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T W Huizinga

Publications and source records attributed to T W Huizinga.

At least 19 recordsLinked to original sources
PubMed2001

Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease.

The contribution of individual Fcgamma receptor (FcgammaR) subclasses to meningococcal phagocytosis was studied. In addition, functional FcgammaR polymorphisms were determined in 50 patients with meningococcal disease (MD), in 183 first-degree relatives of MD patients, and in 239 healthy control subjects, to study the association of FcgammaR genotypes with disease. Efficient internalization of opsonized Neisseria meningitidis serogroup B was mediated via multiple FcgammaR subclasses on phagocytes. Accordingly, a low-efficiency combination of FcgammaRIIa-R/R131, FcgammaRIIIa-F/F158, and FcgammaRIIIb-NA2/2 genotypes was increased significantly in relatives of patients with MD, compared with healthy control subjects (P<.05; odds ratio, 2.6; 95% confidence interval, 1.1-6.3). FcgammaRIIa and FcgammaRIIIa genotype distributions differed between patients with sepsis and those with meningitis. Combined genotypes of FcgammaRIIa and interleukin-10 -1082, which was previously reported as being associated with MD outcome, were distributed randomly in control subjects but not in relatives of patients with MD (P<.01). These data provide further evidence for the association of polymorphic genes on chromosome 1 and MD.

Adolescent↗
PubMed2001

Functional analysis of linker-scan mutants spanning the -376, -308, -244, and -238 polymorphic sites of the TNF-alpha promoter.

Tumor necrosis factor alpha (TNF-alpha) promoter polymorphisms have been linked to a large number of diseases but studies examining the possible direct functional effects of these polymorphisms have been contradictory. Previous studies compared TNF-alpha promoter constructs containing single nucleotide changes. We have now made a series of mutant constructs in which regions of the TNF-alpha promoter containing suspected functional single nucleotide polymorphisms, including -376, -308, -244 and -238, were replaced by a 10 bp linker scan sequence. These constructs were transiently transfected into the T cell line Jurkat, the B cell line Raji, and the monocytic cell line U937, and tested for basal and induced transcriptional activity. Mutant constructs covering both the -308 and -376 polymorphisms showed no significant differences in either basal or induced transcriptional activity. Constructs covering the -244/-238 region showed a small increase in basal activity in the U937 cell line. These results indicate (i) that the -308 and -376 regions are of no functional relevance for TNF-alpha promoter transcription, and (ii) that the -244/-238 region does not influence transcription in some cell lines but may have some role in transcription in others.

B-Lymphocytes↗
PubMed2001

Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus.

Family studies of first-degree relatives and analysis of twins indicate that as much as 75% of the differences in quantitative IL-10 production in man derive from heritable genetic factors. Studies of single nucleotide polymorphisms (SNP) in the proximal 1.0 kb of the IL-10 promoter have yielded inconsistent association with IL-10 production and variable results in promoter-reporter studies. However, in normal donors, an association of quantitative production with certain alleles of the IL-10.R short tandem repeat polymorphism at -4.0 kb suggested that SNPs in the more distal promoter might be informative. We have identified seven novel SNP sites in the genomic sequence of the first 4 kb of the IL-10 promoter region 5' to the ATG start site from Caucasian individuals with either a high or a low IL-10 production phenotype. We have also identified eight SNP haplotypes in the distal promoter that segregate with significant differences in quantitative IL-10 production in normal donors. These SNPs are significantly associated with systemic lupus erythematosus in African-Americans and may define one component of the genetic susceptibility to systemic lupus erythematosus in this group.

5' Untranslated Regions↗
PubMed2001

The influence of synovial fluid on adenovirus-mediated gene transfer to the synovial tissue.

