Inflammation and Immunity SFRBM Education Program Cohen 1

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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_at_uchsc.edu
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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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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//itgmv1.fzk.de/www/itg/diabate/images.htmlf
ig5
http//www.mdsg.umd.edu/oysters/oysblood.htm
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silicone droplets
chromic catgut
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.
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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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 8430(6996)257-63.

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Ligands are PAMPs (pathogen- associated molecular
patterns) Receptors are PRRs (pattern- recognit
ion receptors)
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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.
CCR5, a chemokine receptor
HCC2, a chemokine
Source Aegis (CDC)
Source Protein data base (PDB)
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Human family
Oyster family
http//faculty.haas.berkeley.edu/arose/Asher1st2.h
tm
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
unable to live in the real world).
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Dendritic cell
iccosomes
Dendritic cells are the link between innate and
adaptive immunity. They are superb phagocytes.
David Hunt. Cell Systems Initiative, U. of
Washington.
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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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chemokines
cytokines
PAMP
PRR
T
Immature dendritic cell
Mature dendritic cell
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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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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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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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A helper T cell with the correct receptor
recognizes peptide MHC and becomes activated
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T Cell Receptor
MHC
foreign peptide
Dendritic Cell
T Cell
Pique, Garcia, Wilson Scripps
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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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Inflammation, delayed hypersensitivity
APC
Th1
IL-2, IFN-?
Downregulation of immunity
IL-10, TGFß
APC
Treg
B cell help sometimes suppression of
inflammation
IL-4, IL-5, IL-10
APC
Th2
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Activated T cells divide
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Activated Th1 cells release lymphokines
Many macrophages are attracted
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All cells show peptides from the proteins they
make, including virus and tumor proteins, on MHC
Class I molecules
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Foreign or abnormal peptides MHC are recognized
by a cytotoxic (killer) T cell
Killer T cells (cytotoxic T lymphocytes, CTL)
actually dont 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 interaction.
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The CTL transmits a death signal
Granule exocytosis
Fas Fas ligand
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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.cellsali
ve.com/ctl.htm
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Why adaptive?
Amplification of inflammation T cell clones
expand 64,000 x in 4 days Each activated Th1
cell attracts 1,000 macrophages Cytokine-stimulat
ed macrophages are angry Repertoire Almost
unlimited number of epitopes recognized Memory S
econdary responses sooner, steeper, faster,
higher lower threshold