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Biomedical subjects

C L Verweij

Publications and source records attributed to C L Verweij.

At least 19 recordsLinked to original sources
PubMed2007

Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause. AIM: To identify peripheral blood (PB) gene expression profiles that may distinguish RA subtypes. METHODS: Large-scale expression profiling by cDNA microarrays was performed on PB from 35 patients and 15 healthy individuals. Differential gene expression was analysed by significance analysis of microarrays (SAM), followed by gene ontology analysis of the significant genes. Gene set enrichment analysis was applied to identify pathways relevant to disease. RESULTS: A substantially raised expression of a spectrum of genes involved in immune defence was found in the PB of patients with RA compared with healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in patients with RA compared with healthy individuals, which was confirmed by gene ontology and pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFN(high) patients). Application of pathway analysis revealed that the IFN(high) group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFN(low) group was similar to the controls. CONCLUSION: The IFN type I signature defines a subgroup of patients with RA, with a distinct biomolecular phenotype, characterised by increased activity of the innate defence system, coagulation and complement cascades, and fatty acid metabolism.

Adult↗
PubMed2006

A subtype of multiple sclerosis defined by an activated immune defense program.

Given the heterogeneous nature of multiple sclerosis (MS), we applied DNA microarray technology to determine whether variability is reflected in peripheral blood (PB) cells. In this study, we studied whole-blood gene expression profiles of 29 patients with relapsing-remitting MS (RRMS) and 25 age- and sex-matched healthy controls. We used microarrays with a complexity of 43K cDNAs. The data were analyzed using sophisticated pathway-level analysis in order to provide insight into the deregulated peripheral immune response programs in MS. We found a remarkable elevated expression of a spectrum of genes known to be involved in immune defense in the PB of MS patients compared to healthy individuals. Cluster analysis revealed that the increased expression of these genes was characteristic for approximately half of the patients. In addition, the gene signature in this group of patients was comparable with a virus response program. We conclude that the transcriptional signature of the PB cells reflects the heterogeneity of MS and defines a sub-population of RRMS patients, who exhibit an activated immune defense program that resembles a virus response program, which is supportive for a link between viruses and MS.

Case-Control Studies↗
PubMed2005

[Molecular unraveling of disease by means of DNA-microarrays].

Determination of the human genome sequence and the development of microarray technologies allowing the rapid measurement of all genes in the genome have generated new perspectives for our current biomedical research. Gene expression analysis will make a major contribution to our insight into the underlying biology of disease and will lead to improved methods for diagnostics, prognosis and treatment. Microarray studies create the possiblity to subclassify patients with diseases such as rheumatoid arthritis, diffuse large B-cell lymphoma and breast cancer, with both prognostic and therapeutic consequences. The simultaneous quantification of the activity of all genes in tissues or cells from patients by microarray technology, linked to the clinical parameters, creates a large number of data points, which cannot be analysed without the aid of the advanced application of bioinformatics. As a result, genomic research has become, in part, a bioinformatics discipline that will be integrated with clinical medicine. The microarray technology makes it possible to develop personalized medicine, with a more accurate diagnosis and prognosis for every patient and subsequently a tailored treatment strategy.

Arthritis, Rheumatoid↗
PubMed2004

Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study.

OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent-onset arthritis, we undertook this study to assess the predictive value of RA-specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent-onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in 64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95% confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti-CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.

Adolescent↗
PubMed2004

Is there a future for TNF promoter polymorphisms?

The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied -308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

Autoimmune Diseases↗
PubMed2004

Activation of the STAT1 pathway in rheumatoid arthritis.

