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Biomedical subjects

R Duchmann

Publications and source records attributed to R Duchmann.

At least 37 records · Page 2Linked to original sources
PubMed1997

[Follow-up of Crohn's disease: can hydro-MRI replace fractionated gastrointestinal passage examination?].

PURPOSE: To compare the value of hydro-MRI with follow-through examinations in the follow-up of Crohn's disease. METHOD: 22 patients known to be suffering from Crohn's disease were examined via 1.5 T-MR system; an oral contrast examination using 1000 ml of a 2.5% mannitol solution was performed in all patients. T2-weighted TSE sequences and T1-weighted SE sequences were performed before and after the intravenous injection of Gd-DTPA. To reduce movement artifacts caused by peristalsis of the gut, intravenous injection of 40 mg Buscopan was given. The findings of hydro-MRI were compared with the follow-through examinations. RESULTS: In the upper gastrointestinal tract, the follow-through examination showed clear advantages compared with hydro-MRI for the demonstration of inflammatory changes in the gut; Hydro-MRI was, however, somewhat more reliable in the ileum and colon. It was also more sensitive than the follow-through for the demonstration of enteric fistulae (four as compared with two cases), and in demonstration extraluminal changes (free fluid in six against zero, and inflammatory adherent loops (four against zero)). Amongst the 22 patients, hydro-MRI was equal (in 10) or better (in 8) than the follow-through examination for demonstrating the intestinal manifestations of Crohn's disease, and follow-through was better in only four. CONCLUSION: For follow-up of Crohn's disease, hydro-MRI is at least as good as follow-through examination, and is even preferable, because of the absence of radiation exposure of the usually young patients.

Administration, Oral↗
PubMed1997

Normal interleukin-12 production in individuals with antibodies to Helicobacter pylori.

It is increasingly recognized that the inability of the immune system to clear H. pylori infection is caused by an inadequate immune response and is associated with chronic gastric inflammation. To further investigate the cellular immune response to H. pylori, we studied PBMC from 31 H. pylori antibody-negative and 16 H. pylori antibody-positive individuals for H. pylori-induced DNA synthesis, secretion of the Th1-type cytokine IFN-gamma and secretion of IL-12, a cytokine produced by bacteria-stimulated monocyte/macrophages and a potent inducer of antibacterial immune responses and Th1-type T cells. All experiments were performed using Y. enterocolitica 03 as control. Our results demonstrate that DNA synthesis, IFN-gamma production and IL-12 production induced by H. pylori or Y. enterocolitica 03 did not differ significantly between H. pylori antibody-positive and H. pylori antibody-negative individuals. However, in the H. pylori-positive group there was a tendency, although not statistically significant, to produce less IFN-gamma in response to H. pylori but not Y. enterocolitica. These results demonstrate that monocyte/macrophages from H. pylori-positive individuals secrete normal amounts of IL-12 upon bacterial challenge and suggest that the decreased production of IFN-gamma in H. pylori-positive individuals observed in previous studies is selective for H. pylori and not caused by decreased IL-12 secretion.

Antibodies, Bacterial↗
PubMed1997

Cellular and humoral immunity to the 60-kD heat shock protein in inflammatory bowel disease.

BACKGROUND: Mycobacteria have been considered a possible etiological agent in Crohn's disease. Since cross-reactivity between epitopes of mycobacterial and self-heat shock protein might represent a potential disease mechanism, we determined the cellular and humoral immune responses to the mycobacterial and the human 60-kD heat shock protein, as well as various control antigens. METHODS: We studied samples from 19 patients with Crohn's disease, 12 patients with ulcerative colitis, and from 19 healthy individuals. T cell responses were studied using a standard proliferation assays to purified recombinant mycobacterial and human 60-kD heat shock protein. Antibody levels were measured by establishing an enzyme-linked immunosorbent assays to recombinant purified 60-kD heat shock protein. RESULTS: The proliferative responses to the mycobacterial and the human 60-kD heat shock protein were closely correlated, but the cellular immune response to both antigens was not significantly different between the two patient groups and healthy controls. In addition, antibody levels to heat shock protein were also not significantly different between the three groups. CONCLUSIONS: These results argue strongly against a role for mycobacterial heat shock protein in the pathogenesis of Crohn's disease. However, in view of previous data demonstrating overexpression of 60-kD heat shock protein in inflammatory Crohn's disease tissue, this considerable cellular and humoral autoreactivity suggests an important immunoregulatory role for the 60-kD heat shock protein.

