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H Appel

Publications and source records attributed to H Appel.

At least 19 recordsLinked to original sources
PubMed2006

Massive creatine kinase elevations with quetiapine: report of two cases.

Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.

Adult↗
PubMed2005

Measuring the kernel of time-dependent density functional theory with x-ray absorption spectroscopy of transition metals.

The 2p-3d core-hole interaction in the L2.3 absorption spectra of the transition metals is treated within time-dependent density functional theory. A simple three-level model explains the origin of the strong deviations from the one-particle branching ratio and yields matrix elements of the unknown exchange-correlation kernel directly from experiment.

Journal Article↗
PubMed2004

Analysis of the CD8+ T cell response to the G1 domain of aggrecan in ankylosing spondylitis.

BACKGROUND: CD4+ T cell responses to the G1 domain of aggrecan in patients with ankylosing spondylitis (AS) were recently reported. Whether such an immune response can be seen in the CD8+ subpopulation has not yet been determined. OBJECTIVE: To determine if HLA-B27 restricted G1-specific CD8+ T cells are present in AS and to analyse immunodominant CD8+ T cell epitopes. METHODS: Peripheral blood mononuclear cells of 45 patients with AS were stimulated with overlapping 18-mer peptides covering the whole G1 protein. Results were compared with those for patients with rheumatoid arthritis (RA) and healthy controls. For epitope analysis, G1-specific interferon gamma positive (IFNgamma+) T cells were isolated by magnetic activated cell sorting. After in vitro expansion, CD8+ T cells were restimulated with 14 subpools of G1 peptides. T cells responding to G1 peptide subpools were quantified by flow cytometry according to IFNgamma secretion. Predicted peptides were subsequently confirmed by stimulation with single peptides. RESULTS: G1-specific CD8+ T cell responses were found in 29/45 (64%) patients with AS, 18/35 (51%) patients with RA, but not in healthy controls. Five CD8+ T cell epitopes were identified as immunodominant in five patients. However, the T cell response was not HLA-B27 restricted. Nonamer peptides with an HLA-B27 binding motif did not induce a T cell response. CONCLUSION: A G1 peptide-specific CD8+ T cell response is present in AS but also in patients with RA. It does not seem to be HLA-B27 restricted. Whether such a response has a role in the pathogenesis of AS needs clarification.

Adult↗
PubMed2003

Excitations in time-dependent density-functional theory.

An approximate solution to the time-dependent density-functional theory response equations for finite systems is developed, yielding corrections to the single-pole approximation. These explain why allowed Kohn-Sham transition frequencies and oscillator strengths are usually good approximations to the true values, and why sometimes they are not. The approximation yields simple expressions for Görling-Levy perturbation theory results, and a method for estimating expectation values of the unknown exchange-correlation kernel.

Journal Article↗
PubMed2001

Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases.

The association of HLA-B27 with ankylosing spondylitis and reactive arthritis is the strongest one known between an MHC class I Ag and a disease. We have searched the proteome of the bacterium Chlamydia trachomatis for HLA-B27 binding peptides that are stimulatory for CD8(+) cells both in a model of HLA-B27 transgenic mice and in patients. This was done by combining two biomathematical computer programs, the first of which predicts HLA-B27 peptide binding epitopes, and the second the probability of HLA-B27 peptide generation by the proteasome system. After preselection, immunodominant peptides were identified by Ag-specific flow cytometry. Using this approach we have identified for the first time nine peptides derived from different C. trachomatis proteins that are stimulatory for CD8(+) T cells. Eight of these nine murine-derived peptides were recognized by cytotoxic T cells. The same strategy was used to identify B27-restricted chlamydial peptides in three patients with reactive arthritis. Eleven peptides were found to be stimulatory for patient-derived CD8(+) T cells, of which eight overlapped those found in mice. Additionally, we applied the tetramer technology, showing that a B27/chlamydial peptide containing one of the chlamydial peptides stained CD8(+) T cells in patients with Chlamydia-induced arthritis. This comprehensive approach offers the possibility of clarifying the pathogenesis of B27-associated diseases.

