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Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses.
[papillon-lefèvre syndrome]
Papillon-
Lefèvre
syndrome
(
PLS
)
results
from
mutations
that
inactivate
cysteine
protease
cathepsin
C
(
CTSC
)
,
which
processes
a
variety
of
serine
proteases
considered
essential
for
antimicrobial
defense
.
Despite
serine
protease-
deficient
immune
cell
populations
,
PLS
patients
do
not
exhibit
marked
immunodeficiency
.
Here
,
we
characterized
a
24
-
year
-old
woman
who
had
suffered
from
severe
juvenile
periodontal
disease
,
but
was
otherwise
healthy
,
and
identified
a
homozygous
missense
mutation
in
CTSC
indicative
of
PLS
.
Proteome
analysis
of
patient
neutrophil
granules
revealed
that
several
proteins
that
normally
localize
to
azurophil
granules
,
including
the
major
serine
proteases
,
elastase
,
cathepsin
G
,
and
proteinase
3
,
were
absent
.
Accordingly
,
neutrophils
from
this
patient
were
incapable
of
producing
neutrophil
extracellular
traps
(
NETs
)
in
response
to
ROS
and
were
unable
to
process
endogenous
cathelicidin
hCAP-
18
into
the
antibacterial
peptide
LL-
37
in
response
to
ionomycin
.
In
immature
myeloid
cells
from
patient
bone
marrow
,
biosynthesis
of
CTSC
and
neutrophil
serine
proteases
appeared
normal
along
with
initial
processing
and
sorting
to
cellular
storage
.
In
contrast
,
these
proteins
were
completely
absent
in
mature
neutrophils
,
indicating
that
CTSC
mutation
promotes
protease
degradation
in
more
mature
hematopoietic
subsets
,
but
does
not
affect
protease
production
in
progenitor
cells
.
Together
,
these
data
indicate
CTSC
protects
serine
proteases
from
degradation
in
mature
immune
cells
and
suggest
that
neutrophil
serine
proteases
are
dispensable
for
human
immunoprotection
.
Diseases
Validation
Diseases presenting
"pls patients do not exhibit marked immunodeficiency"
symptom
papillon-lefèvre syndrome
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