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C L Verweij

Publications and source records attributed to C L Verweij.

At least 55 records · Page 3Linked to original sources
PubMed1998

Interleukin 10 secretion in relation to human IL-10 locus haplotypes.

Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) shows large inter-individual variation in interleukin 10 (IL-10) secretion, which has been shown to have a genetic component of over 70%. Alleles at two microsatellite loci in the 4 kb immediately upstream of the human IL-10 transcription initiation site in 132 individuals from 56 Dutch families were defined and assigned as haplotypes. LPS-induced IL-10 secretion was measured by ELISA and related to the IL-10 promoter haplotypes present in 78 unrelated individuals obtained from these families. Analysis showed that LPS-induced IL-10 secretion from unrelated individuals varied with IL-10 promoter haplotypes (P = 0.024; Kruskal-Wallis test). Two observations were made in relation to secreted IL-10 levels and promoter haplotypes; first, those haplotypes containing the allele IL10.R3 were associated with lower IL-10 secretion than haplotypes containing any other IL10.R allele. Second, the haplotype IL10.R2/IL10.G14 was associated with highest IL-10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL-10 secretion. These data demonstrate that the ability to secrete IL-10 can vary in man according to the genetic composition of the IL-10 locus.

Alleles↗
PubMed1998

CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis.

In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1998

Functional analysis of rheumatoid factor-producing B cells from the synovial fluid of rheumatoid arthritis patients.

OBJECTIVE: To understand the regulation of rheumatoid factor (RF) production in rheumatoid arthritis (RA), we studied IgM-RF production by B cells isolated from the synovial fluid (SF). METHODS: Highly purified SF and peripheral blood (PB) B cells were isolated by negative selection in a fluorescence-activated cell sorter (FACS) and then cultured with either L cells, CD40 ligand (CD40L)-transfected L cells, or type B synoviocytes in the presence or absence of interleukin-2 (IL-2), IL-4, or IL-10. Total IgM and IgM-RF were detected after 14 days by enzyme-linked immunosorbent assay. Enzyme-linked immunospot assays were performed to detect cells that spontaneously produced immunoglobulin. SF B cells were also phenotypically characterized by FACS analysis. RESULTS: Terminally differentiated CD20-,CD38+ synovial plasma cells (PC) present in the SF of RA patients secreted IgM-RF in the absence of a stimulus. IgM-RF production markedly increased when SF B cells were cultured in the presence of type B RA synoviocytes together with IL-10, but independently of CD40-CD40L interaction. Although CD20-,CD38+ PC could also be demonstrated in SF B cells from patients with other forms of arthritis, IgM-RF production was restricted to the SF B cell cultures of patients with seropositive RA. The frequency of IgM-RF-producing cells among IgM-producing PC in patients with seropositive RA was estimated to be as much as 50%. CONCLUSION: These data demonstrate that terminally differentiated CD20-,CD38+ IgM-RF-producing B cells are specifically present in the inflamed joints of patients with seropositive RA. There is evidence that the local environment in the rheumatoid joint favors RF production. The relatively high frequency of IgM-RF PC in the SF B cell population provides evidence of a dominant RA-specific antigen-driven response in the development of the synovial PC repertoire.

ADP-ribosyl Cyclase↗
PubMed1998

Functional analysis of a human tumor necrosis factor alpha (TNF-alpha) promoter polymorphism related to joint damage in rheumatoid arthritis.