Adult↗
PubMed1997

Immune responses towards intestinal bacteria--current concepts and future perspectives.

The intestinal mucosa constitutes an important barrier as it separates each individual from a large array of antigens within the bowel lumen. These luminal antigens may either be derived from pathogens or may be derived from harmless constituents such as ingested food or the normal intestinal flora. The dichotomy of potentially harmful and potentially harmless antigens encountered by the mucosal immune system poses the important task that, with regard to bacteria-derived antigens, the gut associated immune system is required to mount an efficient host defense against pathogenic bacteria but to maintain at the same time the regulatory control mechanisms which protect the human organism from hyperresponsiveness, and thus chronic inflammation, towards antigens from the normal intestinal flora. In the present review, we discuss variable host and bacterial factors which are likely to determine whether the immune response to pathogenic or normal intestinal bacteria will have beneficial or detrimental consequences for the human organism. Using infections with the prototype enteropathogens V. cholerae and enteropathogenic E. coli (ETEC), Y. enterocolitica induced reactive arthritis (ReA) and in more detail, inflammatory bowel diseases (IBD) as exemplary clinical situations, we review current hypotheses of how bacteria or their products are encountered by cellular components of the specific immune system and how this may relate to disease pathogenesis and the development of new treatment strategies.

Antigens, Bacterial↗
PubMed1996

Reciprocal regulation of mucosal surface IgA+ B cells by Ig receptor cross-linking and CD40 ligand.

In the present study, we analyze the role of Ig receptor cross-linking in T cell-dependent stimulation of both preswitch (surface IgM+ (sIgM+/sIgD+) B cells and postswitch (sIgA+) B cells. We demonstrate that purified sIgA+ B cells pretreated with anti-IgA-dextran at low concentrations (10 and 100 ng/ml) exhibited an increased response to activated T cells, whereas pretreatment with higher doses (1 and 10 micrograms/ml) led to a profound suppression of IgA secretion (> or = 90%). The suppressive effect of anti-IgA-dextran was accentuated in the presence of IL-2 and attenuated in the presence of IL-4. Anti-IgA-dextran pretreatment had no effect on sIgA+ B cell survival. sIgM+/sIgD+ B cells pretreated with anti-IgD-dextran or anti-IgM-dextran did not show significant inhibition. The increased susceptibility of sIgA+ B cells, but not of sIgM+/sIgD+ B cells, to Ig cross-linking-mediated suppression was confirmed in cross-linking studies with the same Ab (anti-kappa-dextran). Importantly, anti-IgA-dextran-mediated suppression could be reversed by stimulation of sIgA+ B cells with fibroblasts expressing CD40L; such a reversal required persistent exposure to cells expressing high levels of CD40L. These studies imply that Ig receptor cross-linking renders postswitch sIgA+ B cells unresponsive to subsequent stimulation via activated T cells, but this unresponsiveness is overcome by a persistent high level CD40L signal.

Animals↗
PubMed1996

[Enteropathic spondylarthritis in chronic inflammatory bowel diseases: prevalence, manifestation pattern and HLA association].