OBJECTIVE: To determine the effect of synovial fluid (SF) from rheumatoid arthritis (RA) patients on adenovirus type 5 (Ad5)-mediated gene transfer to synoviocytes, and to explore new strategies for vector development based on the neutralization data obtained. METHODS: SF was derived from 63 randomly selected R4 patients. Ten samples were used to study the effect of SF on Ad5-mediated gene transfer in synoviocytes. IgG and <100-kd fractions were purified from these 10 SF, and their effect on gene transfer was determined. Neutralizing activity against wild-type Ad5 (wt-Ad5), wt-Ad26, wt-Ad34, wt-Ad35, and wt-Ad48 was tested in the SF from the remaining 53 patients. RESULTS: Seven of 10 SF samples inhibited Ad5-mediated gene transfer. Purified antibodies exhibited inhibition patterns similar to those seen with unfractionated SF. In 5 of 10 SF samples, low molecular weight fractions inhibited gene transfer at low dilutions. Neutralization of wt-Ad35 by SF from RA patients was less frequent than neutralization of other wt-Ad tested (4% versus 42-72%; n = 53). CONCLUSION: SF from 70% of the RA patients contained neutralizing antibodies that hamper Ad5-mediated gene transfer to synoviocytes. The activity of neutralizing antibodies may be circumvented in the majority of RA patients when vectors based on an Ad35 backbone are used.

Adenoviridae↗
PubMed2001

Infection efficiency of type 5 adenoviral vectors in synovial tissue can be enhanced with a type 16 fiber.

OBJECTIVE: To obtain an adenoviral vector with increased infection efficiency in the synovial tissue compared with conventional vectors based on adenovirus serotype 5 (Ad5), without compromising the specificity of infection. METHODS: Coxsackie adenovirus receptor (CAR) expression was assessed in cultured synoviocytes. Chimeric adenoviruses based on Ad5 but carrying the DNA encoding the fiber of adenovirus from subgroup B (Adll, 16, 35) or D (Ad24, 28, 33, 45, or 47) were constructed and produced on PER.C6 cells. The gene transfer efficiency of these chimera was tested on cultured synoviocytes and peripheral blood mononuclear cells (PBMC). RESULTS: No surface expression of CAR protein was observed on synoviocytes. CAR messenger RNA expression of synoviocytes was found to be low. Of all fiber chimeric vectors tested, vectors carrying the fiber of Ad16 (Ad5.fib16) were most potent, yielding approximately150 times increased transgene expression in cultured synoviocytes compared with those of Ad5. Flow cytometry showed that the increase in transgene expression was caused by the transduction of higher percentages of synoviocytes and higher gene expression per synoviocyte. Experiments with 500 virus particles/cell of Ad5.GFP or Ad5.fib16.GFP resulted in an infection efficiency of 0.6% and 1% in PBMC and 43% and 76% in synoviocytes, respectively. CONCLUSION: Synoviocytes hardly express CAR, which hampers Ad5-mediated gene transfer. Ad5.fib16 is superior to Ad5 vectors for transducing synoviocytes, without compromising the specificity of infection. Our data suggest that Ad5.fib16-mediated gene transfer to synovial tissue improves the therapeutic window.

Arthritis, Rheumatoid↗
PubMed2001

Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Adult↗
PubMed2001

The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients.

OBJECTIVE: To study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver enzyme levels during the study. Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of MTX treatment. RESULTS: Forty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters were not significantly different between the patients with and those without the mutation. CONCLUSION: The C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA. We postulate that the incidence of clinically important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.

Alanine Transaminase↗
PubMed2001

Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals.

Interindividual variation in the expression of tumor necrosis factor alpha (TNF) suggests the existence of functionally distinct TNF alleles that could play a role in susceptibility to TNF associated diseases such as rheumatoid arthritis (RA). To determine whether differential expression of TNF alleles exists, the relative contribution of TNF alleles in total TNF RNA production in peripheral blood mononuclear cells (PBMC) of healthy individuals and synovial tissue of RA patients was analyzed. By using a Tai I restriction fragment length polymorphism (RFLP) located at position +489 in the first intron of the gene, the relative contribution of each allele in precursor transcript production in heterozygous individuals could be measured. By means of this method we studied whether differences exist between TNF alleles in TNF pre-mRNA production. The relative contribution of TNF alleles to the non-spliced RNA pool was measured in PBMC of healthy individuals which were stimulated with LPS, PMA and anti-CD3 and anti-CD28 monoclonal antibodies for different time periods. Moreover, synovial biopsy material of RA patients was analyzed. The results of this study do not reveal a difference in the contribution of distinct TNF alleles in TNF pre-mRNA production upon in vitro and physiological stimulation conditions in healthy individuals and RA patients. Since some of the individuals whose PBMC were tested were also heterozygous for either -308, -1031, -863, -857 TNF promoter/enhancer single nucleotide polymorphisms (SNPs), the data argue against functional relevance of these TNF promoter/enhancer SNPs in the regulation of transcription. In conclusion, the data do not provide evidence for the existence of transcriptionally distinct TNF alleles to explain interindividual variation in TNF expression.