BACKGROUND: Expression of signal transducer and activator of transcription 1 (STAT1), the mediator of interferon (IFN) signalling, is raised in synovial tissue (ST) from patients with rheumatoid arthritis (RA). OBJECTIVES: To determine the extent to which this pathway is activated by phosphorylation in RA synovium. Additionally, to investigate the cellular basis of STAT1 activation in RA ST. METHODS: ST specimens from 12 patients with RA and 14 disease controls (patients with osteoarthritis and reactive arthritis) were analysed by immunohistochemistry, using antibodies to STAT1, tyrosine phosphorylated STAT1, and serine phosphorylated STAT1. Lysates of cultured fibroblast-like synoviocytes stimulated with IFNbeta were analysed by western blotting. Phenotypic characterisation of cells expressing STAT1 in RA ST was performed by double immunolabelling for STAT1 and CD3, CD22, CD55, or CD68. RESULTS: Raised levels of total STAT1 protein and both its activated tyrosine and serine phosphorylated forms were seen in RA synovium as compared with controls. STAT1 was predominantly abundant in T and B lymphocytes in focal inflammatory infiltrates and in fibroblast-like synoviocytes in the intimal lining layer. Raised levels of STAT1 are sustained in cultured RA compared with OA fibroblast-like synoviocytes, and STAT1 serine and tyrosine phosphorylation is rapidly induced upon stimulation with IFNbeta. CONCLUSION: These results demonstrate activation of the STAT1 pathway in RA synovium by raised STAT1 protein expression and concomitantly increased tyrosine (701) and serine (727) phosphorylation. High expression of STAT1 is intrinsic to RA fibroblast-like synoviocytes in the intimal lining layer, whereas activation of the pathway by phosphorylation is an active process.

Adult↗
PubMed2003

Association of polymorphisms of the tumour necrosis factor receptors I and II and rheumatoid arthritis.

OBJECTIVE: To assess the role of polymorphisms of the tumour necrosis factor (TNF) receptors, TNF-RI (p55) and TNF-RII (p75) in the susceptibility to and severity of rheumatoid arthritis (RA) in Dutch patients. METHODS: A total of 319 consecutive RA patients, and a cohort of 90 female RA patients with detailed 12-yr follow-up were genotyped for the TNF-RI exon 1 (+36 A to G) and TNF-RII 3' UTR (+1690 T to C) polymorphisms. RESULTS: The frequencies of the TNF-RI and TNF-RII polymorphisms were determined in both patient groups and healthy controls, but no significant differences were found. To determine the relationship of these polymorphisms to disease severity, the extent of joint damage in the cohort of 90 female RA patients was analysed. No differences in severity were observed. CONCLUSION: These TNF-RI and TNF-RII polymorphisms were not found to be associated with susceptibility to or severity of RA in the Dutch population.

Antigens, CD↗
PubMed2003

Association between polymorphisms in the human chemokine receptor genes CCR2 and CX3CR1 and rheumatoid arthritis.

Cell trafficking into the rheumatoid synovium is thought to play an important role in the inflammation seen in rheumatoid arthritis. Chemokine receptors play a central role in this process, and several common variants are known, including the CCR2 variant, CCR2-64I, and two variants of the CX3CR1 gene, V249I and T280M. All three variants result in functional amino acid substitutions. We studied the association of these chemokine receptor variants with susceptibility to and severity of rheumatoid arthritis in two Dutch patient populations; 282 consecutive rheumatoid arthritis patients from a rheumatology outpatient clinic, and a cohort of 101 female rheumatoid arthritis patients, followed closely for a 12-year period, from whom hand and feet X-rays taken at three year intervals were scored and analyzed in this study. Although there was a trend towards increased severity of disease in patients carrying CX3CR1 variants, this was not independent of known risk factors. We found no evidence for a significant independent role for the CCR2 and CX3CR1 variants in the susceptibility to or severity of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2003

Discovery of distinctive gene expression profiles in rheumatoid synovium using cDNA microarray technology: evidence for the existence of multiple pathways of tissue destruction and repair.

Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria.

Arthritis, Rheumatoid↗
PubMed2003

Human IgG Fc-binding phage antibodies constructed from synovial fluid CD38+ B cells of patients with rheumatoid arthritis show the imprints of an antigen-dependent process of somatic hypermutation and clonal selection.

The persistent presence of rheumatoid factors (RFs) in the circulation is a characteristic phenomenon in patients with rheumatoid arthritis (RA). Recent data indicate that RFs associated with seropositive RA are derived from terminally differentiated CD20-, CD38+ plasma cells (PCs) present in synovial fluids of the inflamed joints. These cells were shown to secrete RFs actively and are thought to originate from germinal centre (GC)-like structures present in the inflamed synovium. To obtain a representative image of the structural properties of IgM and IgG RFs associated with RA, phage antibody display libraries were constructed from CD38+ PCs isolated from the inflamed joints of RF-seropositive patients with RA. Subsequently, human IgG Fc-binding monoclonal phage antibodies were selected and analysed. The data suggest that RA-associated RFs are encoded by a diverse set of VL and a more restricted set of VH regions. VH gene family usage of PC-derived IgM- and IgG-RFs was found to be restricted to the VH1 and 3 gene families, with a preference for VH3, and many different VL genes were shown to contribute to RF specificity. Clonally related VH as well as VL sequences were identified, based on the presence of identical CDR3 regions and shared somatic mutations. In this B cell selection process base-pair substitutions as well as deletions of triplets in CDR regions, leaving the transcripts in frame, were involved. Together, these data provide further evidence for an Ag-driven immune response in the terminal differentiation into RF-producing PCs in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a GC reaction.