BACKGROUND: Enteropathic spondylarthropathies (SpA) are the most frequent extraintestinal manifestation of the chronic inflammatory bowel disease (IBD), Crohn's disease (CD) and Ulcerative Colitis (UC). It was the aim of the present study, to analyze a large number of IBD patients for the prevalence and pattern of joint manifestation and the association of SpA with the extend of bowel involvement and HLA-haplotype. PATIENTS AND METHODS: 521 patients (409 CD and 112 UC) were prospectively analyzed over a period of one year. SpA was diagnosed on the basis of an appropriate patient history as well as clinical, radiological and immunoserological parameters. RESULTS: SpA was diagnosed in 10.7% of all CD and 14.4% of all UC patients. In 26.8% of all patients symptoms of SpA occurred prior to and in 14.4% simultaneously with IBD. 28.1% of all patients presented with isolated peripheral arthritis, 26.8% of all patients showed an isolated involvement of the spine or sacroiliic joints and 45.1% of all patients presented with combined involvement. 2/12 UC patients with SpA suffered from rectosigmoiditis, 5/12 from partial colitis and 5/12 had pancolitis. In CD patients with SpA, 8/59 had isolated colitis, 8/59 ileocolitis and 31/59 isolated small bowel involvement. There was a positive correlation between SpA and HLA-B27 (p < 0.01). CONCLUSION: Enteropathic spondylarthropathies are an important extraintestinal manifestation of IBD. Spondylarthropathies occur irrespective of the extend of IBD and frequently become symptomatic prior to IBD. These and recent data describing inflammatory bowel disease in patients with SpA of unknown etiology suggest that both diseases have a common pathogenetic background.

Adult↗
PubMed1996

Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12.

There is now increasing evidence that hyperresponsiveness towards intestinal flora is a crucial event in the pathogenesis of inflammatory bowel disease (IBD). In support of this hypothesis, we recently described in humans that tolerance exists towards indigenous intestinal flora but is broken in active IBD lesions. In the present study, we have attempted to transfer this model into mice from different genetic backgrounds (BALB/c, SJL/J, C3H/HeJ). We found that mononuclear cells from spleen, small bowel and large bowel of mice do not proliferate, i.e. are tolerant when exposed to bacterial sonicates derived from autologous intestine (BsA) but do proliferate, i.e. are immune when exposed to bacterial sonicates derived from the heterologous intestine of syngenic littermates (BsH). Furthermore, we demonstrate that both local and systemic tolerance to BsA is broken in a murine model of chronic intestinal inflammation induced by the hapten reagent 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics several important characteristics of Crohn's disease. Tolerance to BsA was restored and TNBS-induced colitis was abrogated in mice systemically treated with interleukin (IL)-10 or antibodies to IL-12. Treatment specifically restored tolerance to BsA, but did not suppress proliferation to BsH. In summary, we here report a new model for the study of immunity and tolerance towards bacterial products. Our data suggest that tolerance to BsA is an important protective mechanism and that restoration of tolerance intestinal flora by IL-10 and antibodies to IL-12 may be of potential therapeutic utility in patients with inflammatory bowel disease.

Animals↗
PubMed1996

The T cell receptor (TCR) in HLA-B27-restricted T cell responses--an introduction.

Recent data indicate that cytotoxic T lymphocytes (CTL) are involved in the pathogenesis of HLA-B27-associated spondylarthropathies. In the absence of clearly defined "arthritogenic" bacterial or self peptides that are presented by HLA-B27 and recognized by such CD8+CTL, one approach has been to investigate the T cell repertoire of lesional cellular infiltrates by determining T cell receptor (TCR) variable (V) gene segment frequencies. Furthermore, the TCR V alpha and V beta chains of HLA-B27-restricted CTL clones, notably the putative peptide-contacting CDR3-regions of these TCRs, have been sequenced. This article will give a short review of the current literature on the topology of the TCR and its hypervariable CDR3 region, TCR repertoire diversity in rheumatic diseases and will concentrate on TCR V alpha and V beta gene usage in HLA-B27-restricted T cell responses.

Cytotoxicity, Immunologic↗
PubMed1996

Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1).

