369 research outputs found
Ann Rheum Dis
Objective This study was conducted with sera from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and arthritis and lupus-like disease animal models to identify innate immune system-dependent and -independent autoantigens
Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.
Background: Recent evidence suggests that distinction
of subsets of rheumatoid arthritis (RA) depending on anticyclic
citrullinated peptide antibody (anti-CCP) status may
be helpful in distinguishing distinct aetiopathologies and in
predicting the course of disease. HLA-DRB1 shared
epitope (SE) and peptidylarginine deiminase type 4
(PADI4) genotype, both of which have been implicated in
anti-CCP generation, are assumed to be associated with
RA.
Objectives: To elucidate whether PADI4 affects the
clinical characteristics of RA, and whether it would
modulate the effect of anti-CCPs on clinical course. The
combined effect of SE and PADI4 on autoantibody profile
was also analysed.
Methods: 373 patients with RA were studied. SE,
padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear
antibodies (ANAs) were determined. Disease
severity was characterised by cumulative therapy
intensity classified into ordinal categories (CTI-1 to CTI-3)
and by Steinbrocker score.
Results: CTI was significantly associated with disease
duration, erosive disease, disease activity score (DAS) 28
and anti-CCPs. The association of anti-CCPs with CTI was
considerably influenced by padi4_94C.T genotype (C/C:
ORadj=0.93, padj=0.92; C/T: ORadj=2.92,
padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of
padi4_94T exhibited a significant trend towards higher
Steinbrocker scores in univariate and multivariate
analyses. An association of padi4_94C.T with ANAs
was observed, with noteworthy differences depending on
SE status (SE2: ORadj=6.20, padj,0.04; SE+:
ORadj=0.36, padj=0.02) and significant heterogeneity
between the two SE strata (p=0.006).
Conclusions: PADI4 genotype in combination with anti-
CCPs and SE modulates clinical and serological characteristics
of RA
Spatially resolved spectroscopy of alkali metal vapour diffusing inside hollow-core photonic crystal fibres
We present a new type of compact and all-glass based vapour cell integrating
hollow-core photonic crystal fibres. The absence of metals, as in a traditional
vacuum chamber and the much more compact geometry allows for fast and
homogeneous heating. As a consequence we can fill the fibres on much faster
timescales, ranging from minutes to hours. Additionally the all-glass design
ensures optical access along the fibre. This allows live monitoring of the
diffusion of rubidium atoms inside the hollow-core by measuring the
frequency-dependent fluorescence from the atoms. The atomic density is
numerically retrieved using a 5-level system of Bloch-equations.Comment: 9 pages, 5 figure
Crosstalks between integrin alpha 5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation
<p>Abstract</p> <p>Background</p> <p>The potential of mesenchymal stromal cells (MSCs) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors that trigger osteoblast differentiation in MSCs is therefore critical to promote the osteogenic potential of human MSCs. In this study, we used microarray analysis to identify signalling molecules that promote osteogenic differentiation in human bone marrow stroma derived MSCs.</p> <p>Results</p> <p>Microarray analysis and validation experiments showed that the expression of IGF2 and IGFBP2 was increased together with integrin alpha5 (ITGA5) during dexamethasone-induced osteoblast differentiation in human MSCs. This effect was functional since we found that IGF2 and IGFBP2 enhanced the expression of osteoblast phenotypic markers and <it>in vitro </it>osteogenic capacity of hMSCs. Interestingly, we showed that downregulation of endogenous ITGA5 using specific shRNA decreased IGF2 and IGFBP2 expression in hMSCs. Conversely, ITGA5 overexpression upregulated IGF2 and IGFBP2 expression in hMSCs, which indicates tight crosstalks between these molecules. Consistent with this concept, activation of endogenous ITGA5 using a specific antibody that primes the integrin, or a peptide that specifically activates ITGA5 increased IGF2 and IGFBP2 expression in hMSCs. Finally, we showed that pharmacological inhibition of FAK/ERK1/2-MAPKs or PI3K signalling pathways that are enhanced by ITGA5 activation, blunted IGF2 and IGFBP2 expression in hMSCs.</p> <p>Conclusion</p> <p>The results show that ITGA5 is a key mediator of IGF2 and IGFBP2 expression that promotes osteoblast differentiation in human MSCs, and reveal that crosstalks between ITGA5 and IGF2/IGFBP2 signalling are important mechanisms that trigger osteogenic differentiation in human bone marrow derived mesenchymal stromal cells.</p
Angiotensin converting enzyme intron 16 insertion/deletion genotype is associated with plasma C-reactive protein concentration in uteroplacental dysfunction
Introduction: Disturbance of the uteroplacental circulation (UPC) and the
renin-angiotensin system are involved in the pathogenesis of preeclampsia. In
women with history of preeclampsia persistently elevated C-reactive protein
(CRP) levels have been described. The angiotensin-converting enzyme (ACE)
intron 16 insertion/deletion (I/D) genotype is associated with ACE activity
and assumed to be a risk factor for preeclampsia. As ACE generates
proinflammatory angiotensin II, we analysed, whether ACE intron 16 I/D
genotype is associated with CRP and whether this association exhibited a
relation to uteroplacental dysfunction. Materials and methods: A total of 639
women have been followed during pregnancy with repeated measurements of CRP
levels (observations: n=2333). ACE intron 16 I/D genotype was determined, and
its association with CRP was assessed with adjustment for non-independent
observations. Results: CRP levels of ACE D allele carriers were significantly
higher than those of the ACE II (wild-type) genotype (p=0.0003, p adj=0.04).