Animals↗
PubMed2001

Anergy induction by dimeric TCR ligands.

T cells that recognize particular self Ags are thought to be important in the pathogenesis of autoimmune diseases. In multiple sclerosis, susceptibility is associated with HLA-DR2, which can present myelin-derived peptides to CD4(+) T cells. To generate molecules that target such T cells based on the specificity of their TCR, we expressed a soluble dimeric DR2-IgG fusion protein with a bound peptide from myelin basic protein (MBP). Soluble, dimeric DR2/MBP peptide complexes activated MBP-specific T cells in the absence of signals from costimulatory or adhesion molecules. This initial signaling through the TCR rendered the T cells unresponsive (anergic) to subsequent activation by peptide-pulsed APCs. Fluorescent labeling demonstrated that anergic T cells were initially viable, but became susceptible to late apoptosis due to insufficient production of cytokines. Dimerization of the TCR with bivalent MHC class II/peptide complexes therefore allows the induction of anergy in human CD4(+) T cells with a defined MHC/peptide specificity.

Amino Acid Sequence↗
PubMed2000

Kinetics of T-cell receptor binding by bivalent HLA-DR. Peptide complexes that activate antigen-specific human T-cells.

Monovalent major histocompatibility complex-peptide complexes dissociate within seconds from the T-cell receptor (TCR), indicating that dimerization/multimerization may be important during early stages of T-cell activation. Soluble bivalent HLA-DR2.myelin basic protein (MBP) peptide complexes were expressed by replacing the F(ab) arms of an IgG2a antibody with HLA-DR2.MBP peptide complexes. The binding of bivalent HLA-DR2.peptide complexes to recombinant TCR was examined by surface plasmon resonance. The bivalent nature greatly enhanced TCR binding and slowed dissociation from the TCR, with a t((1)/(2)) of 2.1 to 4.6 min. Soluble bivalent HLA-DR2.MBP peptide complexes activated antigen-specific T-cells in the absence of antigen presenting cells. In contrast, soluble antibodies to the TCR.CD3 complex were ineffective, indicating that they failed to induce an active TCR dimer. TCR/CD3 antibodies induced T-cell proliferation when bound by antigen presenting cells that expressed Fc receptors. In the presence of dendritic cells, bivalent HLA-DR2. MBP peptide complexes induced T-cell activation at >100-fold lower concentrations than TCR/CD3 antibodies and were also superior to peptide or antigen. These results demonstrate that bivalent HLA-DR. peptide complexes represent effective ligands for activation of the TCR. The data support a role for TCR dimerization in early TCR signaling and kinetic proofreading.

CD3 Complex↗
PubMed2000

Selective activation and expansion of high-affinity CD4+ T cells in resistant mice upon infection with Leishmania major.

Using multimers of MHC class II molecules linked to a peptide derived from the Leishmania LACK antigen, we have compared the fate of parasite-specific CD4+ T cells in resistant and susceptible mice transgenic for the beta chain of a LACK-specific TCR. Activated T cells were readily detected in the draining lymph nodes of infected animals. Although the kinetics of activation and expansion were similar in both strains, T cells from susceptible and resistant mice expressed low- and high-affinity TCR, respectively. As T cells from resistant mice produced more IFN-gamma and less IL-4 than those from susceptible animals, our results suggest that differences in TCR usage between MHC-matched animals may influence the development of the antiparasite immune response.

Amino Acid Sequence↗
PubMed1999

The 19 kDa protein of Yersinia enterocolitica O:3 is recognized on the cellular and humoral level by patients with Yersinia induced reactive arthritis.

