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Arthritis Research & Therapy 04/2012; 4:1-2. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 6:1-1. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 5:1-1. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 4:1-1. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 3:1-1. · 4.45 Impact Factor
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A Union,
R Humbel,
K Conrad,
G Steiner,
P Schmit,
A Vos,
K De Bosschere,
S Dincq,
H Pottel,
L Meheus,
L Nogueira,
G Serre, F De Keyser
Arthritis Research & Therapy 04/2012; 3:1-1. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 5:1-1. · 4.45 Impact Factor
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B van der Cruyssen, F De Keyser,
H Peeters,
M van den Berghe,
D Marichal,
I Hoffman,
T Van Oostveldt,
D Laukens,
E Remaut,
L Steidler,
D Elewaut,
C Cuvelier,
M de Vos,
H Mielants,
E Veys
Arthritis Research & Therapy 04/2012; 5:1-2. · 4.45 Impact Factor
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Arthritis Research & Therapy 04/2012; 4:1-1. · 4.45 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Detection of systemic sclerosis-associated antibodies (SSc-Ab) in routine clinical practice is mostly restricted to anti-centromere and anti-topoisomerase-I antibodies. However, also other SSc-Ab (e.g. anti-RNA-polymerase-III, anti-PM/Scl, anti-fibrillarin and anti-Th/To) have been shown to be valuable diagnostic and prognostic markers for the disease, but testing methodologies for their detection are laborious and time-consuming. This study aimed to optimize interpretational criteria of a multiparameter lineblot (LB) for the parallel detection of SSc-Ab. We also assessed its global diagnostic value as an alternative for combined conventional techniques (CCT) in the serological workup of systemic sclerosis (SSc) patients.
The presence of SSc-Ab (anti-centromere, anti-topoisomerase-I, anti-RNA-polymerase-III, anti-PM/Scl, anti-fibrillarin and anti-Th/To) was identified by LB on 145 consecutive SSc patients and on 277 disease controls. Diagnostic sensitivity and specificity were calculated for both individual reactivities and the global LB. Cohen's kappa coefficient was used to examine agreement between LB and CCT and guided the definition of final interpretational criteria for LB.
Applying the optimal cut-off values and interpretational criteria, LB identified SSc-Ab in 110 SSc patients (sensitivity=76%) and in 19 disease controls (specificity=93%). Globally, there was a substantial agreement between CCT and LB (κ=0.787, concordance 92.4%). LB and CCT showed a very good correlation (κ>0.800) for most SSc-Ab (anti-centromere, anti-topoisomerase-I, anti-RNA-polymerase-III and anti-PM/Scl). The best agreement for anti-RNA-polymerase-III and anti-PM/Scl was achieved when positivity for both components was taken as a criterion.
LB is a reliable alternative for the laborious and time-consuming conventional techniques in the diagnostic workup of SSc, especially for the detection of anti-centromere, anti-topoisomerase-I, anti-RNA-polymerase-III and anti-PM/Scl.
Journal of immunological methods 03/2012; 379(1-2):53-60. · 2.35 Impact Factor
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J-E Martin,
F D Carmona,
J C A Broen,
C P Simeón,
M C Vonk,
P Carreira,
R Ríos-Fernández,
G Espinosa,
E Vicente-Rabaneda,
C Tolosa, [......],
Ø Palm,
M M Chee,
J M van Laar,
C Denton,
A Herrick,
J Worthington,
B P C Koeleman,
T R D J Radstake,
C Fonseca,
J Martín
[show abstract]
[hide abstract]
ABSTRACT: Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.
Genes and immunity 02/2012; 13(2):191-6. · 4.22 Impact Factor
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L M Diaz-Gallo,
P Gourh,
J Broen,
C Simeon,
V Fonollosa,
N Ortego-Centeno,
S Agarwal,
M C Vonk,
M Coenen,
G Riemekasten, [......],
G Espinosa,
I Castellvi,
T Witte, F de Keyser,
M Vanthuyne,
M D Mayes,
T R D J Radstake,
F C Arnett,
J Martin,
B Rueda
[show abstract]
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ABSTRACT: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.
3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.
The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).
The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.
Annals of the rheumatic diseases 03/2011; 70(3):454-62. · 8.11 Impact Factor
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B Vandooren,
T Cantaert,
M-J van Lierop,
E Bos,
L De Rycke,
E M Veys, F De Keyser,
B Bresnihan,
F P Luyten,
P C Verdonk,
P P Tak,
A H Boots,
D Baeten
[show abstract]
[hide abstract]
ABSTRACT: In mice, melanoma inhibitory activity (MIA) is a chondrocyte-specific molecule with similar regulation to collagen type II. As MIA is a small secreted protein, its value as cartilage biomarker in human inflammatory arthritis was assessed.
MIA tissue distribution was studied by quantitative PCR and immunohistochemistry. The regulation of MIA production was studied in vivo in rheumatoid arthritis (RA) (n = 37) and spondyloarthritis (SpA) (n = 30) synovial fluid (SF), and in vitro in alginate embedded human chondrocytes. Therapeutic modulation of serum MIA was evaluated during tumour necrosis factor (TNF)alpha and interleukin (IL)1 blockade in RA.
