Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 9, 2024
Fine-mapping
and
functional
studies
implicate
rs117701653,
a
non-coding
single
nucleotide
polymorphism
in
the
CD28/CTLA4/ICOS
locus,
as
risk
variant
for
rheumatoid
arthritis
type
1
diabetes.
Here,
using
DNA
pulldown,
mass
spectrometry,
genome
editing
eQTL
analysis,
we
establish
that
disease-associated
allele
is
functional,
reducing
affinity
inhibitory
chromosomal
regulator
SMCHD1
to
enhance
expression
of
inducible
T-cell
costimulator
(ICOS)
memory
CD4+
T
cells
from
healthy
donors.
Higher
ICOS
paralleled
by
an
increase
circulating
peripheral
helper
(Tph)
and,
patients,
blood
joint
fluid
Tph
well
plasmablasts.
Correspondingly,
ligation
carriage
rs117701653
accelerate
cell
differentiation
into
CXCR5-PD-1high
producing
IL-21
CXCL13.
Thus,
mechanistic
dissection
human
autoimmunity
discloses
previously
undefined
pathway
through
which
regulates
development
abundance.
Nature,
Год журнала:
2023,
Номер
623(7987), С. 616 - 624
Опубликована: Ноя. 8, 2023
Abstract
Rheumatoid
arthritis
is
a
prototypical
autoimmune
disease
that
causes
joint
inflammation
and
destruction
1
.
There
currently
no
cure
for
rheumatoid
arthritis,
the
effectiveness
of
treatments
varies
across
patients,
suggesting
an
undefined
pathogenic
diversity
1,2
Here,
to
deconstruct
cell
states
pathways
characterize
this
heterogeneity,
we
profiled
full
spectrum
cells
in
inflamed
synovium
from
patients
with
arthritis.
We
used
multi-modal
single-cell
RNA-sequencing
surface
protein
data
coupled
histology
synovial
tissue
79
donors
build
atlas
includes
more
than
314,000
cells.
stratified
tissues
into
six
groups,
referred
as
cell-type
abundance
phenotypes
(CTAPs),
each
characterized
by
selectively
enriched
states.
These
CTAPs
demonstrate
ranging
samples
T
B
those
largely
lacking
lymphocytes.
Disease-relevant
states,
cytokines,
risk
genes,
serology
metrics
are
associated
particular
CTAPs.
dynamic
can
predict
treatment
response,
highlighting
clinical
utility
classifying
phenotypes.
This
comprehensive
molecular,
tissue-based
stratification
reveal
new
insights
pathology
heterogeneity
could
inform
novel
targeted
treatments.
Nature,
Год журнала:
2024,
Номер
625(7994), С. 321 - 328
Опубликована: Янв. 10, 2024
Multiple
sclerosis
(MS)
is
a
neuro-inflammatory
and
neurodegenerative
disease
that
most
prevalent
in
Northern
Europe.
Although
it
known
inherited
risk
for
MS
located
within
or
close
proximity
to
immune-related
genes,
unknown
when,
where
how
this
genetic
originated
Expert Opinion on Investigational Drugs,
Год журнала:
2023,
Номер
32(4), С. 333 - 344
Опубликована: Апрель 3, 2023
Introduction
JAK
(Janus
kinase)
is
a
type
of
non-receptor
tyrosine
kinase
that
includes
JAK1,
JAK2,
JAK3,
and
Tyk2.
Currently,
there
are
five
inhibitors
approved
for
treating
rheumatoid
arthritis.
These
vary
in
their
selectivity
different
isoforms.Area
covered
This
review
outlines
the
mode
actions
results
Phase
III
trials
which
have
been
treatment
arthritis.Expert
commentary
potential
to
finely
tune
immunity
inflammation
patients
with
The
vitro
data
indicates
IL-6
signaling
suppressed
by
all
inhibitors,
while
tofacitinib
exhibits
most
extensive
suppression
cytokines
via
pathway.
Peficitinib
suppresses
common
gamma
cytokines,
filgotinib
interferon.
Furthermore,
baricitinib
upadacitinib
appear
be
inclined
toward
suppressing
interferon
IL-12
family.
Despite
specific
target
profiles,
any
these
drugs
can
inhibit
other
JAKs
if
blood
levels
surpass
certain
threshold.
As
result,
predicting
vivo
remains
challenging
task.
inhibitor
seems
vital
option
difficult-to-treat
arthritis
patients,
it
expected
precision
medicine
approaches
will
enhance
its
effectiveness
future.
Abstract
Polygenic
scores
(PGS)
can
be
used
for
risk
stratification
by
quantifying
individuals’
genetic
predisposition
to
disease,
and
many
potentially
clinically
useful
applications
have
been
proposed.
