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Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex.
[epidermolysis bullosa simplex]
Epidermolysis
bullosa
simplex
(
EBS
)
is
a
skin
disorder
caused
by
fully-penetrant
mutations
in
the
keratin
genes
KRT
5
and
KRT
14
,
leading
to
extensive
cytolysis
and
cell
fragility
of
basal
keratinocytes
.
EBS
is
subject
to
environmental
conditions
and
displays
high
intra-
and
interfamilial
variability
,
suggesting
modifying
loci
.
Here
,
we
demonstrate
that
upregulation
of
certain
cytokines
accompanies
mutations
in
keratin
5
(
K
5
)
but
not
in
keratin
14
(
K
14
)
.
We
find
for
the
first
time
that
cytokines
macrophage
chemotactic
protein
(
MCP
)
-
1
/
[
chemokine
(
C-C
motif
)
ligand
2
]
(
CCL
2
)
,
macrophage
inflammatory
protein
(
MIP
)
-
3
beta
/
CCL
19
and
MIP
-
3
alpha
/
CCL
20
,
all
regulated
by
nuclear
factor
kappa
B
(
NFkappaB
)
and
involved
in
the
recruitment
,
maturation
,
and
migration
of
Langerhans
cells
(
LCs
)
in
the
epidermis
,
are
upregulated
in
the
skin
of
K
5
(
-
/
-
)
,
but
not
of
K
14
(
-
/
-
)
mice
.
In
neonatal
K
5
(
-
/
-
)
epidermis
,
the
number
of
LCs
was
increased
two-fold
.
At
the
same
time
,
tumor
necrosis
factor
alpha
(
TNFalpha
)
remained
unaltered
,
demonstrating
the
specificity
of
that
process
.
Most
remarkably
,
enhanced
LC
recruitment
within
the
epidermis
was
found
in
five
EBS
patients
carrying
mutations
in
the
KRT
5
gene
but
not
in
EBS
patients
with
KRT
14
gene
mutations
.
In
agreement
with
the
NFkappaB-dependent
regulation
of
these
cytokines
,
we
found
a
decrease
in
p
120
-
catenin
in
the
basal
epidermis
of
K
5
(
-
/
-
)
mice
.
These
data
provide
the
first
explanation
for
distinct
,
keratin-
type
-
specific
genotype-phenotype
correlations
in
EBS
and
represent
a
rationale
to
investigate
gene
loci
affecting
skin
pathology
in
EBS
.
Diseases
Validation
Diseases presenting
"factor alpha"
symptom
epidermolysis bullosa simplex
inclusion body myositis
severe combined immunodeficiency
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