MIA was primarily expressed by chondrocytes in the human joint. SF MIA levels were lower in RA than in SpA despite similar levels of overall synovial inflammation. Further analysis indicated that these levels were inversely correlated with the degree of joint inflammation in RA, but not in SpA, and that the levels of TNFalpha and IL1beta were significantly increased in RA versus SpA. Accordingly, these proinflammatory cytokines suppressed MIA mRNA and protein in cultured chondrocytes. This suppression was paralleled by suppression of cartilage anabolism as assessed by collagen type 2 and aggrecan mRNA. Treatment of patients with RA with TNF blockade or IL1 blockade induced an increase of serum MIA levels.
The decreased levels of MIA in the inflamed RA joint and the coregulation of MIA and cartilage matrix molecules by proinflammatory cytokines indicate that joint inflammation in RA not only drives accelerated cartilage degradation but also suppresses cartilage anabolism. This inflammation-driven suppression is reversible in vivo.
Annals of the rheumatic diseases 06/2009; 68(6):1044-50. · 8.11 Impact Factor
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I E A Hoffman,
B R Lauwerys, F De Keyser,
T W J Huizinga,
D Isenberg,
L Cebecauer,
J Dehoorne,
R Joos,
G Hendrickx,
F Houssiau,
D Elewaut
[show abstract]
[hide abstract]
ABSTRACT: To investigate differences in clinical signs and symptoms, and in antinuclear antibodies (ANA), between patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE).
Clinical and serological data of 56 patients with juvenile-onset SLE were compared with data of 194 patients with adult-onset SLE. ANA were determined by line immunoassay and by indirect immunofluorescence on Crithidia luciliae.
Renal involvement, encephalopathy and haemolytic anaemia were seen, and anti-dsDNA, anti-ribosomal P and antihistone antibodies found, significantly more often in juvenile-onset SLE. Anti-dsDNA antibodies were directly associated, and anti-ribosomal P antibodies inversely associated, with renal involvement in juvenile-onset SLE. In juvenile patients with SLE and anti-dsDNA and without anti-ribosomal P antibodies the odds ratio for glomerulonephritis was 9.00; no patients with anti-ribosomal P but without anti-dsDNA had renal involvement.
Patients with juvenile-onset SLE more often have renal involvement and encephalopathy than patients with adult-onset SLE. Anti-ribosomal P, anti-dsDNA and antihistone antibodies are more often found in patients with juvenile-onset SLE.
Annals of the rheumatic diseases 11/2008; 68(3):412-5. · 8.11 Impact Factor
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[show abstract]
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ABSTRACT: To investigate the presence and characteristics of citrullinated vimentin in protein extracts of inflamed synovial tissue.
Cytosolic protein extracts obtained from RA (n = 14) and SpA patients (n = 14) were analysed by gel electrophoresis and western blotting. Citrullinated vimentin isoforms were visualized by a combination of anti-modified citrulline (AMC) staining and anti-vimentin detections (V9, H-84). This was subsequently confirmed by immunoprecipitation. Autoantibody detection was verified using sera obtained form RA (n = 6) and SpA (n = 6) patients.
A specific cluster of spots displayed on the 2D gel images of cytosolic synovial tissue extracts, was identified by mass spectrometry as vimentin. Interestingly, our results suggested that these isoforms could be the result of caspase cleavage. In addition, these cleaved forms of vimentin were found to be citrullinated in synovial cytosolic protein extracts of inflammatory arthritides, mainly in RA patients. Caspase-3 is able to cleave vimentin at amino acid 85. Western blot analysis with a specific antibody against amino acids 1-84 of vimentin (H-84) confirmed that the citrullinated isoforms of vimentin were lacking this part of the protein. These results were also confirmed by immunoprecipitation of vimentin derived from cytosolic protein extracts of RA and SpA patients. Furthermore, the presence of autoantibodies against these citrullinated processed forms of vimentin was found to be predominantly associated with RA patients.
These findings show the presence of processed citrullinated vimentin in inflammatory arthritides, mainly in RA and suggest a possible origin of the ACPA immune response in RA.
Rheumatology (Oxford, England) 06/2008; 47(5):597-604. · 4.24 Impact Factor
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[show abstract]
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ABSTRACT: Different methods exist to demonstrate anti-citrullinated protein/peptide antibodies (ACPA).
To evaluate discrepancy between four ACPA tests.
Population 1 consisted of patients with a new diagnostic problem, including 86 patients with rheumatoid arthritis (RA) and 450 patients without RA. Population 2 consisted of 155 patients with RA who had long-standing disease. Population 3 consisted of 188 patients with psoriatic arthritis and in population 4 there were 192 patients with systemic lupus erythematosus. Populations 1 and 2 were tested with the anti-human fibrinogen antibody (AhfibA) test, anti-CCP2 from Eurodiagnostica (CCP2-euro), anti-CCP2 from Pharmacia (CCP2-phar) and anti-CCP3 test by Inova (CCP3). Samples were annotated as discrepant if positive in one and negative in at least one other test. Each discrepant sample was re-analysed in a different run. Populations 3 and 4 were analysed in the CCP2-euro and AhFibA test.
