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nuclear translocation of IRF3 and IRF7 and production of IFN-β and IFN-α
[60]
. In contrast to the TLR nucleic acid sensors that are transmembrane
proteins associated with the endosomes, RLRs localize to the cytosolic
compartment
[14,57]
. This suggests that RLRs preferentially sense replicat-
ing viral genomes and/or their by-products in the cytoplasm, while TLRs
sense nucleic acids of pathogens taken up into the endosome. RIG-I and
MDA5 detect distinct dsRNA forms that differ in structure and length. The
distinct ligand preferences of the MDA5 and RIG-I receptors confer spe-
cific recognition of disparate viruses
[14,57,56]
. RIG-I senses or detects
paramyxoviruses, rhabdovirus, and flavivirus, while MDA5 senses picorna-
viruses and is also involved in the recognition of West Nile, measles virus,
and LCMV
[14,57,58]
. Studies have shown that RIG-I, like TLR3, can also
recognize DNA viruses by detecting RNA intermediates generated through
the RNA polymerase III-mediated transcription of dsDNA
[61]
. In contrast,
the third member, LGP2, which does not have the CARD, may serve either
as a negative regulator of RIG-I and MDA5 or as a positive inducer of the
type I IFN response depending on the type of viruses
[13,55-57]
. Poly(I:C),
a synthetic analog of viral dsRNA, which was believed to stimulate only
TLR3, is now known to stimulate MDA5 as well
[62,63]
. Therefore, all of the
stimulatory and adaptive immune modulatory effects of poly(I:C) could be
a consequence of the stimulation of MDA5 in addition to effects on TLR3.
For example, MDA5 signaling has been shown to play an important role in
poly(I:C)-induced NK cell activation
[62]
.
431
A study examining disease-associated single-nucleotide polymorphisms
(SNPs) in the human genome has revealed that “loss-of-function” muta-
tions in the RIG-I and MDA5 genes correlate with resistance to type 1 dia-
betes
[64]
.
Intracellular TLRs and allogeneic hsct
TLR7/8
In murine models, a TLR7 agonist (an imidazoquinoline derivative, R-848)
administered along with donor splenocytes to recipients with established
mixed chimerism (B6-BALB/c mixed chimeras) and tolerance caused
them to develop severe GVHD, in contrast to mixed chimeras that received
only donor splenocytes
[65]
. The localized administration of TLR7 agonist
resulted in a loss of tolerance and induction of GVHD locally, while systemic
administration caused systemic and conventional GVHD. These observa-
tions demonstrate that localized tissue inflammation caused by intracel-
lular TLR7/8 ligand controls the recruitment of alloreactive T cells to GVHD
target organs
[65]
. The GVH reaction in these animals was characterized by
T-cell expansion and activation, with similar upregulation of skin- as well as
gut-homing molecules
[65]
. These observations indicate that tissue inflam-
mation, induced by signaling intracellular TLR7, controls the development
of GVHD at the local level. Administration of TLR7/8 agonist (3M-011)
after conventional allogeneic bone marrow transplantation (BMT), in the
absence of mixed chimerism, significantly enhanced GVHD-related mor-
tality in MHC-mismatched models
[66]
. By contrast, pretreatment (prior to
allo-BMT) with the same TLR7/8 agonist significantly delayed and reduced
GVHD lethality and resulted in increased levels of the immunosuppressive
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