Alleles↗
PubMed2001

Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF-308A in systemic lupus erythematosus.

Differences in allelic distribution at loci surrounding the human HLA-DRB1 and tumor necrosis factor (TNF) genes have been observed in association with systemic lupus erythematosus (SLE). We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to polymorphic markers in the chromosomal region encompassed by HLA-DRB1 and HLA-C. Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, microsatellites D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2 and the single nucleotide polymorphism at position -308 in the promoter of TNF. The independent contribution of alleles to disease susceptibility was estimated by cross-tabulation and multivariate logistic regression. Possession of TNF-308A was associated with susceptibility to SLE (odds ratio [95% confidence interval], 3.70 [2.24-6.11]). This remained present after stratification on possession of HLA-DR3 (pooled odds ratio, 2.53 [1.37-4.70]). Stratification revealed a possible association of possession of C1_2_5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF-308A. A gene dosage effect was observed for -308A only (homozygotes, 7.75 [3.01-20.0], heterozygotes, 3.15 [1.85-5.37]). In multivariate analysis, possession of HLA-DR3, TNF-308A, and C1_2_5*192 remained independently associated with susceptibility to SLE (2.58 [1.29-5.18], 2.76 [1.43-5.31], and 0.26 [0.10-0.66], respectively). The association of possession of TNF-308A with susceptibility to SLE cannot be attributed to linkage to HLA-DR3 alone, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be in the vicinity of marker C1_2_5.

Adult↗
PubMed2001

Imaging modalities in central nervous system systemic lupus erythematosus.

Within the past few years, a clearly defined case definition system for central nervous system systemic lupus erythematosus (CNS-SLE) has been established. This has allowed cross-study comparisons of patients fulfilling the specific case definitions. New imaging techniques used on the subgroup of CNS-SLE patients that did not have any evidence for infarctions suggest that in these patients symptoms are associated with a diffuse process in the brain. Most likely this process leads to axonal damage and demyelination, ultimately leading to cerebral atrophy. With respect to the diagnostic work-up of SLE patients with neuropsychiatric symptoms, it has become clear that cranial magnetic resonance imaging is the technique of choice. Preliminary studies using quantitative magnetic resonance imaging techniques suggest that patients with neuropsychiatric symptoms caused by active CNS-SLE can be differentiated from patients with the same symptoms caused by residual disease.

Brain↗
PubMed2001

UVA-1 cold light treatment of SLE: a double blind, placebo controlled crossover trial.

OBJECTIVE: Treatment of patients with systemic lupus erythematosus (SLE) often implies strong drugs with possibly serious side effects. Thus there is a need for new immunosuppressive treatments. Long wave ultraviolet A (UVA-1) cold light therapy is an anti-inflammatory, immunomodulatory treatment with a possible systemic effect and few side effects. In the current study low dose UVA-1 cold light treatment was tested to determine whether it reduces disease activity in SLE. METHODS: Eleven patients with SLE were treated with UVA-1 cold light treatment and a placebo light treatment in a double blind, placebo controlled, crossover study. In two consecutive 12 week periods the patients were treated in the first three weeks with UVA-1 and placebo treatment or vice versa. The primary variables were the SLE Disease Activity Index (SLEDAI) and SLE Activity Measure (SLAM). RESULTS: The mean SLAM and SLEDAI showed a significant decrease of 30.4% (p=0.0005) and 37.9% (p=0.016) respectively after three weeks of UVA-1 and a non-significant decline of 9.3% (p=0.43) and 12.2% (p=0.54) respectively after three weeks of placebo treatment. In this small trial the difference in reduction of the disease activity indices during UVA-1 compared with during placebo treatment failed to reach the conventional border of significance (p=0.07). The total score of quality of life measure RAND-36 did not improve significantly, but the subscore for vitality did improve. CONCLUSION: Low dose UVA-1 cold light treatment was strongly suggestive of lowering disease activity in this double blind placebo controlled study, and no side effects occurred.

