Biology Reference
In-Depth Information
AIM2
AIM2 is a member of the hematopoietic interferon-inducible nuclear pro-
teins with a 200-amino-acid repeat (HIN-200) family; it contains a pyrin
domain at the N-terminal and recognizes cytosolic viral dsDNA
[82]
. AIM2
is the only “sensor” to directly interact with a cognate stimulus, i.e., dsDNA,
through a HIN-200 domain present at the C-terminal
[82,101]
. AIM2 asso-
ciates with apoptosis-associated speck-like protein containing a caspase
activation and recruitment domain (ASC) via pyrin domain interactions to
form the AIM2 inflammasome, which also results in the activation of cas-
pase 1
[82,96,102]
. Reports also show that leukocytes from SLE patients
express higher levels of AIM2 relative to control individuals, suggesting the
involvement of AIM2 in SLE pathogenesis
[103]
.
NLRs and allogeneic HSCT
NOD2-deficient recipients showed more severe GVHD in MHC-mismatched
and matched murine models of GVHD
[104]
. Chimeric recipient mice dem-
onstrated that NOD2 deficiency in the hematopoietic system and not in
the nonhematopoietic system was critical for aggravation of experimental
GVHD
[104]
. By contrast, NOD2 deficiency in donor T cells or BM had no
impact on the development of GVHD
[104]
. DCs from NOD2-deficient ani-
mals showed greater ability to stimulate allogeneic donor T cells.
436
Several clinical studies have analyzed the association between NOD2
and GVHD. While some suggested a connection between NOD2 SNPs
and increased GVHD, others failed to do so. NOD2 SNPs (SNPs 8, 12, and
13) that have been associated with CD were found to be associated with
clinical outcome after allogeneic HSCT
[105,106]
. A significant correlation
was observed between higher incidence and severity of GVHD and NOD2
SNPs in both donors and recipients
[105,106]
. This association was much
more profound in matched related donor (MRD) BMTs. A different study
with fewer patients and following T-cell-depleted allo-HSCT also demon-
strated a correlation with GVHD and the incidence of above-noted NOD2
SNPs
[107]
. However, another study found that the incidence of GVHD
was higher in recipients with NOD2 SNPs receiving grafts from donors
with NOD2 SNPs, but GVHD was reduced in wild-type recipients of grafts
from donors with NOD2 SNPs, suggesting that a NOD2 SNP in donor cells
mitigates GVH response
[108]
. By contrast these NOD2 SNPs appeared to
have no impact on the incidence of GVHD in some other studies
[109,110]
.
Similarly NOD2 SNPs either had no impact on GVHD or were associated
with low GVHD in unrelated donor transplant recipients following alem-
tuzumab prophylaxis or in pediatric patients
[111,112]
. The conflicting
results between the various clinical studies on the role of NOD2 polymor-
phisms during GVHD are probably attributable to the differences between
the study cohorts, including the NOD2 SNP frequency, overall incidence
of GVHD, T-cell depletion, type of conditioning regimen, intestinal micro-
bial decontamination, donor source, and environmental factors—all fur-
ther compounded by the small numbers of patients. Thus the clinical role
of NOD2 in modulating alloreactivity is complex, and certain transplan-
tation-specific strategies such as T-cell depletion or gut decontamination
may modulate the impact of NOD2.
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