Here,
we
review
the
latest
potential
benefits
of
PGS
in
clinic
challenges
implementation.
could
augment
through
combined
use
with
traditional
factors
(demographics,
disease-specific
factors,
family
history,
etc.),
support
diagnostic
pathways,
predict
groups
therapeutic
benefits,
increase
efficiency
clinical
trials.
However,
there
exist
maximizing
utility
PGS,
including
FAIR
(Findable,
Accessible,
Interoperable,
Reusable)
standardized
sharing
genomic
data
needed
develop
recalculate
equitable
performance
across
populations
ancestries,
generation
robust
reproducible
calculations,
responsible
communication
interpretation
results.
We
outline
how
these
may
overcome
analytically
more
diverse
as
well
highlight
sustained
community
efforts
achieve
equitable,
impactful,
healthcare.
Abstract
Rheumatoid
arthritis
(RA)
is
a
chronic
autoimmune
disease
characterized
by
the
unresolved
synovial
inflammation
for
tissues‐destructive
consequence,
which
remains
one
of
significant
causes
disability
and
labor
loss,
affecting
about
0.2–1%
global
population.
Although
treatments
with
disease‐modifying
antirheumatic
drugs
(DMARDs)
are
effective
to
control
decrease
bone
destruction,
overall
remission
rates
RA
still
stay
at
low
level.
Therefore,
uncovering
pathogenesis
expediting
clinical
transformation
imminently
in
need.
Here,
we
summarize
immunological
basis,
inflammatory
pathways,
genetic
epigenetic
alterations,
metabolic
disorders
RA,
highlights
on
abnormality
immune
cells
atlas,
epigenetics,
immunometabolism.
Besides
an
overview
first‐line
medications
including
conventional
DMARDs,
biologics,
small
molecule
agents,
discuss
depth
promising
targeted
therapies
under
or
preclinical
trials,
especially
regulators.
Additionally,
prospects
precision
medicine
based
biopsy
RNA‐sequencing
cell
mesenchymal
stem
chimeric
antigen
receptor
T‐cell
also
looked
forward.
The
advancements
innovations
accelerates
progress
treatments.
The
majority
of
disease-associated
variants
identified
through
genome-wide
association
studies
are
located
outside
protein-coding
regions.
Prioritizing
candidate
regulatory
and
gene
targets
to
identify
potential
biological
mechanisms
for
further
functional
experiments
can
be
challenging.
To
address
this
challenge,
we
developed
FORGEdb
(
https://forgedb.cancer.gov/
;
https://forge2.altiusinstitute.org/files/forgedb.html
https://doi.org/10.5281/zenodo.10067458
),
a
standalone
web-based
tool
that
integrates
multiple
datasets,
delivering
information
on
associated
elements,
transcription
factor
binding
sites,
target
genes
over
37
million
variants.
scores
provide
researchers
with
quantitative
assessment
the
relative
importance
each
variant
targeted
experiments.
Journal of Translational Medicine,
Год журнала:
2023,
Номер
21(1)
Опубликована: Сен. 11, 2023
Abstract
Introduction
Rheumatoid
arthritis
(RA)
is
a
chronic
inflammatory
illness
that
mostly
affects
the
joints
of
hands
and
feet
can
reduce
life
expectancy
by
an
average
3
to
10
years.
Although
tremendous
progress
has
been
achieved
in
treatment
RA,
large
minority
patients
continue
respond
poorly
existing
medications,
owing
part
lack
appropriate
therapeutic
targets.
Methods
To
find
targets
for
Mendelian
randomization
(MR)
was
performed.
Cis-expression
quantitative
trait
loci
(cis-eQTL,
exposure)
data
were
obtained
from
eQTLGen
Consortium
(sample
size
31,684).
Summary
statistics
RA
(outcome)
two
largest
independent
cohorts:
sample
sizes
97,173
(22,350
cases
74,823
controls)
269,377
(8279
261,098),
respectively.
Colocalisation
analysis
used
test
whether
risk
gene
expression
driven
common
SNPs.
Drug
prediction
molecular
docking
further
validate
medicinal
value
drug
Results
Seven
significant
both
cohorts
MR
supported
localization.
PheWAS
at
level
showed
only
ATP2A1
associated
with
other
traits.
These
genes
are
strongly
immune
function
terms
biological
significance.
Molecular
excellent
binding
drugs
proteins
available
structural
data.
Conclusion
This
study
identifies
seven
potential
RA.
Drugs
designed
target
these
have
higher
chance
success
clinical
trials
expected
help
prioritise
development
save
on
costs.