VCAM-1 was first identified as an adhesion molecule induced on human endothelial cells (HEC) by inflammatory cytokines such as IL-1, tumour necrosis factor (TNF), and lipopolysaccharide (LPS). The molecule binds to a variety of leucocytes, including B cells, T cells, basophils, eosinophils and monocytes. Vascular expression of VCAM-1 has been associated with a number of disease states, including rheumatoid arthritis and vasculitis. The detection of anti-neutrophil cytoplasmic antibodies (ANCA), especially to proteinase 3 (PR3), has become important in the diagnosis of Wegener's granulomatosis (WG) and related vasculitides. Recently we were able to demonstrate a direct effect of anti-PR3 antibodies on neutrophil-endothelial interactions (Blood 1993; 82:1221). Binding of anti-PR3 antibodies to their antigen translocated into the membrane of HEC leads to an enhanced adhesion of neutrophils via induction of E-selectin (Clin Exp Immunol 1993; 94:440). The aim of this study was to investigate the effect of anti-PR3 antibodies on the expression of VCAM-1. HEC were isolated from umbilical vein and cultured on microtitre plates. After preincubation with purified anti-PR3 antibody, purified control antibodies (SS-A, SS-B, RNP) (IgG and F(ab')2 fragments) or different cytokines (controls), VCAM-1 was detected on the surface of unfixed HEC by cyto-ELISA and polymerase chain reaction analysis. Incubation of HEC with anti-PR3 antibodies led to a marked increase of endothelial VCAM-1 expression with a peak after 8 h. Incubation with TNF-alpha also led to maximal VCAM-1 expression after 4-6 h (control). Increased adhesion of T lymphocytes to HEC after binding of anti-PR3 antibodies to their antigen could be confirmed by performing adherence assays. This effect could be inhibited by antibodies to VLA-4. In conclusion, we have been able to show that cytokine-like effects of anti-PR3 antibodies on HEC are not limited to induction of neutrophil adhesion. Anti-PR3 antibodies may thus contribute to the regulation of T lymphocyte migration from the blood by HEC in ANCA-related vasculitides.

Antibodies↗
PubMed1996

HLA-B27-restricted cytotoxic T lymphocyte responses to arthritogenic enterobacteria or self-antigens are dominated by closely related TCRBV gene segments. A study in patients with reactive arthritis.

Identification of the T-cell receptors (TCR) used by synovial cytotoxic T lymphocytes (CTL) of patients with reactive arthritis (ReA) may be crucial to better understanding the pathogenetic mechanism underlying the HLA-B27 association of spondylarthropathies. The authors, therefore, sequenced 25 TCRB chains from HLA-B27-restricted CD8+ CTL clones and two clonal lines specific for self- or Yersinia enterocolitica antigen isolated from synovial fluids of 3 HLA-B27+ patients with ReA and PBL of one healthy HLA-B27+ individual. Fourteen non-HLA-B27-restricted CTL served as controls. Both autoreactive and Y. enterocolitica specific HLA-B27-restricted CTL used a highly limited set of VB genes with preferential rearrangement of three closely related VB families (VB 13, 14, 17), suggesting that these families contain a preferred site for contact with the HLA-B27 molecule. In addition, the presence of limited TCRBJ usage, limited heterogeneity in CDR3 sequences and dominant clones from individual donors among these CTL indicate that TCRB chain usage is further restricted by a limited set of peptides bound to the HLA-B27 molecule. Limited TCR usage by SF CTL of ReA patients may lay a basis for therapeutical manipulation of the T-cell response in the spondylarthropathies.

Adult↗
PubMed1996

Bacteria-specific T-cell clones are selective in their reactivity towards different enterobacteria or H. pylori and increased in inflammatory bowel disease.

In the present study the authors investigated the T-cell response to different enterobacteria or Helicobacter pylori and tested the hypothesis that the frequency of bacteria-specific T cells is increased in the intestine of patients with active inflammatory bowel disease (IBD), i.e. Crohn's disease (CD) and ulcerative colitis (UC). The analysis of a large panel of T-cell clones (Tc) (n = 888) from peripheral blood, non-inflamed and inflamed intestine from IBD patients and control individuals shows that both peripheral blood and intestinal T-cell clones were selectively stimulated by either Salmonella typhimurium, Yersinia enterocolitica 03, Escherichia coli or Helicobacter pylori sonicates, that only < 3% of all bacteria-reactive Tc were crossreactive and that proliferation to bacterial sonicates was inhibited by anti-MHC class II antibody. In addition, bacteria-specific Tc from IBD patients were more frequently isolated from inflamed intestine than from peripheral blood (P = 0.0039) or non-inflamed intestine. These data, from a large number of T-cell clones, are the first systematic analysis describing the response of individual T cells towards different bacterial species (ssp.). They show that T cells with specificity for distinct antigens or superantigens that are characteristic for a defined bacteria ssp. are present in normal, and increased in inflamed, IBD-intestine. These bacteria-specific Tc may play a role in IBD pathogenesis.