OBJECTIVE: Gastrointestinal infections with Yersinia enterocolitica O:3 (YE O:3) can trigger reactive arthritis (ReA). The cellular immune response seems to be of pathogenic importance in ReA, since synovial fluid mononuclear cells (SFMC) of patients with ReA have been shown to recognize YE O:3 antigens. One of these, a 19 kDa protein identified as the beta-urease subunit of YE, has been identified as a target of SFMC. We investigated the humoral immune response to this antigen. METHODS: Sera of 32 patients with SFMC proliferation to YE O:3 diagnosed as having ReA (n = 16) and undifferentiated oligoarthritis (UOA, n = 16), and of patients with other rheumatic diseases (n = 32) and healthy persons (n = 12) were investigated for the humoral response to the biochemically purified 19 kDa protein of YE. Anti-19 kDa antibodies (ab) were identified by immunoblotting; ab to the Yersinia outer membrane protein (YOP) antigen were detected by ELISA. Proliferation of SFMC to 19 kDa and other YE O:3 antigens was tested in 12 patients in parallel. RESULTS: SFMC of all 32 patients with ReA and UOA showed the highest proliferation to YE O:3 (13.7+/-7.5), and 10/12 of these patients had the highest stimulation index to the 19 kDa (14.9+/-6.4). Anti-19 kDa IgG ab were detected in 93% and 55% and anti-19 kDa IgA ab in 56% and 36% of the ReA and UOA patients, respectively, compared to 26% (p = 0.002) and 8% (p = 0.001) in controls. IgG ab to the 19 kDa were sensitive (93%) and IgA ab specific (92%) to detect patients with a synovial cellular response to YE. IgG ab to YOP were found in 62% and IgA ab in 46% of the ReA patients and in 32% (p = 0.002) and 13% (p = 0.004) of the controls. CONCLUSION: This study provides evidence of a cellular and a significant humoral immune response to the 19 kDa protein in Yersinia triggered arthritis. Detection of IgG antibodies to the 19 kDa correlates with a synovial cellular immune response in YE induced arthritis. These antibodies can be used as a screening system for research and possibly also for clinical purposes, since absence of such antibodies seems to negatively predict YE O:3 directed immune reactivity.

Adolescent↗
PubMed1998

Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heat-shock protein 60 drives a major immune response.

OBJECTIVE: In Yersinia enterocolitica-triggered reactive arthritis (Yersinia ReA), the synovial T cell response is primarily directed against bacterial components, which are mostly unknown. This study was performed to investigate the synovial proliferative T cell response to a panel of recombinant Yersinia antigens in patients with Yersinia ReA and in controls. METHODS: Synovial fluid mononuclear cells (SFMC) were obtained from 4 patients with Yersinia ReA and from 14 patients with arthritides of different etiology. SFMC were stimulated with 5 recombinant Yersinia antigens (the 19-kd urease beta subunit, 13-kd ribosomal L23 protein, 32-kd ribosomal L2 protein, 18-kd outer membrane protein H, and Y. enterocolitica heat-shock protein 60 [hsp60]), and with human, Chlamydia trachomatis, and Borrelia burgdorferi hsp60. Three T cell clones specific for Y. enterocolitica hsp60 were generated from 1 patient with Yersinia ReA. Antigen-induced cytokine release was measured by enzyme-linked immunosorbent assay. RESULTS: SFMC from all 4 patients with Yersinia ReA responded to each of the Yersinia antigens except the 13-kd protein. These antigens were also recognized by SFMC from a subgroup of patients with undifferentiated arthritis (n = 4), but not by SFMC from other patients with arthritis of different etiology (n = 10). Y. enterocolitica hsp60 induced the strongest proliferative response in all cases. Two types of hsp60-reactive T cell clones could be obtained. One clone responded to all hsp60 variants, including the human variant, and showed a type 2 T helper (Th2)-like cytokine-secretion pattern. In contrast, another clone with specificity for the bacterial hsp60 proteins, but not the human equivalent, reacted with a more Th1-like pattern. CONCLUSION: In Y. enterocolitica-triggered ReA, at least 4 immunodominant T cell antigens exist, which might be used in lymphocyte proliferation assays to identify patients with Yersinia ReA. The hsp60 is a strong antigen, inducing both bacteria-specific and potentially autoreactive CD4+ T cells of both the Th1 and Th2 type.

