immunity
B cell help;
sometimes
suppression
of inflammation
Cohen 18
Activated
T cells
divide
T
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Cohen 19
T
Activated Th1 cells
release
lymphokines
Many macrophages
are attracted
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Cohen 20
All cells show peptides
from the proteins they
make, including virus and
tumor proteins, on MHC
Class I molecules
V
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V
V
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Cohen 21
Foreign or abnormal
peptides + MHC
are recognized by a
cytotoxic (killer) T cell
V
V
V
CTL
Killer T cells (cytotoxic T lymphocytes, CTL) actually don’t kill; they induce
their targets to kill themselves by apoptosis. There are two pathways, one
dependent on the exocytosis of granules, the other on transmembrane
signaling
via the Fas- Fas ligand
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Cohen 22
The CTL transmits
a death signal
Granule exocytosis
V
V
V
CTL
Fas: Fas ligand
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Cohen 23
The abnormal cell dies by
the process of apoptosis
At the meeting a video of a CTL inducing
apoptosis in a virus-infected cell was shown. It
was obtained from Cells Alive!
http://www.cellsalive.com/ctl.htm
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Cohen 24
Why adaptive?
Amplification of inflammation
T cell clones expand 64,000 x in 4 days
Each activated Th1 cell attracts 1,000 macrophages
Cytokine-stimulated macrophages are “angry”
Repertoire
Almost unlimited number of epitopes recognized
Memory
Secondary responses: sooner, steeper, faster, higher
lower threshold
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Cohen 25