Adult↗
PubMed1996

TCRB junctional regions from HLA-B27-restricted T cells and HLA-B27 binding peptides display conserved hydropathy profiles in the absence of primary sequence homology.

Analysis of formal amino acid sequence identity between different TCRB chain (TCRB) hypervariable regions (CDR3) is commonly used to localize relevant sites of TCR antigen interaction or to yield indirect information on unknown corresponding antigens. However, this analysis sometimes fails to demonstrate expected concordances, e.g. between CDR3 from T cell clones of identical reactivity. Since this may be due to ignorance of physico-chemical parameters, we have now use hydropathy profile analysis as an additional method to examine TCRB-CDR3 and putative peptide antigens. Superimposed hydropathy plots (SHOP) of 20 TCRB-CDR3 from HLA-B27-restricted autoreactive and Yersinia enterocolitica-specific synovial cytotoxic T lymphocytes (CTL) isolated from patients with reactive arthritis (ReA) revealed restricted distribution of polar amino acids resulting in characteristically different SHOP profiles between the two CTL groups. Similarly, Yersinia-derived and self nonapeptides known to bind HLA-B27 differed in SHOP profiles. To validate the method we have extended SHOP analysis to published TCRB sequence data from additional TCRB-CDR3 from peptide-specific CTL but not in TCRB from HLA-B27-alloreactive CTL or non-HLA-B27-restricted control CTL. We here demonstrate that SHOP may improve TCR-CDR3 sequence analysis by detection of structural constraints which remain cryptic by conventional sequence analysis. Our data suggest that electrostatic properties rather than rigid sequence motifs determine T cell specificities.

Amino Acid Sequence↗
PubMed1996

Rare pre-core stop-codon mutant nt. 1897 predominates over wide-spread mutant nt. 1896 in an unusual course of chronic hepatitis B.

We present a patient with an unusual course of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B who had repeated reactivations of his disease progressing to cirrhosis with terminal liver failure. Each flare up presented like an acute hepatitis with very high titres of hepatitis B virus (HBV) and high inflammatory activity followed by rapid clearance of viraemia. The pre-core genome of HBV isolated from sera during 5 years of follow up was analysed. Direct sequencing of polymerase chain reaction (PCR) products derived from consecutive sera showed a rare pre-core stop-codon mutation at nucleotide (nt.) 1897 G --> A with an accompanying mutation nt. 1857 C --> T as well as a stop-codon mutation nt. 1896 G --> A. By cloning and sequencing of PCR products the mutant strain with mutation nt. 1897 was shown to predominate over viral strains with a mutation nt. 1896 during the course of disease, although the stop-codon mutation nt. 1896 in general is observed more frequently. Both mutations allow viral replication by stabilizing the encapsidation signal 'epsilon'. This allowed HBV replication at a very high level as observed during flare ups. The absence of HBeAg may be responsible for the massive cytotoxic T-cell response towards hepatocytes which might explain the rapid progression to liver cirrhosis although no, or very little, HBV replication was observed for long periods. However, there is no clear explanation as to why the nt. 1897 mutant strain overwhelmed the other virus strains.

Adult↗
PubMed1996

Differential usage of T-cell receptor V beta gene families by CD4+ and CD8+ T cells in patients with CD8hi common variable immunodeficiency: evidence of a post-thymic effect.