BACKGROUND: Functional heterogeneity in the tumor necrosis factor alpha (TNF-alpha) gene may be responsible for the TNF-alpha response in infectious and autoimmune diseases. Recently, the TNF-238 promoter polymorphism was observed as being associated with a more destructive disease in rheumatoid arthritis (RA). To determine the relation between TNF-238 and disease progression, the extent of joint destruction in a cohort of 101 RA patients followed for 12 years was analyzed. Furthermore, we have attempted to link this polymorphism to TNF-alpha gene transcription in monocytes and lymphocytes in vitro. PATIENTS, MATERIALS, AND METHODS: The extent of joint destruction determined on X-rays of hands and feet assessed after 0, 3, 6, and 12 years was compared with TNF-238 genotypes. Functional consequences of TNF-alpha gene polymorphisms using reporter gene constructs were analyzed in cells of the monocyte and lymphocyte lineage by means of transient transfection systems. RESULTS: The rate of joint damage in -238GA patients was lower than that in the -238GG patients, independent of HLA-DR4. Damage after 12 years was 76 +/- 30 for the -238GA versus 126 +/- 13 for the -238GG patients as determined by the van der Heijde's modification of Sharp's method. Furthermore, TNF-238A was found to be in linkage disequilibrium with an additional polymorphism at position -376. Functional assays revealed no significant differences in the level of inducible reporter gene expression between the TNF-238/-376 promoter constructs in the cell types tested. CONCLUSION: In a prospective study, we show that the TNF-238GG genotype contributes to progression of joint destruction in RA, independent of the presence of HLA-DR4. However, in vitro transfection assays indicate that TNF-238A by itself or in combination with TNF-376A is not likely to be of direct functional relevance for transcriptional activation. Therefore, these polymorphisms may serve as markers for additional polymorphisms in the TNF/LT locus or neighboring genes that may influence disease severity.

Adult↗
PubMed1997

Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis.

In rheumatoid arthritis (RA), the functional status of T cells is incompletely understood. Synovial T cells display phenotypic evidence of former activation, but there is poor production of T cell-derived cytokines in the synovium. In addition, synovial T cell proliferation upon mitogenic and antigenic stimulation was decreased compared with that in peripheral blood T cells. Moreover, previous reports revealed that early Ca2+ rises induced by TCR/CD3 stimulation were decreased in RA T cells compared with those in healthy controls. To investigate the molecular mechanisms of RA synovial T cell hyporesponsiveness, we analyzed the TCR/CD3-mediated protein tyrosine phosphorylation in RA peripheral blood and synovial fluid (SF) T cells. SF T cells exhibited a decreased overall tyrosine phosphorylation pattern upon stimulation. Most notably, the induction of phosphorylation of p38 was virtually absent. Moreover, we found that tyrosine phosphorylation of the TCR zeta-chain, one of the most proximal events in TCR signaling, is clearly diminished in RA SF T cells. The decrease in tyrosine phosphorylation was accompanied by a decrease in detectable levels of zeta-protein within synovial T cells. These results suggest that a defective TCR signaling underlies the hyporesponsiveness of synovial T cells in RA.

Arthritis, Rheumatoid↗
PubMed1997

Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis.

In rheumatoid arthritis (RA), T cells isolated from the synovial fluid (SF) show impaired responses to mitogenic stimulation compared with T cells from the peripheral blood (PB). Here it is reported that hyporesponsiveness of SF T cells correlated with a significant decrease in the levels of the intracellular redox-regulating agent glutathione (GSH). GSH was decreased in both CD4+ (p = 0.0022) and CD8+ (p = 0.0010) SF T cell subsets compared with PB CD4+ and CD8+ T cells in RA patients. Levels of thioredoxin (TRX), another key redox mediator, previously found to be secreted under conditions of oxidative stress, were found to be significantly increased in SF compared with plasma samples of RA patients (p = 0.005). Increased levels of TRX in the SF of inflamed joints was found to be associated with RA when compared with other arthritides (p = 0.007). Restoration of GSH levels in SF T cells with N-acetyl-L-cysteine (NAC), enhanced mitogenic induced proliferative responses and IL-2 production. Collectively, these data impute an important role to an altered redox state in the hyporesponsiveness of joint T cells in patients with RA.

Adult↗
PubMed1997

Genetic influence on cytokine production and fatal meningococcal disease.

BACKGROUND: To assess the genetic influence on cytokine production and its contribution to fatal outcome, we determined the capacity to produce tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) in families of patients who had had meningococcal disease. METHODS: We studied 190 first-degree relatives of 61 patients with meningococcal disease; we also studied 26 monozygotic twins. Production of cytokines was determined during endotoxin stimulation of whole-blood samples ex-vivo. Heritability was estimated in a pedigree-based maximum-likelihood model. DNA was typed for the G to A transition polymorphisms at position -308 and -238 in the TNF gene promoter. FINDINGS: Heritability in monozygotic twins was 0.60 for the production of TNF and 0.75 for the production of IL-10. Families with low TNF production had a tenfold increased risk for fatal outcome (OR 8.9, 95% CI 1.8-45), whereas high IL-10 production increased the risk 20-fold (19.5, 2.3-165). Families with both characteristics had the greatest risk. The transition polymorphisms in the TNF gene promoter were not associated with outcome. INTERPRETATION: Genetic factors substantially influence production of cytokines. An innate anti-inflammatory cytokine profile may contribute to fatal meningococcal disease.

