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Overexpression of MHC class I in muscle of lymphocyte-deficient mice causes a severe myopathy with induction of the unfolded protein response.
[inclusion body myositis]
Muscle
fibers
do
not
normally
express
major
histocompatibility
complex
class
I
(
MHC-
I
)
molecules
,
and
their
reexpression
is
a
hallmark
of
inflammatory
myopathies
.
It
has
been
shown
in
mice
that
overexpression
of
MHC-
I
induces
a
poorly
inflammatory
myositis
accompanied
by
the
unfolded
protein
response
(
UPR
)
,
but
it
is
unclear
whether
it
is
attributable
to
T
-
cell-mediated
MHC-
I
-dependent
immune
responses
or
to
MHC-
I
forced
expression
per
se
.
Indeed
,
besides
presenting
antigenic
peptides
to
CD
8
(
+
)
T
cells
,
MHC-
I
may
also
possibly
exert
nonimmunologic
,
yet
poorly
understood
pathogenic
effects
.
Thus
,
we
investigated
the
pathogenicity
of
MHC-
I
expression
in
muscle
independently
of
its
immune
functions
.
HT
transgenic
mice
that
conditionally
overexpress
H-
2
K
(
b
)
in
muscle
were
bred
to
an
immunodeficient
Rag
2
(
-
/
-
)
background
.
The
muscle
proteome
was
analyzed
by
label-free
high
-resolution
protein
quantitation
and
Western
blot
.
Despite
the
absence
of
adaptive
immunity
,
HT
Rag
2
(
-
/
-
)
mice
developed
a
very
severe
myopathy
associated
with
the
cytoplasmic
accumulation
of
H-
2
K
(
b
)
molecules
.
The
UPR
was
manifest
by
up-regulation
of
characteristic
proteins
.
In
humans
,
we
found
that
HLA
class
I
molecules
not
only
were
expressed
at
the
sarcolemma
but
also
could
accumulate
intracellularly
in
some
patients
with
inclusion
body
myositis
.
Accordingly
,
the
UPR
was
triggered
as
a
function
of
the
degree
of
HLA
accumulation
in
myofibers
.
Hence
,
reexpression
of
MHC-
I
in
normally
negative
myofibers
exerts
pathogenic
effects
independently
of
its
immune
function
.
Diseases
Validation
Diseases presenting
"muscle fibers"
symptom
epidermolysis bullosa simplex
focal myositis
inclusion body myositis
pyomyositis
systemic capillary leak syndrome
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