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Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome.
[omenn syndrome]
Hypomorphic
RAG
mutations
,
leading
to
limited
V
(
D
)
J
rearrangements
,
cause
Omenn
syndrome
(
OS
)
,
a
peculiar
severe
combined
immunodeficiency
associated
with
autoimmune
-like
manifestations
.
Whether
B
cells
play
a
role
in
OS
pathogenesis
is
so
far
unexplored
.
Here
we
report
the
detection
of
plasma
cells
in
lymphoid
organs
of
OS
patients
,
in
which
circulating
B
cells
are
undetectable
.
Hypomorphic
Rag
2
(
R
229
Q
)
knock-
in
mice
,
which
recapitulate
OS
,
revealed
,
beyond
severe
B
cell
developmental
arrest
,
a
normal
or
even
enlarged
compartment
of
immunoglobulin-secreting
cells
(
ISC
)
.
The
size
of
this
ISC
compartment
correlated
with
increased
expression
of
Blimp
1
and
Xbp
1
,
and
these
ISC
were
sustained
by
elevated
levels
of
T
cell
derived
homeostatic
and
effector
cytokines
.
The
detection
of
high
affinity
pathogenic
autoantibodies
toward
target
organs
indicated
defaults
in
B
cell
selection
and
tolerance
induction
.
We
hypothesize
that
impaired
B
cell
receptor
(
BCR
)
editing
and
a
serum
B
cell
activating
factor
(
BAFF
)
abundance
might
contribute
toward
the
development
of
a
pathogenic
B
cell
repertoire
in
hypomorphic
Rag
2
(
R
229
Q
)
knock-
in
mice
.
BAFF-R
blockade
reduced
serum
levels
of
nucleic
acid-
specific
autoantibodies
and
significantly
ameliorated
inflammatory
tissue
damage
.
These
findings
highlight
a
role
for
B
cells
in
OS
pathogenesis
.
Diseases
Validation
Diseases presenting
"nucleic acid-specific autoantibodies"
symptom
omenn syndrome
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