Antigen Presenting Cells (APCs)
393
APCs provide signal 1 via MHC-peptide
complexes engaging TCRs. Since APCs
appear to be unable to distinguish self-
peptide from foreign peptide and since
self-reactive T cells do exist in our body,
th
es
a
f
egu
a
r
do
fth
es
e
l
f–n
on
s
e
l
fd
i
s
-
crimination model is signal 2. Signal 2 is
only provided via costimulators of APCs
that have recognized patterns of non-
self molecules found only on evolutionary
distinct organisms, such as bacteria or
viruses. This is thought to be accomplished
via PRRs, for example, TLRs. However,
even Janeway, who pioneered the idea of
pattern recognition serving for costimula-
tion, pointed out that PRRs cannot explain
autoimmunity or immune responses to
tumors or transplants. Moreover, it is still
open how the immune system deals with
a changing self. The self–nonself discrim-
ination model, for example, fails to give
us a clue why vertebrates do not attack
themselves at puberty and why females
do not reject their own newly lactating
breasts when they begin to produce milk
proteins that were not part of self until
that time.
The danger model pioneered by Mat-
zinger gives an answer to these questions.
This model is based on the hypothesis
that the ultimate controlling signals are
endogenous, not exogenous. They are the
alarm signals that emanate from stressed
or injured tissues (Fig. 12). Hence, cells
of normal bodily tissue, when distressed,
send signals that are called
danger signals
,
which serve to activate local APCs. Healthy
cells, in fact, may send calming signals to
local APCs, whereas cells that are damaged
or die by necrosis should favor maturation
of APCs. In contrast, cells that die by apop-
tosis, a process of normal programmed cell
death, should merely send signals that may
favor phagocytosis but should not induce
the expression of costimulatory molecules.
This view is consistent with ±ndings where
necrotic cells do induce maturation of DCs,
but not apoptotic cells. This correlates with
the liberation of Hsps from necrotic but
not apoptotic cells. Strikingly, apoptotic
cells that have undergone heat stress were
also able to activate DCs. As yet, Hsps are
the only candidate for endogenous media-
tors of danger.
Necrotic or
distressed
cell
Normal
cell
Apoptotic
cell
Alarm
signal
Mature DC
Fig. 12
The danger model DCs receive an alarm signal from injured,
distressed, or necrotic cells leading to their maturation. This is not the case
with normal cells or in cells dying by apoptosis.
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