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Biomedical subjects

B O Roep

Publications and source records attributed to B O Roep.

At least 19 recordsLinked to original sources
PubMed2006

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes.

RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P=0.002), 38.7% (P=0.007) and 41.0% (P=0.01)) and were less frequently present in patients compared to controls (P=0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P=0.003; odds ratio (OR)=0.55; confidence interval (CI): 0.37-0.83; case/control: P=0.03; OR=0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile.

Adolescent↗
PubMed2006

Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5.

The authors studied the HLA profile of 23 white Dutch patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK Ab+ MG) and found an association with HLA-DR14-DQ5 (odds ratio 8.5; 95% CI 3.9 to 18.7; p = 4.9 x 10(-5)). Fifty-two percent of the patients carried the DR14 allele compared with 5% of the controls (p = 1.0 x 10(-8)). This association between MuSK Ab+ MG and a relatively rare HLA haplotype differs from the previously described association of early-onset acetylcholine receptor Ab+ MG with HLA-B8-DR3.

Adolescent↗
PubMed2006

Mechanisms of antibody immunotherapy on clonal islet reactive T cells.

Clinical intervention trials evaluating the efficacy of antibody immunotherapy in type 1 diabetes are in progress. We tested effects on prediabetic islet antigen-specific autoreactive T cells of antithymocyte globulin (ATG) and humanized monoclonal antibodies against CD3 (ChAglyCD3) or CD25 (daclizumab) with regard to downmodulation of the target protein, proliferation, cytokine production, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and survival. ATG leads to depletion of autoreactive CD4+ T cells by ADCC, CDC, and apoptosis, whereas anti-CD3 and anti-CD25 inhibited T-cell autoreactivity in a nondepleting fashion. ATG treatment led to a cytokine burst of Th1- and Th2-associated cytokines. Modulation of cytokine release through humanized monoclonal antibodies was moderate and selective: anti-CD25 led to increased release of IL-2 and reduced production of TNFalpha, whereas anti-CD3 decreased release of interferon-y and IL-5 and increased secretion of IL-10. ATG and the humanized monoclonal antibodies displayed contrasting mechanisms of action.

Antibodies, Monoclonal↗
PubMed2006

Association of interferon-gamma and interleukin 10 genotypes and serum levels with partial clinical remission in type 1 diabetes.

We studied whether serum interferon (IFN)-gamma or interleukin (IL)-10 levels and their corresponding functional polymorphic genotypes are associated with partial remission of type 1 diabetes (T1D). A multi-centre study was undertaken in patients with newly diagnosed T1D and matched controls. T1D patients were followed for 3 months and characterized for remission status. Partial clinical remission was defined as a daily insulin dose <or= 0.38 units/kg/24 h with an HbA1c <or= 7.5%. Thirty-three patients and 32 controls were phenotyped for serum concentrations of IFN-gamma and IL-10 and genotyped for functional polymorphisms of the IFN-gamma and IL-10 genes. Sixteen of 25 informative patients (63%) remitted. Serum IFN-gamma concentrations were significantly decreased in remitters but increased in non-remitters compared to controls, and did not change over time in any group. IFN-gamma genotypes corresponded with serum levels in controls and non-remitters, but not in remitters who displayed the lowest serum IFN-gamma levels despite more often carrying high-producing IFN-gamma genotypes. Neither the frequency of IL-10 genotypes nor serum IL-10 concentration differed between patients and controls. The combination of high-producing IFN-gamma genotype together with low serum IFN-gamma concentration at the time of diagnosis provided a strong positive predictive value for remission. Serum IFN-gamma concentrations predicted by genotype and observed serum levels were discordant in remitters, suggestive of regulation overruling genetic predisposition. Although high-producing genotypes were less frequent in remitters, they were predictive of remission in combination with low serum IFN-gamma levels. These data imply that remission is partially immune-mediated and involves regulation of IFN-gamma transcription.

Analysis of Variance↗
PubMed2006

Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus.

AIMS: The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines. SUBJECTS AND METHODS: Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group. CONCLUSION: Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.

Autoantibodies↗
PubMed2005

[Transplantation of the islets of Langerhans in patients with diabetes mellitus type 1].

Since 1921 and until recently, insulin by injection has been the only treatment for patients with diabetes mellitus type 1. After pancreas transplantation, which became possible in 1977, the next logical step to cure patients with diabetes mellitus type 1 is the transplantation of the islets of Langerhans. In the last few years, the results of islet transplantation are markedly improved thanks to developments in the isolation technique and better immunosuppressive protocols. Ongoing problems in islet transplantation are allo-immunity, auto-immunity and the growing shortage of donor pancreases. Alternatives to pancreas donation, be it post-mortem or from a living donor, could be: sources for islets are xenotransplantation with the aid of pig islets and beta-cell neogenesis from embryonic stem cells or pancreatic duct cells.