ADP-ribosyl Cyclase↗
PubMed2002

Polyreactivity of human IgG Fc-binding phage antibodies constructed from synovial fluid CD38+ B cells of patients with rheumatoid arthritis.

Recent data indicate that rheumatoid factors (RFs) that occur in patients with rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated CD20-, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody display libraries were constructed using CD38+ plasma cells isolated from SFs of two RF-seropositive RA patients. The libraries were enriched for phage antibodies (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V genes were analysed. These data provided further evidence for an Ag-driven immune response in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a germinal center reaction. In the present study, the functional characteristics of these HuIgG Fc-binding monoclonal (mo) Phabs were further analysed in order to provide more insight into the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding moPhabs tested (n=48; derived from four different libraries) displayed polyreactivity. Structural analysis of the CDR3 regions revealed characteristic features of polyreactive Igs. Most H chain CDR3 regions harboured tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S). Supportive for a dominant role of VH in specificity, exchange of VL regions with a single VH region yielded moPhabs with similar specificities. All together, the data suggest the presence of an Ag-driven process in the joints of patients with RA, including somatic mutation and clonal selection entailing isotype switching, resulting in the differentiation of B cells into polyreactive RF-secreting plasma cells.

ADP-ribosyl Cyclase↗
PubMed2002

Relationship of polymorphisms of the Interleukin-1 gene cluster to occurrence and severity of rheumatoid arthritis.

Interleukin-1 (IL-1) has been implicated in the pathogenesis of rheumatoid arthritis (RA). We investigated whether IotaL-1 gene locus polymorphisms are associated with susceptibility to or severity of RA. Genotyping for IL-1alpha, IL-1beta and IL-1Ra single nucleotide polymorphisms (SNPs) performed in a cross-sectional group of 312 consecutive RA patients (RA-group 1) and a cohort of 94 incident female RA patients (RA-group 2) revealed that the rare IL-1RN + 2017 C allele was significantly increased in RA compared to controls (n = 245). A retrospective analysis in RA-group 1 showed no significant associations between IL-1 genotypes and disease severity. A prospective study in RA-group 2 demonstrated that the extent of joint destruction over 12 years was higher in patients genotyped heterozygous for the IL-1 A + 4845, IL-1B + 3953 and IL-1RN + 5111 SNPs compared to homozygous wildtype patients, although differences did not reach statistical significance. These data indicate that the IL-1RN + 2017 polymorphism is associated with susceptibility to RA.

Alleles↗
PubMed2002

Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter polymorphism.

IL-13 is strongly implicated in the development of asthma and chronic obstructive pulmonary disease (COPD). We previously identified an IL-13 promoter polymorphism (-1055 C to T) that is associated with allergic asthma. We now report an increased frequency of the -1055 T allele in COPD patients compared to healthy controls (P=0.002) and compared to a second control group consisting of smoking individuals with normal lung function (P=0.01). A closely linked IL-13 exon polymorphism is present at normal allelic frequencies (P=0.3 and 0.4, respectively). In addition, we observed a normal distribution of two IL-4 polymorphisms at positions -590 and +33 (P=0.2 and 0.9, respectively). These results could implicate a functional role for the IL-13 promoter polymorphism in the enhanced risk to develop COPD.

Adult↗
PubMed2001

Silencer activity of NFATc2 in the interleukin-12 receptor beta 2 proximal promoter in human T helper cells.