In population 1, ACPA positivity was found in 17 of 450 (3.8%) patients without RA; 14 (82%) of these 17 samples were discrepant. In contrast, 61 of 86 (70.9%) patients with RA were ACPA positive of whom 18 of 61 (29.5%) were discrepant (70.9% vs. 29.5%, p<0.001). The discrepancies between tests could be partly attributed to borderline results, inter-assay discrepancy and inter-test variability. They were more prevalent in patients with systemic lupus erythematosus who were ACPA positive than in those with psoriatic arthritis who were ACPA positive.
Discrepancy between different ACPA tests was observed attributable to the occurrence of borderline results, inter-assay variability and mainly to inter-test variability. The lowest inter-test discrepancy is observed between tests that use the same substrate.
Annals of the rheumatic diseases 05/2008; 67(4):542-6. · 8.11 Impact Factor
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[show abstract]
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ABSTRACT: We investigated the possible association of rheumatoid arthritis (RA) with single nucleotide polymorphisms (SNP) within the ficolin (FCN) genes. Two SNPs in the FCN1 gene, four SNPs in the FCN2 gene and one SNP in the FCN3 gene were studied.
The SNPs within the FCN genes were detected by an experimental INNO-LiPA methodology (Innogenetics, Belgium) in a population consisting of 338 RA patients and 595 controls. The significant SNPs were further evaluated in two subpopulations and related to carriage of the human leukocyte antigen-shared epitope (HLA-SE), rheumatoid factor (RF) and the presence of anti-citrullinated protein/peptide antibodies (ACPA).
Two SNPs in the FCN1 gene were significantly associated with RA: the A allele rs2989727 was significantly increased in RA patients (67%) compared with controls (60%) (P = 0.002). Also, the frequency of the G allele of rs1071583 was increased in RA patients (68%) compared with controls (61%) (P = 0.003). Analysis of agreement between SNPs suggested strong linkage between rs2989727 and rs1071583. Carriage of a FCN1 SNP was independent of carriage of the HLA-SE, RF status and ACPA positivity.
We describe two linked SNPs in the FCN1 gene that are associated with the development of RA.
Rheumatology (Oxford, England) 01/2008; 46(12):1792-5. · 4.24 Impact Factor
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Rheumatology 10/2007; 46(9):1510; author reply 1510. · 4.06 Impact Factor
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M J C van Lierop,
L den Hoed,
J Houbiers,
J Vencovsky,
S Ruzickova,
O Krystufkova,
M van Schaardenburg,
F van den Hoogen,
B Vandooren,
D Baeten, F De Keyser,
G Sønderstrup,
E Bos,
A M Boots
[show abstract]
[hide abstract]
ABSTRACT: The cartilage proteins melanoma inhibitory activity (MIA) and human cartilage gp-39 (HC gp-39) are candidate autoantigens in rheumatoid arthritis (RA). The present study was undertaken to investigate the endogenous HLA-DR4-restricted presentation of these self proteins, in order to seek in vivo evidence in support of their potential immunologic role.
MIA and HC gp-39 were assessed in synovial fluid (SF) by enzyme-linked immunosorbent assay and in synovial tissue (ST) by immunohistochemistry. Presentation by SF cells was investigated using specific, HLA-DR-restricted T cell hybridomas.
MIA and HC gp-39 were detected in RA SF and ST, as well as in specimens from patients with other forms of arthritis. When HC gp-39-specific and MIA-specific HLA-DR4-restricted T cell hybridomas raised in HLA-DR4-transgenic mice were incubated with RA SF cells as antigen-presenting cells in the presence of HC gp-39 or MIA peptides, the corresponding T cell hybridomas showed strong responses, which were blocked by anti-HLA-DR antibodies. Weaker but qualitatively similar responses were observed with exogenous protein, indicating uptake and processing of these antigens by SF cells. More importantly, without addition of peptide or protein, endogenous presentation of MIA and HC gp-39 was detected in SF cells from 53% and 80% of HLA-DRB1*0401-positive RA patients, respectively. In addition, SF cells from 3 of 10 patients with spondylarthritis exhibited endogenous HC gp-39 presentation.
These data indicate that immunodominant epitopes of MIA and HC gp-39 are actively presented in an HLA-DR-restricted manner in the inflamed RA joint. The question remains as to whether this leads to activation of autoreactive T cells, which could play a role in either the immunopathology or the immunomodulation of arthritis.
Arthritis & Rheumatism 08/2007; 56(7):2150-9. · 7.87 Impact Factor
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Annals of the Rheumatic Diseases 02/2007; 66(1):138-40. · 8.73 Impact Factor