Adolescent↗
PubMed1997

Comparative in-vivo and in-vitro 99Mo-time-differential-perturbed-angular-correlation studies on the nitrogenase MoFe protein and on other Mo species of different N2-fixing bacteria.

Klebsiella pneumoniae, Azotobacter vinelandii and Rhodobacter capsulatus were cultivated in media containing 99MoO4(2-) . The distribution of 99Mo in cells grown under conditions of repression and derepression of nitrogenase synthesis, was investigated by anion-exchange (DEAE-Sephacel) chromatography. Cells of K. pneumoniae took up MoO4(2-) only under conditions of derepression of nitrogenase thus serving the formation of the FeMo cofactor of the MoFe protein (Kp1) as the predominant Mo-containing species. In the case of A. vinelandii, under diazotrophic growth conditions, molybdenum was preferably incorporated into the nitrogenase MoFe protein (Av1). However, if excess amounts of molybdate were present in the medium, molybdenum was also bound to the Mo-storage protein. In the presence of 20 mM NH4+, conditions which completely repress nitrogenase formation, molybdenum accumulated in the Mo-storage protein exclusively. This protein proved to be unstable towards DEAE-Sephacel, apparently releasing all the molybdenum in form of MoO4(2-) during the fractionation procedure. R. capsulatus contained, in addition to the MoFe protein (Rc1), significant amounts of other not-yet-identified Mo species, which partially are formed under conditions of both, repression and derepression of nitrogenase. The Mo centers of all these compounds were characterized by measuring the nuclear quadrupole interaction of the process 99Mo(beta-)99Tc using time differential perturbed angular correlation spectroscopy. The quadrupole coupling constant (v(Q)) determined for the Mo center in MoFe proteins was consistently in the range 66-81 MHz. The values of the coupling constants determined with intact cells and with the isolated, partially purified, MoFe proteins were in very good agreement. For the Mo-storage protein of A. vinelandii, a quadrupole coupling constant of approximately 180 MHz was determined by measurements performed with nitrogenase-repressed cells as well as with gel-filtered cell-free extracts. Our work proves that the relevant study of hyperfine interactions allows the identification of the MoFe protein and also other Mo proteins in vivo as well as in vitro.

Azotobacter vinelandii↗
PubMed1997

[Autoantibodies against centrosomes in a patient with limited systemic sclerosis with ulcera cruris and arteriopathy--case report and review of the literature].

A 63 year old woman developed painful, up to 15 x 7 cm large ulcers on both lower limbs and an acral necrosis on the right big toe. The patient had no symptoms of intermittent claudication, but a history of 40 package years of cigarette smoking. Angiography showed circumscript stenosis of medium-sized vessels, deformed vessel segments, and rarification and obstruction of peripheral vessels. Arterial occlusive disease was diagnosed, and percutaneous transluminal angioplasty (PTA) of the right common iliac artery and both femoral arteries performed. However, despite documented patency of these vessels clinical symptoms worsened. The consulting rheumatologist found a history of Raynaud's syndrome, acral necrosis of the fourth finger of the right hand, sclerodactylia, and microstomia. Capillaroscopy revealed megacapillaries and vessel rarification. High titers of antinuclear antibodies with specificity for centrosomes (1:10240), which have not been described in this context to date, were detected and limited systemic sclerosis of the CREST type was diagnosed. Treatment with iloprost (50 micrograms/day i.v.) and pulsed cyclophosphamide (800 mg i.v./month) resulted in almost complete healing of the crural and digital ulcers and a significant reduction of the analgetic medication.

Antibodies, Antinuclear↗
PubMed1995

Development of a finite element model of the human skull.

