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Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency.
[omenn syndrome]
The
contribution
of
B
cells
to
the
pathology
of
Omenn
syndrome
and
leaky
severe
combined
immunodeficiency
(
SCID
)
has
not
been
previously
investigated
.
We
have
studied
a
mut
/
mut
mouse
model
of
leaky
SCID
with
a
homozygous
Rag
1
S
723
C
mutation
that
impairs
,
but
does
not
abrogate
,
V
(
D
)
J
recombination
activity
.
In
spite
of
a
severe
block
at
the
pro-
B
cell
stage
and
profound
B
cell
lymphopenia
,
significant
serum
levels
of
immunoglobulin
(
Ig
)
G
,
IgM
,
IgA
,
and
IgE
and
a
high
proportion
of
Ig-secreting
cells
were
detected
in
mut
/
mut
mice
.
Antibody
responses
to
trinitrophenyl
(
TNP
)
-
Ficoll
and
production
of
high
-affinity
antibodies
to
TNP-keyhole
limpet
hemocyanin
were
severely
impaired
,
even
after
adoptive
transfer
of
wild-
type
CD
4
(
+
)
T
cells
.
Mut
/
mut
mice
produced
high
amounts
of
low
-affinity
self-reactive
antibodies
and
showed
significant
lymphocytic
infiltrates
in
peripheral
tissues
.
Autoantibody
production
was
associated
with
impaired
receptor
editing
and
increased
serum
B
cell-activating
factor
(
BAFF
)
concentrations
.
Autoantibodies
and
elevated
BAFF
levels
were
also
identified
in
patients
with
Omenn
syndrome
and
leaky
SCID
as
a
result
of
hypomorphic
RAG
mutations
.
These
data
indicate
that
the
stochastic
generation
of
an
autoreactive
B
cell
repertoire
,
which
is
associated
with
defects
in
central
and
peripheral
checkpoints
of
B
cell
tolerance
,
is
an
important
,
previously
unrecognized
,
aspect
of
immunodeficiencies
associated
with
hypomorphic
RAG
mutations
.
Diseases
Validation
Diseases presenting
"high-affinity antibodies"
symptom
gm1 gangliosidosis
omenn syndrome
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