Diabetes Mellitus, Type 1↗
PubMed2005

Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population.

Protein tyrosine phosphatase PTPN22 is involved in the negative regulation of T-cell responsiveness. Recently, the association of a coding variant of the PTPN22 gene-R620W(1858C>T) with a number of autoimmune diseases has been described. Therefore, we tested the association of PTPN22 1858*T allele in Dutch early onset type 1 diabetes (T1D) and rheumatoid arthritis (RA) patients, as well as celiac disease (CD) patients, for which no previous study of PTPN22 has been reported. The PTPN22 variant was strongly associated with T1D in cases vs controls (P=2 x 10(-7), OR=2.3, 95% CI=1.7-3.1) as well as in a transmission disequilibrium test in nuclear trio's (P=9 x 10(-9), OR=3.3, CI=2.1-5.0), RA (case/control: P=0.003, OR=1.8 CI =1.2-2.6), but not CD, in spite of a trend of increased homozygosity (P=0.05) and early age at onset (P=0.01). PTPN22 is not generally associated with T-cell mediated autoimmune diseases, although it might play a role in the CD patients with early clinical manifestation.

Adolescent↗
PubMed2004

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice.

AIMS/HYPOTHESIS: An important prerequisite for the initiation of pancreatic islet inflammation is the recruitment of pathogenic T cells. We investigated the in vivo migration patterns of human islet-reactive T cell clones after transfer into compromised hosts. METHODS: NOD-scid mice were injected with a mixture of human autoreactive T cells and antigen-presenting cells. Survival and migration of T cells was analysed by fluorescence-activated cell sorter and immunohistochemical analysis of various tissues. RESULTS: Autoreactive T cells and antigen-presenting cells survived at least 14 days in vivo and accumulated in spleen, pancreatic tissue and pancreas draining lymph nodes, but not elsewhere, as early as 4 days after transfer. This homing was dependent on co-injection of human antigen-presenting cells loaded with autoantigen. Finally, we found that this process is enhanced by streptozotocin treatment. Streptozotocin treatment did not affect the constitutive homing to pancreas draining lymph nodes. Histological analysis of pancreatic tissue sections showed some autoreactive T cells around the islets of Langerhans, comparable to early peri-islet insulitis. However, the majority of pancreas-infiltrating T cells accumulated around blood vessels in the exocrine pancreas. All T cell clones expressed the chemokine receptor CXCR3 that is associated with homing to insulitic lesions in men and mice. CONCLUSIONS/INTERPRETATION: Our study provides the first evidence of in vivo accumulation in pancreatic tissue of islet-reactive T cells derived from type 1 diabetic patients. The fact that such T cells do not penetrate islets is in line with the concept that additional factors may be required for the entry of T cells into inflamed islets to become diabetogenic.

Animals↗
PubMed2004

Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 Type 1 diabetes.

AIMS/HYPOTHESIS: Preproinsulin is a target T cell autoantigen in human Type 1 diabetes. This study analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (autoantibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabetic patients. METHODS: A preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4(+)CD45RA(-) and CD4(+)CD45RA(+) T cell subfractions, representing memory and naive and recently primed T cells respectively. RESULTS: In CD4(+) T cell subsets we identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabetic HLA-matched control subjects. In Ab+ subjects, a C-peptide epitope C13-29 and insulin B-chain epitope B11-27 were preferentially recognised, whereas insulin-treated Type 1 diabetic patients reacted to native insulin and B-chain epitope B1-16. In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNgamma, IL-2) and Th2 (IL-4) cytokines was detectable, wheras in CD45RA(+) and CD45RA(-) subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNgamma content. In insulin-treated Type 1 diabetic patients, naive and recently primed CD4(+) cells were characterised by increasd IFNgamma, TNFalpha, and IL-5. CONCLUSIONS/INTERPRETATION: Our data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2-dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes. Characteristic immunodominant epitopes and cytokine patterns distinguish diabetic patients and Ab+ subjects from HLA-matched healthy individuals. This could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials.

Adolescent↗
PubMed2004

Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes.

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10(*)R2, IL-4(*)C, VDR(*)C and IGF-I(*)wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.

Adolescent↗
PubMed2004

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease.

Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha 1, beta 1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

Case-Control Studies↗
PubMed2004

Insulin-like growth factor 1 promoter polymorphism influences insulin gene variable number of tandem repeat-associated risk for juvenile onset type 1 diabetes.