In this study, we report that differences between T-cell receptor (TCR) V beta gene family usage in CD4+ and CD8+ T cells are significantly greater in a subgroup of patients with common variable immunodeficiency (CVI) and high levels of activated CD8+ T cells (CD8hi CVI) than in controls (P < 0.001). In CD8hi CVI patients, such differences were also significantly greater for V beta 12 than for other V beta families. As the causes of the differential usage of V beta gene families by CD4+ and CD8+ T cells are under investigation, it was interesting that the combined differences between V beta gene family usage in the CD4+ and CD8+ T-cell subpopulations as a whole were significantly lower than the combined differences between individual V beta gene family usage in either CD4+ or CD8+ T-cell subpopulations (P < 0.001 in both control and CD8hi CVI patients). Further, the pattern of V beta gene family usage in CD4+ T cells was remarkably similar to that in CD8+ T cells in both groups. These data strongly suggest that differences in V beta gene family usage arising from coselection by major histocompatibility complex (MHC) class I versus MHC class II restriction elements do not fundamentally distort 'basic' V beta gene family usage patterns. They also support the concept that differences in CD4+ and CD8+ T-cell V beta gene family usage, which were increased in CD8hi CVI, can arise from high-affinity interactions between disease-associated antigens or superantigens and T cells in the post-thymic T-cell compartment.

Base Sequence↗
PubMed1995

Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD)

Hyporesponsiveness to a universe of bacterial and dietary antigens from the gut lumen is a hallmark of the intestinal immune system. Since hyperresponsiveness against these antigens might be associated with inflammation, we studied the immune response to the indigenous intestinal microflora in peripheral blood, inflamed and non-inflamed human intestine. Lamina propria monocuclear cells (LPMC) isolated from inflamed intestine but not peripheral blood mononuclear cells (PBMC) of IBD patients with active inflammatory disease strongly proliferated after co-culture with sonicates of bacteria from autologous intestine (BsA). Proliferation was inhibitable by anti-MHC class II MoAb, suggesting that it was driven by antigen. LPMC from adjacent non-inflamed intestinal areas of the same IBD patients and PBMC or LPMC isolated from non-inflamed intestine of controls and patients with IBD in remission, in contrast, did not proliferate. PBMC or LPMC which had been tolerant to bacteria from autologous intestine, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestine (BsH). This proliferation was associated with an expansion of CD8+ T cells, increased expression of activation markers on both CD4+ and CD8+ lymphocyte subsets, and production of IL-12, interferon-gamma (IFN-gamma), and IL-10 protein. These results show that tolerance selectively exists to intestinal flora from autologous but not heterologous intestine, and that tolerance is broken in intestinal inflammation. This may be an important mechanism for the perpetuation of chronic IBD.

Adult↗
PubMed1995

Thymoma and pure red cell aplasia in a patient with systemic lupus erythematosus.

We present the case of a female patient with a diagnosis of systemic lupus erythematosus (SLE) at the age of 54 years. At the age of 63 years, she suffered from malignant thymoma and 3 years after removal of the thymoma a diagnosis of pure red cell aplasia (PRCA) was established. This is, to our knowledge, the first report of the occurrence of SLE, thymoma and PRCA in the same patient. The case is discussed with regard to the already known associations between these diseases.

Adult↗
PubMed1993

Quantitative measurement of human T-cell receptor V beta subfamilies by reverse transcription-polymerase chain reaction using synthetic internal mRNA standards.

Quantitative determination of T-cell receptor (TCR) V beta expression is necessary to define the changes in TCR-V beta subfamily expression that occur during T-cell maturation and selection and to detect alterations of the TCR-V beta repertoire that may be associated with human diseases. Here we describe and validate a quantitative reverse transcription-polymerase chain reaction (RT-PCR) technique to determine human TCR-V beta subfamily mRNA levels (as well as other mRNA species), based on the use of synthetic poly(A) mRNA internal standards that are coprocessed with native (sample) mRNA transcripts. The technique allows simultaneous reverse transcription of sample and standard mRNA and thus obviates errors arising during reverse transcription. In addition, the technique allows coamplification of several concentrations of standard mRNA (cDNA) with sample mRNA (cDNA) under conditions in which these mRNAs amplify with equal efficiency; thus, it avoids errors resulting from saturation of competition effects. Finally, the technique is sensitive to lower than 1.5-fold differences in input mRNA. To apply the technique, we also describe methods for the generation of poly(A) mRNA internal standards that can be used to quantitate TCR-V beta 2/6/7 and TCR-C beta mRNA.

Antigens, Bacterial↗