Adolescent↗
PubMed1997

TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients.

TNF-alpha production in whole blood cultures upon stimulation with LPS was determined in 179 individuals from 61 families in order to characterise the magnitude of inherited differences in TNF-alpha production. The three families characterised by highest TNF production showed 7.1 +/- 0.3 ng TNF/ml upon culture with 10 ng LPS and 10.2 +/- 0.2 ng TNF/ml upon culture with 1000 ng LPS. in contrast to the three families characterised by the lowest TNF production that showed a production of 1.6 +/- 0.1 ng TNF upon culture with 10 ng and 2.5 +/- 0.2 ng/ml upon culture with 1000 ng LPS/ml. This difference could not be attributed to the promoter polymorphisms -308 G to A. -238 G to A or -376 G to A, although the -238 GA donors produced 2.1 +/- 0.9 ng TNF upon culture with 10 ng endotoxin compared to 3.2 +/- 2.2 ng TNF for the -238 GG donors. In line with these results the frequency of the -238 GG genotype was increased in hospitalized MS patients in a nursing home (100% 238GG, n = 57) compared to MS patients in an outpatient's clinic (94% 238GG, n = 98) or Dutch controls (90% 238GG, n = 180). These results suggest that the -238 GG genotype is differently distributed in hospitalized MS patients in a nursing home.

Disease Susceptibility↗
PubMed1997

Polymorphisms within the human tumor necrosis factor-alpha promoter region in human immunodeficiency virus type 1-seropositive persons.

The question is addressed whether particular tumor necrosis factor-alpha (TNF-alpha) polymorphisms are associated with clinical course and outcome of human immunodeficiency virus type 1 (HIV-1) infection. The distribution of four TNF-alpha guanine (G) to adenosine (A) transition polymorphisms at positions -376, -308, -238, and -163 of the 5' promoter region of the TNF-alpha gene was studied in a nested case-control study among HIV-1-seropositive participants of the Amsterdam Cohort. None of the polymorphisms was significantly associated with long-term asymptomatic survival after HIV-1 infection compared with progression to clinical AIDS. Moreover, specific AIDS-defining illnesses or biologic phenotype of the HIV-1 virus were not associated with TNF-alpha alleles. The results of this study do not point toward a role for known TNF-alpha G to A transition polymorphisms in the clinical course of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease?

Genetic factors associated with rheumatoid arthritis (RA) might involve variant tumour necrosis factor (TNF)-alpha genes. Therefore, polymorphisms at positions -308, -238, -376, -163 and +70 relative to the transcription initiation site were studied with respect to the susceptibility to, or severity of, RA. TNF-alpha genotypes of 283 RA patients and 116 healthy individuals were determined. Clinical data were obtained from patient files and questionnaires. The distribution of TNF-alpha alleles was similar in RA patients and healthy controls. With respect to disease severity, the TNF-alpha -238GA genotype was found to be associated with the absence of erosions [odds ratio (OR) 4.1, confidence interval 1.0-17]. In addition, this genotype was associated with a lower number of hand joints affected by erosions within the first 3 yr of disease onset compared to -238GG. The association between the -238 polymorphism and radiographic progression was independent of the presence of HLA-DR4. In line with this observation, the OR for the presence of erosions in patients with both risk factors (DR4 and -238GG) compared to patients who lack these factors was 11.1 (1.8-6.8). No associations between the TNF-alpha -308, +70 and -376 alleles and susceptibility to, or severity of, RA could be demonstrated. Our data indicate that the TNF-alpha -238GA genotype is associated with decreased radiologically detectable progression of RA.

Adenine↗
PubMed1997

Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells.

