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Biomedical subjects

Tom W J Huizinga

Publications and source records attributed to Tom W J Huizinga.

At least 55 records · Page 3Linked to original sources
PubMed2005

Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.

OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.

Arthritis, Rheumatoid↗
PubMed2005

Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954.

BACKGROUND: Loosening is a major complication in prosthesis surgery. To stabilize loosened orthopedic implants, the interface tissue surrounding the implant must be removed. As an alternative to manual removal, we explored the possibility of removing the tissue by gene-directed enzyme prodrug therapy. In the current study we investigated whether interface cells can be transduced by an HAdV-5 vector carrying the E.coli-derived nitroreductase gene and sensitized to the prodrug CB1954. METHODS: The gene transfer efficiency into cultures of diploid human interface cells was tested by exposing these cells to various concentrations of Ad.CMV.LacZ. Subsequently, we studied the susceptibility of cells to the NTR/CB1954 combination. RESULTS: X-gal staining of the Ad.CMV.LacZ-transduced cell cultures revealed that, at 200 plaque-forming units (pfu)/cell, 74% of the cells expressed the LacZ gene. Infection with an NTR construct in interface cell lines resulted in a 60-fold sensitization to the prodrug CB1954. In addition we observed that iotrolan (Isovist) contrast medium had no effect on viability of the cells. However, the presence of the contrast medium completely inhibited adenovirus-mediated gene transfer. CONCLUSIONS: From these data we conclude that HAdV-5-based vectors carrying nitroreductase can be used to sensitize interface tissue. Instead of contrast medium the clinical protocol will use an alternative visualization procedure.

Adenoviridae↗
PubMed2005

Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans.

Expression of the transcription factor Foxp3 (forkhead box P3) has been implicated as a key element for CD25(+) T regulatory cell function in mice. However, literature over similar involvement of FOXP3 expression in human T regulatory cells is limited. We found that, unlike murine cells, FOXP3 mRNA expression could be induced in human CD25(-) and CD8(+) peripheral blood mononuclear cells, which were both negative for FOXP3 mRNA expression after isolation. Expression of FOXP3 mRNA began as soon as 24-40 hours after stimulation, demonstrating a correlation between activation and FOXP3 mRNA expression in human cells. In order to determine whether FOXP3 expression is confined to CD4(+)CD25(+) T cells with a regulatory phenotype, we analyzed several well-defined T-cell clones and lines with various specificities. Surprisingly, expression of FOXP3 mRNA was detected in all clones and limited to the CD25(hi) populations. Nonetheless, the CD25(hi) fraction did not display regulatory properties because both the CD25(hi) and CD25(low) populations exhibited a similar proliferative- and interferon-gamma-secreting potential after antigenic stimulation. These results indicate that FOXP3 expression in humans, unlike mice, may not be specific for cells with a regulatory phenotype and may be only a consequence of activation status.

Animals↗
PubMed2005

Understanding the genetic contribution to rheumatoid arthritis.

PURPOSE OF REVIEW: The identification of the genetic variants that mediate the risk for susceptibility and severity of rheumatoid arthritis will allow the development of new drug targets and also increase the ability to predict disease course. Technical and methodologic progress has fueled the advances in this field. RECENT FINDINGS: The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. This genetic variant regulates the threshold of T cell activation. Intriguingly, this variant is a risk factor for diabetes as well. Moreover, it has been shown that multiple genetic variants in one pathway (both in a transcription factor, RUNX-1, as in the transcription factor binding site of RUNX1 in the SLC22A4 gene) can each confer very small risks but by gene-gene interactions can confer a ninefold risk for rheumatoid arthritis. These genetic risk factors have been found to confer risk for multiple autoimmune diseases. Phenotype-genotype interactions were described by the enhanced prevalence of a rheumatoid arthritis-specific autoantibody (anti-cyclic citrullinated peptide antibodies) in rheumatoid arthritis patients that harbor the rheumatoid arthritis-associated human leukocyte antigen class II genes, the shared epitope alleles. An environmental factor, smoking was demonstrated to confer risk for rheumatoid arthritis, especially in patients positive for both shared epitope and rheumatoid arthritis-specific anti-cyclic citrullinated peptide antibodies. SUMMARY: Two new pathways, T cell receptor signaling and a hematopoietic-specific signal transduction pathway, have been discovered that allow future pharmacologic interventions. The description of the new genetic risk factors and the interaction with environmental triggers as well as phenotypic features are gradually expanding the ability to predict disease susceptibility and course.

Arthritis, Rheumatoid↗
PubMed2005

The role of interleukin 10 promoter polymorphisms in the susceptibility of distal interphalangeal osteoarthritis.