Insulin-like growth factor 1 (IGF1) plays an important role in the development and function of pancreatic beta-cells and contributes to infant growth, which we recently reported to be associated with type 1 diabetes (T1D). Here, we studied an IGF1 microsatellite in 206 families with T1D and its interaction with the polymorphism near the insulin (INS) gene variable number of tandem repeats. The IGF1 microsatellite was associated with T1D (P = 0.045), which was mainly caused by a protective effect of the 194 bp allele (36% transmission to affected offspring). Interestingly, co-segregation of this IGF1 194 bp allele affected the risk of INS alleles. These results provide the first evidence for an association of IGF1 with T1D and imply that co-inheritance of these functional genetic variants of IGF1 and insulin predispose to T1D.

Chromosome Mapping↗
PubMed2002

Modulation of autoimmunity to beta-cell antigens by proteases.

AIMS/HYPOTHESIS: Proteases are used in therapy for autoimmune diseases yet the mechanism of their action remains to be determined. We studied the immunological basis of protease therapy in the context of Type I (insulin-dependent) diabetes mellitus. METHODS: We studied the effects of proteases (trypsin, papain, chymotrypsin, bromelain) on immune reactivity of a series of autoreactive T-cell clones from prediabetic subjects and patients with a recent onset of Type I diabetes and specific to the autoantigens GAD65, IA-2 and insulin-secretory granule protein. RESULTS: Cell surface expression of adhesion, co-stimulatory and homing molecules on both antigen-presenting cells and T cells was changed after protease treatment. Cytokine analyses showed a selective inhibition of proinflammatory (Th-1) but not Th-2 cytokine production. Autoreactive T-cell proliferation was inhibited at pharmacological serum concentrations, whereas non-specific proliferation to phytohaemagglutinin was not affected at these concentrations. Preincubation experiments on T cells and antigen-presenting cells separately showed that this effect was mediated by APCs, but not T-cells. CONCLUSION/INTERPRETATION: Proteases have pleiotropic immunological effects supporting an immunomodulatory potential for the intervention of chronic inflammatory diseases and Th-1 mediated oedema formation.

Amino Acid Sequence↗
PubMed2002

Elevated IL-16 levels in patients with systemic lupus erythematosus are associated with disease severity but not with genetic susceptibility to lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by several immunological abnormalities. The pathogenic importance of T cells in this disease is well established. Interleukin-16 (IL-16) is a cytokine which is mainly produced by CD8+ T cells and induces chemotaxis of CD4+ T cells and monocytes. IL-16 levels have been shown to be elevated in SLE patients in a cross-sectional study, but the mechanism is unknown. To explore whether the increased IL-16 levels are associated with genetic background or the disease itself, we investigated the IL-16 level in healthy first-degree family members of SLE patients and SLE patients who were followed over time with regard to disease activity. We observed high IL-16 levels in SLE patients with severe disease compared to SLE patients with non-severe disease and healthy controls. Furthermore, IL-16 levels in first-degree relatives were not different from those in healthy controls. These results suggest that high IL-16 levels are associated with severity of SLE, but not with genetic susceptibility to SLE. Finally, we followed the disease activity of SLE patients over time, which showed significant correlation between the SLE disease activity index and IL-16, ESR and the complement components C3, C4 and CH50. In conclusion, these results implicate an association of IL-16 with SLE.

Adult↗
PubMed2002

Molecular mimicry in type 1 diabetes: immune cross-reactivity between islet autoantigen and human cytomegalovirus but not Coxsackie virus.

Type 1 diabetes is caused by a T cell-mediated autoimmune destruction of the pancreatic beta cells. Molecular mimicry between viral pathogens and beta cell protein has been a popular theory to explain loss of tolerance in type 1 diabetes. However, functional data in support of this hypothesis have been lacking, presumably because the homologies were defined on the basis of linear similarities in peptide sequences, which ignores the criteria of HLA versus T cell receptor contact residues in peptide epitopes required for T cell recognition. We applied a HLA-binding dedicated peptide microarray analysis using autoreactive T cell clones specific for the autoantigen GAD65 to determine the algorithm of T cell recognition by this given T cell clone. The subsequent database search identified a 100% fit with cytomegalovirus peptide, which was subsequently shown to be recognized by these clonal T cells. However, T cell clones reactive with linear homologies previously described as putative candidates for T cell cross-reactivity between GAD65 and Coxsackie virus peptide were unable to recognize the homologous counterparts.

Amino Acid Sequence↗