This relation was allele-dose dependent (p<10−4, p adj<0.02). Association
between ACE I/D and CRP was significantly restricted to patients presenting
with impaired UPC in univariate (p<0.04) and multivariate analyses (p=0.01).
Conclusions: The ACE I/D genotype is significantly associated with CRP
elevations during pregnancies complicated by disturbed UPC. Whether this
effect on CRP is involved in pathogenesis of preeclampsia has to be
elucidated
Fluorescence optical imaging for treatment monitoring in patients with early and active rheumatoid arthritis in a 1-year follow-up period
BACKGROUND:
Fluorescence optical imaging (FOI) enables visualization of inflammation in the hands in rheumatic joint diseases with currently a lack of long-term follow-up studies.
OBJECTIVE:
To investigate FOI for treatment monitoring in a homogenous cohort of patients with early (disease duration  3.2) RA over a period of 12 months.
METHODS:
Thirty-five RA patients (24 (68.6%) females, mean age 53.3 years (SD 13.6)) were investigated clinically by DAS28, tender joint count (TJC) and swollen joint count (SJC) and by FOI in phases 1-3 and PrimaVistaMode (PVM) before therapy change and after 12 months. The FOI activity score (FOIAS) was calculated based on individual joint scores from 0 to 3 in 30 joints per patient, adding up to a sum score (0-90).
RESULTS:
We found a statistically significant reduction of FOIAS in phase 1 from baseline (median 5.0, IQR 24.96) to follow-up (median 1.0, IQR 4.0) in all patients (p = 0.0045), both in responders and non-responders according to EULAR response criteria by DAS28. Statistically significant reductions over 12 months were found for median DAS28(ESR) 5.61 to 3.31, TJC 7.0 to 1.0, and SJC 5.0 to 1.0 (each p <  0.001). No statistically significant correlations were detected between the FOIAS change in phase 1 and DAS28(ESR), TJC, or SJC. Correlations between the other phases and clinical outcomes were weak to moderate.
CONCLUSION:
Reduced early enhancement in FOI phase 1 can be observed in clinically responding and non-responding early RA patients under treatment. Regarding potential marker performance, FOI probably shows a reduction of inflammation more objectively
Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures
Objective. The factors that induce remission of RA during pregnancy and the relapse occurring after delivery remain an enigma. In a previous study, we investigated gene-expression profiles of peripheral blood mononuclear cells (PBMC) in patients with RA and healthy women in late pregnancy and postpartum. Profiles of samples from both groups were similar in late pregnancy with elevated monocyte and decreased lymphocyte signatures. Postpartum, in RA PBMC the high level of monocyte transcripts persisted. Further increase was observed in adhesion, migration and signalling processes related to monocytes but also in lymphocytes despite similar clinical activity due to intensified drug treatment. This prompted us to investigate correlations between clinical parameters of disease activity and gene profiles. Methods. Transcriptome data were correlated with RADAI, CRP, monocyte and lymphocyte counts. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations, monocytes and lymphocytes signatures were used as reference information. Results. Comparative analysis of PBMC expression profiles from RA patients during and after pregnancy with RADAI and CRP revealed a correlation of these disease activity parameters predominantly with monocyte transcripts. Genes related to cellular programs of adhesion, migration and response to infections were upregulated. Comparing clinically active and not-active RA patients postpartum revealed a cluster of 19 genes that could also identify active disease during pregnancy. Conclusion. The data suggest that an increase of the RADAI and an elevation of CRP is a consequence of molecular activation of monocytes. Furthermore, they indicate that molecular activation of T lymphocytes may remain clinically unrecognized postpartum. It is conceivable that a set of 19 genes may qualify as molecular disease activity marke
A customized monocyte cDNA microarray for diagnosis of rheumatoid arthritis and prognosis of anti-TNF-α therapy
Background
In rheumatoid arthritis (RA) macrophages (Mf) play a pivotal role. They become highly activated in synovitis and at the cartilage–pannus junction. Furthermore, therapeutic neutralization of molecules produced by activated Mf lead to clinical improvement in RA, and circulating monocytes (MO) of the peripheral blood in patients with RA spontaneously express proinflammatory genes (IL-1β, IL-6, TNF).
Methods
A custom RA-MO cDNA microarray was generated using differentially expressed genes obtained from gene subtraction and from comparative whole genome wide U133A analysis in normal donors, active and anti-TNF-α created RA patients. Genes were selected using MAS 5.0, multtest and PAM. The custom microarray consists of 313 genes including guide dots, and positive (housekeeping genes and spike controls) and negative controls for image and statistical analysis. Each probe was spotted in 16 replicates.
Results
The RA-MO chipset-II was validated using the following: non-stimulated and LPS, PMA, Vit.D3+LPS, PMA+LPS stimulated U937 cells; nonstimulated and LPS stimulated healthy donor MO; MO from normal donors (n = 3) and RA patients before and during anti-TNF-α treatment (n = 5 each); and synovial tissue from normal individuals (n = 2) and RA patients (n = 2). Not only LPS/PMA regulated genes but also RA specific and anti-TNF-α regulated genes were validated. In addition, we could clarify whether these genes are differentially transcribed only in MO or whether they can also be found in RA tissue Mf. Our data indicate a high degree of reproducibility that is sufficient for diagnostic applications and therapy monitoring.
Conclusion
The RA-MO chipset-II microarray is competitive and flexible for enlargement of the number of genes. The current gene selection will contribute to validating the role of monocytes in disease activity, to therapeutic interventions, and may improve the knowledge on the regulation of pathways in activated monocytes in chronic inflammation
- …