Discovery and validation of blood methylation variation associated with the response tumor necrosis factor inhibitors in rheumatoid arthritis
Ontology highlight
ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints that has been associated with changes in the blood methylome. There is high interest to determine if this accessible epigenetic variation is associated with relevant clinical outcomes.
Project description:Rheumatoid arthritis (RA) is a chronic autoinflammatory disorder that affects small joints. Despite intense efforts, there isno definitive marker yet for early diagnosis RA and for monitoring the progression of this disease. We sought to catalog the proteins present in the synovial fluid of patients with rheumatoid arthritis. To identify lower abundance proteins, we undertook two approaches – we depleted the abundant proteins using a multiple affinity removal system (MARS14) column and we enriched glycoproteins using a lectin affinity column. The peptides were analyzed by LC-MS/MS on a high resolution Fourier transform mass spectrometer.
Project description:Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced inter-patient heterogeneity. To characterize RA at the molecular level and to uncover key pathomechanisms, we performed whole-genome gene expression analyses. Synovial tissues from rheumatoid arthritis patients were compared to those from osteoarthritis patients and to normal donors. Keywords: disease state analysis
Project description:Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints involved with genetic and epigenetic aberrant. Recent evidence found more and more importance of the epigenetic contribution, especially the DNA methylation, to the pathogenesis of rheumatoid arthritis. To understand the extent and nature of dysregulated DNA methylation in rheumatoid arthritis T cells, we performed a genome-wide DNA methylation study in CD4+ T cells in 12 rheumatoid arthritis patients compared to 12 matched normal healthy controls. [Methods and Result] Cytosine methylation status was quantified with Illumina methylation 450K microarray (HM450K, 485512 CpG sites). We identified 810 hypomethylated and 392 hypermethylated CG sites in RA CD4+ T cells compared to normal controls, representing 383 and 785 genes hypermethylated and hypomethylated in RA patients (P<3.4*10-7). Cluster analysis based on significantly differential methylated loci showed distinct separation between RA and normal controls. Gene ontology analysis showed alternative splicing (P=1.2*10-7, FDR) and phosphoprotein (1.7*10-2, FDR) were significantly aberrant in RA patients, indicating the abnormal of transcript alternative splicing and protein modification mediated by DNA methylation might play important role in the pathogenesis of rheumatoid arthritis. What’s more, the result showed human leukocyte antigen (HLA) region was frequently hypomethylated in RA patients, including HLA-DRB6, HLA-DQA1 and HLA-E, however, HLA-DQB1 showed different methylation profiles with significant hypermethylation in CpG island region and hypomethylation in CpG shelf region. Outsite of the MHC region, the most hypermethylated genes in RA included HDAC4, NXN, TBCD and TMEM61 while the most significant hypomethylated genes included ITIH3, TCN2, PRDM16, SLC1A5 and GALNT9. [Conclusion] Genome-wide DNA methylation patterns revealed significant DNA methylation change in CD4+ T cells from patients with rheumatoid arthritis. 12 rheumatoid arthritis and 12 matched health individuals
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000550.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
Project description:Anti-citrullinated protein antibodies (ACPAs) are one of the hallmarks in rheumatoid arthritis (RA), but the in vivo function remained unclear. To investigate the effects of ACPAs, we expressed monoclonal ACPAs derived from RA patients, and analyzed the functions in mouse models, as well as the reactivity to tissue and peptides/proteins. All ACPAs showed no arthritogenicity and could not induce pain-like behavior in mice whereas one of them (E4) profoundly protected against antibody-induced arthritis. E4 showed a tissue binding pattern restricted to skin epithelial cells, to macrophages and dendritic cells in lymphoid tissue and to cartilage from mouse and human arthritic joints. Proteomic analysis showed that E4 had a distinct binding pattern to macrophage and RA synovial fluid proteins (e.g. alpha-enolase). The protective effect was epitope specific but also dependent on Fc-FCGR2B interaction on macrophages following the immune complex formation, resulting an increased IL-10 production and osteoclastogenesis reduction. The findings suggest that certain ACPAs could be protective in arthritis with therapeutic potentials.
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis - Age Dependant
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000549.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
Project description:Anti-citrullinated protein antibodies (ACPAs) are one of the hallmarks in rheumatoid arthritis (RA), but the in vivo function remained unclear. To investigate the effects of ACPAs, we expressed monoclonal ACPAs derived from RA patients, and analyzed the functions in mouse models, as well as the reactivity to tissue and peptides/proteins. All ACPAs showed no arthritogenicity and could not induce pain-like behavior in mice whereas one of them (E4) profoundly protected against antibody-induced arthritis. E4 showed a tissue binding pattern restricted to skin epithelial cells, to macrophages and dendritic cells in lymphoid tissue and to cartilage from mouse and human arthritic joints. Proteomic analysis showed that E4 had a distinct binding pattern to macrophage and RA synovial fluid proteins (e.g. alpha-enolase). The protective effect was epitope specific but also dependent on Fc-FCGR2B interaction on macrophages following the immune complex formation, resulting an increased IL-10 production and osteoclastogenesis reduction. The findings suggest that certain ACPAs could be protective in arthritis with therapeutic potentials.
Project description:Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Microarray analysis of 83 synovial samples provides insight into the expression-level differences between patients at the site of disease activity. Synovial samples from Rheumatoid Arthritis patients were obtained during joint resection and profiled using microarrays.
Project description:The transcriptome of PBMC from rheumatoid arthritis patient hasn't been compenhensively profiled, and heterogeneous characteristics of blood monocytes in RA patients are much unknown. We performed the single cell transcriptomic analysis of PBMC from rheumatoid arthritis (RA) patient, and monocyte populations were extracted during the analysis. CD127 expression associated expression pattern of inflammatory genes was identified in RA patient's blood monocytes.
Project description:Rheumatoid arthritis is an autoimmune inflammatory joint condition which primarily affects the synovium of joints, characterised by synovial inflammation as well as articular cartilage and underlying bone destruction. Within this study, the proteomes of serum obtained from rheumatoid arthritis patients, and appropriate human controls, were analysed using liquid chromatography-tandem mass spectrometry. ProteoMiner™ equalisation columns were used to deplete high abundant proteins and reduce the protein concentration dynamic range.