Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
Each of these PRRs may allow for the distinction between “self” and “non-self” by the
recognition of specialized microbial components. However, in 1994, Polly Matzinger
proposed “the danger model”, another theory that describes the signals that activate APCs
and explains how and when the immune system decides to mount an inflammatory response
(Matzinger, 1994). In Matzinger’s model, the immune system would be more concerned with
damage than foreigness and, as a result, would be more activated by alarm signals from
injured tissues than by the recognition of non-self components. Both Janeway’s and
Matzinger’s models assume that APCs can be activated by signals from their environment but
Janeway restricted these signals to the detection of PAMPs, whereas Matzinger hypothesized
the involvement of more general danger signals, both exogenous molecules from pathogens,
or endogenous signals released from injured tissues of the host. For instance, danger signals
can be molecules derived from a pathogen (PAMP) but also RNA, heat shock proteins,
hydrophobic molecules or components of the extracellular matrix. Under normal conditions,
these components are not detectable by the immune system but after damage they can be
released in the microenvironment and activate immune cells.
(b) Damage-Associated Molecular Patterns (DAMPs)
In 1999, Gallucci and colleagues demonstrated that DCs can be activated by mechanical
stimulation without the addition of any exogenous molecules (Gallucci et al., 1999).
Concurrently, necrosis was described as a cell death mechanism producing generally more
danger signals than apoptosis, which was considered as a controlled and less damage-signal
inducing form of cell death. Thus began the field of investigation into Damage-Associated
Molecular Patterns (DAMPs) (Chen and Nunez, 2010) (Table 3). Among the first molecular
damage signals described were heat-shock proteins, which were shown to activate dendritic
cells when they were released from dying cells (Basu et al., 2000). The DNA-binding protein
High-Mobility Group Box 1 protein (HMGB1) was also discovered to be an important
mediator of damage signaling, since it induces inflammation. Furthermore, it is involved in
the differential damage signaling activities of necrotic versus apopotic cells. Other molecules
such as extracellular ATP or uric acid have also been shown to be released after injury and
have the ability to activate the immune system. Interestingly, some of these DAMPs can also
be detected by PRRs such as TLRs (Ohashi et al., 2000). Another pathway discovered only
recently, the inflammasome, acts as a molecular platform capable of converging danger
stimuli including both PAMPs and DAMPs (Schroder and Tschopp, 2010). The activation of
this complex triggers the release of inflammatory cytokines such as IL-1β and IL-18.
34