OBJECTIVE: The efficacy of both chloroquine and hydroxychloroquine in rheumatoid arthritis (RA) has been proved in controlled clinical trials. Despite similar chemical characteristics, it is believed the clinical efficacy of chloroquine is superior to that of hydroxychloroquine in patients with RA. Excessive production of proinflammatory cytokines was shown to contribute to the pathogenesis of RA. From different studies testing either chloroquine or hydroxychloroquine, it could be concluded that both drugs differentially inhibit cytokine production. METHODS: We compared the effects of both chloroquine and hydroxychloroquine on stimulated peripheral blood mononuclear cells (PBMC) with respect to cytokine production. Therefore, PBMC were tested for tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and interferon-gamma (IFN-gamma) by specific ELISA, after stimulation with phytohemagglutinin (PHA) or lipopolysaccharide (LPS) in the presence or absence of different concentrations of chloroquine or hydroxychloroquine. RESULTS: We observed that chloroquine and hydroxychloroquine equally inhibit PHA induced TNF-alpha and IFN-gamma production, and LPS induced TNF-alpha and IL-6 production, while PHA induced IL-6 production was not affected. CONCLUSION: Chloroquine and hydroxychloroquine display similar effects on PHA and LPS induced cytokine production by PBMC under identical in vitro conditions. These findings may help in understanding the mechanism of action of these drugs on RA.

Adult↗
PubMed1997

Tumor necrosis factor in Plasmodium falciparum malaria: high plasma level is associated with fever, but high production capacity is associated with rapid fever clearance.

In the present study, we investigated 91 patients with Plasmodium falciparum malaria of different severity in a highly endemic area. Patients were examined at least twice daily until clearance of parasites and fever. Plasma cytokine concentrations without and after ex vivo PHA stimulation of whole blood were determined. On admission we found elevated plasma concentrations of TNF, IFN-gamma, and IL-10 compared to levels during and after chemotherapy. Plasma TNF levels on admission were significantly different between patients with severe and mild malaria (differentiated in schoolchildren and adults). The PHA elicited TNF production capacity of peripheral blood leucocytes was suppressed during the acute phase of malaria. High TNF production capacity was associated with faster fever clearance and parasite clearance and, in patients with severe malaria, with higher blood glucose levels. In conclusion we observed circulating TNF concentrations in malaria patients dependent on the severity of disease, which is itself dependent on age, and an association of a high TNF production capacity with parameters for accelerated cure and good prognosis.

Adolescent↗
PubMed1996

Alternative splicing of IgA Fc receptor (CD89) transcripts.

An alternatively spliced CD89 transcript is present in peripheral blood mononuclear cells (PBMC) and U937 cells. The alternatively spliced CD89 mRNA species lacks the exon 4 sequence, encompassing 288 nucleotides, that encodes the extracellular membrane-proximal immunoglobulin-like domain (EC2).

Alternative Splicing↗
PubMed1996

Nuclear appearance of a factor that binds the CD28 response element within the interleukin-2 enhancer correlates with interleukin-2 production.

Activation of T lymphocytes requires the combined signaling of the T cell receptor and costimulatory molecules such as CD28. The ability of T cells to produce interleukin-2 (IL-2) is a critical control point in T lymphocyte activation. The IL-2 enhancer contains a functional motif named CD28 response element (CD28RE) that serves a role as a target for mitogenic T cell activation signals. The CD28RE sequence reveals similarity to the consensus kappaB binding motif. Here we demonstrate that CD28RE binds an inducible protein with a molecular mass of approximately 35 kDa called nuclear factor of mitogenic-activated T cells (NF-MATp35) that is clearly different from the known NF- kappaB/Rel family members. Induction of NF-MATp35 was shown to depend on de novo protein synthesis and was restricted to T cells that received a mitogenic combination of T cell stimuli, not necessarily including CD28 signaling. Nonmitogenic T cell stimulation did not result in appearance of NF-MATp35. These results indicate that mitogenic combinations of T cell activation signals are integrated at the level of NF-MATp35 induction. Similar to its effect on IL-2 production, cyclosporin A inhibited the induction of NF-MATp35. Taken together, these data demonstrate that the nuclear appearance of NF-MATp35 shows excellent correlation with IL-2 production, which is a unique characteristic among nuclear factors implicated in the control of IL-2 gene expression.

Base Sequence↗