Interleukin 12 (IL-12) is a potent enhancer of interferon gamma production by activated T cells. The high-affinity IL-12 receptor (IL-12R) is a heterodimer of a beta1 and a beta2 subunit. Expression of the signaling IL-12Rbeta2 chain is usually low, as compared with the more abundant beta1 chain, and may be rate-limiting for IL-12 sensitivity. Little is known about the mechanisms controlling IL-12Rbeta2 gene expression. Reporter gene assays in IL-12Rbeta2-expressing Jurkat cells showed that truncation of the region from -151 to -61 abrogated promoter activity. The proximal promoter region does not contain a typical TATA box, suggesting a role for SP-1. Indeed, mutagenesis of the -63 SP-1 consensus site decreased transcription by 50%. Electrophoretic mobility shift experiments confirmed the binding of SP-1 and SP-3 at this site. In contrast, truncation of -252 to -192 increased promoter activity. Likewise, mutagenesis of the consensus nuclear factor of activated T cells site at -206 increased promoter activity by 70%, suggesting silencer activity of this element. Electrophoretic mobility shift experiments with primary Th (T helper) cells showed the formation of a specific, T-cell receptor-inducible complex at this site that is sensitive to cyclosporin A and supershifted with anti-NFATc2 in both Th1 and Th2 cells. Accordingly, cyclosporin A dose-dependently increased IL-12Rbeta2 mRNA expression. These first data on IL-12Rbeta2 gene regulation indicate a TATA-less promoter, depending on SP-1/SP-3 transcription factors, and a negative regulatory NFAT element at -206. This element may contribute to the overall low level of IL-12Rbeta2 expression on Th cells.

Base Sequence↗
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

Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis.

OBJECTIVE: To understand the regulation of anti-citrulline-containing peptide antibody (anti-CCP) production in rheumatoid arthritis (RA), production of anti-CCP by B cells derived from peripheral blood (PB), bone marrow (BM), and synovial fluid (SF) was examined. METHODS: Purified PB and SF B cells were isolated by negative selection and then cultured in the absence or presence of L-CD40 ligand cells and interleukin-10 or anti-CD3-activated T cells. Total IgM and IgM-anti-CCP were detected after 14 days of culture by enzyme-linked immunosorbent assay. Enzyme-linked immunospot assays were performed to analyze the frequency of cells that spontaneously produced IgM-anti-CCP in BM and SF B cells. RESULTS: IgM-anti-CCP autoantibodies were induced in PB B cells from healthy controls and RA patients following coculture with activated T cells or application of the CD40 activation system, whereas no production could be detected when PB B cells were cultured in the absence of a stimulus. SF and BM B cells from anti-CCP-seropositive RA patients, but not anti-CCP-seronegative patients, actively produced IgM-anti-CCP without stimulation. The frequency of spontaneous production of IgM-anti-CCP among the IgM-secreting cells ranged from 2.2% to 25%. CONCLUSION: These results indicate the presence of B cell precursors for anti-CCP autoantibodies that are able to produce antibodies upon stimulation in the PB B cell repertoire of healthy controls and patients with RA. In contrast, B cells that actively secreted anti-CCP were specifically present in the BM and SF compartment of anti-CCP-seropositive RA patients. The local presence of anti-CCP-secreting cells in the inflamed joints provides evidence for an antigen-driven maturation of CCP-specific B cells at the site of inflammation in RA.

Antibody Formation↗
PubMed2001

Presence of a population of CD20+, CD38- B lymphocytes with defective proliferative responsiveness in the synovial compartment of patients with rheumatoid arthritis.

OBJECTIVE: To provide a comprehensive understanding of the humoral immune response that takes place at the site of inflammation in rheumatoid arthritis (RA), we studied the functional properties of synovial B cells. In particular, the response to various modes of mitogen stimulation was investigated. METHODS: Purified synovial fluid (SF) B cells were cultured in the presence of CD40 ligand (CD40L)-expressing fibroblasts and cytokines, activated T cells, or phorbol myristate acetate (PMA)/ionomycin. Proliferation was determined by 3H-thymidine incorporation. Release of intracellular calcium was studied by flow cytometry. RESULTS: The inflamed joints of RA patients contained a population of CD20+,CD38- B cells with dramatically impaired mitogen responsiveness. Although the Ig-producing capacity was intact, these cells failed to proliferate in response to (a) CD40 in the presence of interleukin-2 (IL-2) and IL-10, (b) activated T cells, or (c) stimulation via the B cell receptor. Moreover, SF CD20+,CD38- B cells revealed a defective B cell receptor-induced Ca2+ influx, reminiscent of anergic B cells. Release of intracellular Ca2+ by ionomycin in the presence of the protein kinase C activator PMA did not restore the proliferative capacity. These findings indicate blockades in the proximal and distal intermediates involved in mitogen signaling. CONCLUSION: SF CD20+,CD38- B cells have functionally impaired proliferative responsiveness. The capacity of these cells to respond to activation by the production of Ig supports the notion that these cells might serve as Ig-producing effector cells and, as such, play a role in the pathophysiology of RA.

ADP-ribosyl Cyclase↗