OBJECTIVE: The interleukin (IL)-10 single nucleotide promoter polymorphism (SNP) -2849A is associated with decreased IL-10 production as measured by lipopolysaccharide (LPS) stimulated whole blood cultures. A low innate production of IL-10 using the same assay is associated with an increased risk of familial osteoarthritis (OA). We investigated the association of 7 novel SNP located downstream of the IL-10 transcription start site: -2849,-2763, -1330, -1082, -819, and -592, constituting the 4 ancient haplotypes, with distal interphalangeal (DIP) OA. METHODS: The study population comprised consecutive patients with and without radiological DIP OA (Kellgren-Lawrence score of > or = 2 in one joint) aged 40-70 years from a cohort of subjects with different types of arthritis in an early stage referred to an Early Arthritis Clinic (EAC). DNA typing for IL-10 SNP as well as radiographs of the hands were performed at clinic enrolment. Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and psoriatic arthritis were excluded. RESULTS: The distribution of DIP OA and IL-10 SNP were comparable to representative samples of the Dutch population. In the cohort of 172 subjects, 57 had DIP OA (33%) and 115 (67%) had no DIP OA. No significant association was found between DIP OA and IL-10 SNP and the 4 common haplotypes IL10.1, IL10.2, IL10.3, and IL10.4. CONCLUSION: Our data suggest that IL-10 SNP, including -2849, which is associated with differential production, do not play a major role in the susceptibility of DIP OA.

Adult↗
PubMed2004

Control of systemic B cell-mediated autoimmune disease by nonmyeloablative conditioning and major histocompatibility complex-mismatched allogeneic bone marrow transplantation.

Systemic autoimmune disease (AID) can be controlled with conventional therapies in most patients. However, relapses are common, leading to progressive disability and premature death. Nonmyeloablative conditioning and allogeneic bone marrow transplantation (BMT) could be an effective treatment for severe AID, because of mild toxicity of the conditioning and the potential benefits of donor chimerism. We examined the effects of this treatment in experimental autoimmune arthritis. Our results demonstrate the induction of complete donor chimerism and significant suppression of disease activity. No clinical graft-versus-host disease (GVHD) was observed. The beneficial effects were most likely caused by the elimination of plasma cells producing pathogenic autoantibodies, because these antibodies disappeared rapidly after BMT. Although this type of treatment was effective in organ-specific T-cell-mediated AID, the present study provides convincing evidence that nonmyeloablative conditioning and allogeneic BMT can effectively treat severe B-cell-mediated AID with a systemic inflammatory component.

Animals↗
PubMed2004

Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis.

The class of immune response against autoantigens could profoundly influence the onset and/or outcome of autoimmune diseases. Until now, there is only limited information on the antigen-specific balance between proinflammatory and regulatory responses in humans. Here we analyzed the natural immune response against a candidate autoantigen in rheumatoid arthritis, human cartilage glycoprotein-39 (HC gp-39). Peripheral blood mononuclear cells from healthy individuals reacted against HC gp-39 with the production of IL-10 but not IFN-gamma. Ex vivo assays indicated that the naturally occurring HC gp-39-specific immune response in bulk is powerful enough to suppress antigen-specific recall responses, demonstrating that rather than being unresponsive, the HC gp-39-directed immune response in healthy individuals shows a strong bias toward a regulatory phenotype. Moreover, CD4(+) T cell lines directed against HC gp-39 expressed CD25, glucocorticoid-induced tumor necrosis factor receptor, and Foxp3 molecules and were capable of suppressing antigen-specific T cell responses. Cell-cell contact was required for this suppression. As opposed to healthy individuals, the HC gp-39-directed immune response in 50% of patients with rheumatoid arthritis exhibits polarization toward a proinflammatory T helper 1 phenotype and is significantly less powerful in suppressing antigen-specific recall responses. Together these findings indicate that the presence of HC gp-39-specific immune responses in healthy individuals may have an inhibitory effect on inflammatory responses in areas where HC gp-39 is present. Furthermore, these data indicate that the class of HC gp-39-directed immune response in rheumatoid arthritis patients has shifted from an antiinflammatory toward a proinflammatory phenotype.

Adipokines↗
PubMed2004

Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels.

The hallmark of fibrosis is the excessive accumulation of collagen. The deposited collagen contains increased pyridinoline cross-link levels due to an overhydroxylation of lysine residues within the collagen telopeptides. Lysyl hydroxylase 2b (LH2b) is the only lysyl hydroxylase consistently up-regulated in several forms of fibrosis, suggesting that an enhanced LH2b level is responsible for the overhydroxylation of collagen telopeptides. The present paper reports the effect of profibrotic cytokines on the expression of collagen, lysyl hydroxylases and lysyl oxidase in normal human skin fibroblasts, as well as the effect on pyridinoline formation in the deposited matrix. All three isoforms of TGF-beta induce a substantial increase in LH2b mRNA levels, also when expressed relatively to the mRNA levels of collagen type I alpha2 (COL1A2). The TGF-beta isoforms also clearly influence the collagen cross-linking pathway, since higher levels of pyridinoline cross-links were measured. Similar stimulatory effects on LH2b/COL1A2 mRNA expression and pyridinoline formation were observed for IL-4, activin A, and TNF-alpha. An exception was BMP-2, which has no effect on LH2b/COL1A2 mRNA levels nor on pyridinoline formation. Our data show for the first time that two processes, i.e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines.