Adolescent↗
PubMed2001

Soluble CD95 concentrations are increased in patients with severe systemic lupus erythematosus, but not in their first degree relatives.

OBJECTIVE: Plasma concentrations of soluble CD95 (sCD95) are raised in patients with systemic lupus erythematosus (SLE) before clinical relapses become manifest. Increased sCD95 concentrations may therefore be a familial characteristic that is associated with susceptibility to severe disease. To test this, sCD95 concentrations were measured in healthy first degree relatives of patients with severe and non-severe SLE. METHODS: Seventy seven first degree relatives of 26 patients with severe, and 72 relatives of 25 patients with non-severe lupus were studied. Controls were 42 first degree relatives of 17 patients with chronic cutaneous lupus erythematosus (CCLE) and 63 partners of the patients with their first degree relatives. Severe lupus was defined as both multi-organ disease and cyclophosphamide treatment, non-severe lupus as neither. Organ damage was assessed with the SLICC-ACR index, disease activity with SLEDAI. RESULTS: Soluble CD95 concentrations in relatives of patients with severe SLE were similar to those in relatives of patients with non-severe SLE, relatives of patients with CCLE, and controls (median (interquartile range) sCD95 concentration 0.59 (0.52-0.66) v 0.57 (0.50-0.63), 0.56 (0.51-0.71), and 0.55 (0.49-0.61) ng/ml, p=0.25, p=0.94, and p=0.17, respectively). Increased concentrations of sCD95, however, were found in patients with severe SLE compared with those in patients with non-severe SLE, patients with CCLE, and control relatives (0.77 (0.70-0.97) v 0.60 (0.54-0.67), 0.57 (0.54-0.71), and 0.57 (0.52-0.63) ng/ml, respectively, p<0.001). Concentrations of sCD95 were significantly correlated with damage index scores (rs=0.47, p<0.01). Basic and clinical characteristics of patients with SLE, including SLEDAI scores, could not explain these observations. CONCLUSION: Soluble CD95 concentrations are associated with severity of the disease and not with susceptibility for severe SLE.

Adult↗
PubMed2001

Autoantibodies within families of patients with systemic lupus erythematosus are not directed against the same nuclear antigens.

OBJECTIVE: The presence of antinuclear autoantibodies in systemic lupus erythematosus (SLE) is influenced by genetic factors. The presence of autoantibodies in healthy family members of patients has been reported. Our hypothesis was that autoantibodies are directed against the same antigens in first-degree family members of patients with SLE as in their patient relative. METHODS: Plasma was harvested from 50 patients with SLE, 154 unaffected first-degree family members, and 330 healthy controls. Presence of autoantibodies against 14 specific nuclear antigens was tested by the ELISA based line immunoassay INNO-LIA method. RESULTS: Seventy-four percent of patients, 32% of first-degree family members, and 1.5% of healthy controls had antibodies against any nuclear antigen. Most frequent autoantibodies in the patients were anti-histone and anti-SSA, whereas in the family members these were anti-RNP-C and anti-Topo-I/Scl. Presence and specificity of autoantibodies in family members were independent of the presence or absence of that autoantibody in their patient relative (chi-square p > 0.1 for all 14 antigens). CONCLUSION: Autoantibodies in family members and their patient relatives are not directed against the same nuclear antigens. Thus a familial aspecific dysfunction of the B lymphocyte is the most likely explanation for autoantibody production in SLE.

Adult↗