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A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome.
[omenn syndrome]
Rag
enzymes
are
the
main
players
in
V
(
D
)
J
recombination
,
the
process
responsible
for
rearrangement
of
TCR
and
Ig
genes
.
Hypomorphic
Rag
mutations
in
humans
,
which
maintain
partial
V
(
D
)
J
activity
,
cause
a
peculiar
SCID
associated
with
autoimmune
-like
manifestations
,
Omenn
syndrome
(
OS
)
.
Although
a
deficient
ability
to
sustain
thymopoiesis
and
to
produce
a
diverse
T
and
B
cell
repertoire
explains
the
increased
susceptibility
to
severe
infections
,
the
molecular
and
cellular
mechanisms
underlying
the
spectrum
of
clinical
and
immunological
features
of
OS
remain
poorly
defined
.
In
order
to
better
define
the
molecular
and
cellular
pathophysiology
of
OS
,
we
generated
a
knockin
murine
model
carrying
the
Rag
2
R
229
Q
mutation
previously
described
in
several
patients
with
OS
and
leaky
forms
of
SCID
.
These
Rag
2
(
R
229
Q
/
R
229
Q
)
mice
showed
oligoclonal
T
cells
,
absence
of
circulating
B
cells
,
and
peripheral
eosinophilia
.
In
addition
,
activated
T
cells
infiltrated
gut
and
skin
,
causing
diarrhea
,
alopecia
,
and
,
in
some
cases
,
severe
erythrodermia
.
These
findings
were
associated
with
reduced
thymic
expression
of
Aire
and
markedly
reduced
numbers
of
naturally
occurring
Tregs
and
NKT
lymphocytes
.
In
conclusion
,
Rag
2
(
R
229
Q
/
R
229
Q
)
mice
mimicked
most
symptoms
of
human
OS
;
our
findings
support
the
notion
that
impaired
immune
tolerance
and
defective
immune
regulation
are
involved
in
the
pathophysiology
of
OS
.
Diseases
Validation
Diseases presenting
"reduced thymic expression"
symptom
omenn syndrome
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