Activins↗
PubMed2004

Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level.

Interleukin-10 (IL10) is a cytokine with key regulatory and anti-inflammatory function involved in the pathogenesis of various diseases. Although the large interindividual differences in the production of IL10 have been extensively associated with polymorphisms and haplotypes of the IL10 gene, surprisingly little evidence exists that this variation is actually dictated by IL10 haplotypes. Using the technique of allele-specific transcript quantification, the ratio between two alleles (A and G) of the IL10 gene was characterized in 15 healthy heterozygous individuals. Two groups were identified whereby donors in group 1 exhibited a 1 : 1 ratio, whereas those in group 2 exhibited a ratio>1 (P<0.0017). We found that donors heterozygous for haplotype IL10.2 (one of the four ancient IL10 haplotypes) were only prevalent in the group that showed higher allelic expression ratios. In this study we show that IL10 alleles are indeed differentially transcribed in cells from heterozygous individuals and that IL10 haplotypes dictate production of IL10. These findings show that interindividual differences in IL10 protein levels can be explained at the transcriptional level.

Chromosome Mapping↗
PubMed2004

Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming.

With the increase in life expectancy, death from cardiovascular disease has risen greatly. There is increasing evidence that inflammation plays an important role in cardiovascular disease. We postulate that the development of cardiovascular disease in old age is a late consequence of evolutionary programming for a pro-inflammatory response to resist infections in early age. In 311 women, aged 85 yr old, the production of the pro- and anti-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined in lipopolysaccharide-stimulated whole blood samples and studied prospectively in association with cardiovascular mortality. High TNF-alpha was a risk factor for death from cardiovascular disease (relative risk [RR] = 1.56; 95% confidence interval [CI]: 1-2.40), whereas high IL-10 was protective (RR = 0.58; 95% CI: 0.40-0.85). A genetic variant of the IL-10 gene promoter, which is associated with lower IL-10 production, was found to predispose to a 2.8-fold higher cardiovascular mortality risk (95% CI: 1.17-6.60). Reproductive success, which was studied as a measure of evolutionary programming because it trades off with early survival by pro-inflammatory resistance genes, was negatively associated with an increasing production of TNF-alpha (RR = 0.77; 95% CI: 0.68-0.88), while a positive association with IL-10 was found (RR = 1.22; 95% CI: 1.05-1.41). We suggest that cardiovascular mortality is a late consequence of evolutionary programming for a pro-inflammatory response.

Adult↗
PubMed2004

Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis.

OBJECTIVE: In the K/BxN mouse model, autoantibodies against glucose-6-phosphate isomerase (GPI) cause arthritis. The relevance of this model for human disease remains a subject of controversy. We set out to determine whether GPI autoantibodies occur in patients with rheumatoid arthritis (RA) and, if so, at what stage of the RA. METHODS: Using an enzyme-linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI. Patients were grouped according to disease duration and presence of rheumatoid nodules, rheumatoid vasculitis, and Felty's syndrome, which are extraarticular complications of RA. RESULTS: Elevated levels of autoantibodies against GPI were present in 5% of patients with uncomplicated RA and 4% of controls. In RA complicated by extraarticular manifestations, anti-GPI antibodies were observed in 18% of patients with rheumatoid nodules, 45% of patients with rheumatoid vasculitis, and 92% of patients with Felty's syndrome. CONCLUSION: In patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications.

Adult↗
PubMed2004

Association of the interleukin-1 gene cluster with radiographic signs of osteoarthritis of the hip.

OBJECTIVE: To study the role of the interleukin-1 beta gene (IL1B) and the IL-1 receptor antagonist gene (IL1RN) in relation to the occurrence of radiographic osteoarthritis (ROA) in the hip, knee, and hand and disc degeneration of the spine. METHODS: The study population consisted of a random sample of 886 subjects (ages 55-65 years) from a population-based cohort (the Rotterdam study). Two polymorphisms within IL1B (3953C>T and -511C>T) and one within IL1RN (the variable-number tandem repeat [VNTR]) were analyzed and used in an association study of the occurrence of ROA. Haplotyping and simultaneous logistic regression analysis were performed to investigate whether the associations observed were independent. RESULTS: Associations with a predisposition for hip ROA were observed for heterozygous and homozygous carriers of the rare IL1B allele -511T (crude odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.0-3.4 and OR 2.9, 95% CI 1.4-6.3, respectively) and of the IL1RN VNTR allele 2 (crude OR 2.0, 95% CI 1.1-3.4 and OR 3.3, 95% CI 1.4-7.8, respectively). An additive effect was observed for carriers of risk alleles of both polymorphisms, with a significant linear-by-linear association (P = 0.00022). CONCLUSION: Our findings suggest that the IL-1 gene cluster polymorphisms may play a significant role in the pathogenesis of OA of the hip.

Aged↗
PubMed2004

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis.

OBJECTIVE: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). METHODS: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. RESULTS: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). CONCLUSION: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

Adolescent↗
PubMed2004

Antigen-specific immunomodulation of collagen-induced arthritis with tumor necrosis factor-stimulated dendritic cells.

OBJECTIVE: Dendritic cells (DCs) are crucial for the initiation of T cell immunity and therefore play an important role in the initiation and regulation of immune responses in arthritis. Full mobilization of effector T cells depends on the proper maturation of DCs. Current evidence indicates that the type of T cell response induced is crucially dependent on the activation status of the DCs. In this study, we explored the immunologic effects of differentially matured DCs on the development of collagen-induced arthritis (CIA). METHODS: Bone marrow-derived DCs were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Before immunization with bovine type II collagen (CII) protein, mice were repeatedly injected with DCs that had been pulsed with CII. Immature, semimature, or fully mature DCs were injected. Mice were boosted on day 21 after CII immunization, and the disease course was monitored. RESULTS: While vaccination with immature or lipopolysaccharide-activated DCs had no significant effect on the disease course, administration of antigen-loaded, tumor necrosis factor (TNF)-modulated DCs propagated in GM-CSF with or without interleukin-4 resulted in a delayed onset of arthritis and a lower clinical score. The response was antigen-specific, since TNF-treated DCs pulsed with a control antigen did not modify the disease course. A specific decrease in the collagen-specific "Th1-associated" IgG2a response was observed, whereas IgG1 titers were unaffected. CONCLUSION: CIA can be prevented through vaccination with TNF-matured DCs in an antigen-specific manner. These findings provide a rationale for immunotherapy using DCs in rheumatoid arthritis.

Animals↗
PubMed2004

Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study.

Aging is associated with an impaired capacity of the immune system to respond properly to danger signals, such as infection and cancer. Here, we provide evidence that an impaired innate immune response, as measured by a low production capacity of pro- and anti-inflammatory cytokines upon ex vivo standardized danger signalling with bacterial LPS, is predictive for frailty in elderly people: participants who at age 85-year produced low levels of LPS-induced IL-1beta, IL-6, TNF-alpha and IL-1Ra and IL-10, were found to have a more than 2-fold elevated overall mortality risk, independent of chronic illnesses (relative risk is 2.21, 95% confidence interval 1.27-3.82, P = 0.005), compared to peers with a higher production of any of the pro- and/or anti-inflammatory cytokines. A significant genetic association with the IL-10 promoter gene was found, indicating that people who are genetically predisposed low cytokine producers are at a higher risk of losing the capacity to respond properly to danger signals with aging. We conclude that a malfunctioning innate immune response predicts frailty in old age and is under specific (immuno-) genetic control.

Aged↗
PubMed2004

Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon.

Fibrosis is characterized by an excessive accumulation of collagen which contains increased levels of pyridinoline cross-links. The occurrence of pyridinolines in the matrix is an important criterion in assessing the irreversibility of fibrosis, which suggests that collagen containing pyridinoline cross-links significantly contributes to the unwanted collagen accumulation. Pyridinoline cross-links are derived from hydroxylated lysine residues located within the collagen telopeptides (hydroxyallysine pathway). Here, we have investigated whether the increase in hydroxyallysine-derived cross-links in fibrotic conditions can be ascribed to an increased expression of one of the lysyl hydroxylases (LH1, LH2 with its splice variants LH2a and LH2b, or LH3) and/or to an increased expression of lysyl oxidase (LOX). In fibroblast cultures of hypertrophic scars, keloid and palmar fascia of Dupuytren's patients, as well as in activated hepatic stellate cells, increased levels of LH2b mRNA expression were observed. Only minor amounts of LH2a were present. In addition, no consistent increase in the mRNA expression levels of LH1, LH3 and LOX could be detected, suggesting that LH2b is responsible for the overhydroxylation of the collagen telopeptides and the concomitant formation of pyridinolines as found in the collagen matrix deposited in long-term cultures by the same fibrotic cells. This is consistent with our previous observation that LH2b is a telopeptide lysyl hydroxylase. We conclude that the increased expression of LH2b, leading to the increased formation of pyridinoline cross-links, is present in a wide variety of fibrotic disorders and thus represents a general fibrotic phenomenon.

Amino Acids↗