Head injury is the most frequent injury resulting from traffic accidents. Head injury mechanisms are difficult to study experimentally due to the variety of impact conditions involved, as well as ethical issues, such as the use of human cadavers and animals. Finite element modeling is a comprehensive technique through which human head impact tolerance can be studied. A finite element human head model would ideally allow for the assessment of the injurious effects of different impact conditions and enable the development of enhanced head injury and protection criteria. The paper describes the development of a three-dimensional finite element model based on the anatomical features of the adult human cranium. The complex cranial geometry was measured from a series of two-dimensional computer tomography images. The CT scans were transformed with a self-developed preprocessor into a finite element mesh. To model the skull's impact responses, valid material properties are required. The mechanical characteristics of cranial bone were investigated experimentally at Heidelberg University's Institute for Forensic Medicine. To create a sample of material properties for use in the human head model, statistical analyses of the experimental results were undertaken. The tests were modeled with the finite element method and a numerical material model representing the mechanical properties of the human skull bone was developed. The first approach to validate the model and to investigate different boundary conditions by using experimental data is shown.

Accidents, Traffic↗
PubMed1994

The evolutionarily conserved ribosomal protein L23 and the cationic urease beta-subunit of Yersinia enterocolitica O:3 belong to the immunodominant antigens in Yersinia-triggered reactive arthritis: implications for autoimmunity.

BACKGROUND: Reactive arthritis (ReA) is a T cell mediated inflammatory process. The immune response is primarily directed against a triggering organism, although autoimmunity has been invoked in long-lasting, antibiotic-resistant disease. Although a variety of different species are known to trigger Reactive arthritis, the clinical manifestations are strikingly similar as well as closely associated to the HLA-B27 (70%). MATERIALS AND METHODS: Various antigenic fractions and single antigens of Yersinia enterocolitica were prepared, and their immunological activity was assessed by proliferation of synovial fluid mononuclear cells from 10 Reactive arthritis patients. The gene encoding one hitherto unknown antigen has been sequenced. Nonapeptides deduced from sequences of the target antigens were tested in an assembly assay. RESULTS: Two immunodominant proteins of Yersinia enterocolitica were found, one being the urease beta-subunit and the other the 50 S ribosomal protein L23. The latter has been sequenced and belongs to the evolutionarily conserved ribosomal proteins with homology to procaryotes and eucaryotes. One nonapeptide derived from the urease beta-subunit was identified as a possible epitope for HLA-B27-restricted cytotoxic T cells by its high affinity. This epitope is also highly conserved. CONCLUSION: Sharing of conserved immunodominant proteins between different disease triggering microorganisms could provide an explanation of the shared clinical picture in Reactive arthritis. Moreover, autoimmunity in Reactive arthritis might be mediated by antigen mimicry between evolutionarily conserved epitopes of ribosomal proteins and their host analogs.

Adolescent↗
PubMed1993

Metal-induced conformational changes in transferrins.

Recent studies on iron-loaded transferrins have revealed a conformational change upon binding iron due to a domain closure. It has been suggested that the domain closure may be the key for the receptor recognition of the metal loaded transferrin (Grossmann et al., 1992). Small angle X-ray scattering has been used to provide direct structural information on the conformational changes that may take place upon the binding and release of different metals to the transferrins in solution. The data show that In3+ and Cu2+ induce the same domain closure as Fe3+; Al3+ causes a conformational change of somewhat smaller magnitude while Hf4+ does not induce any conformational change. The results are discussed in terms of the molecular recognition of metal loaded transferrin by the receptor.

Metals↗
PubMed1992

X-ray solution scattering reveals conformational changes upon iron uptake in lactoferrin, serum and ovo-transferrins.

X-ray solution scattering has been used for studying the structural changes that take place upon uptake and release of iron from serum and chicken ovo-transferrin and human lactoferrin. In the case of chicken ovo-transferrin, data have been obtained for both the intact protein and the isolated N and C-lobes with and without iron. These studies reveal that both lobes undergo a change that is consistent with an opening of the inter-domain cleft when iron is removed from the protein. We suggest that the conformational change of the protein increases the specificity of receptor binding and that the closed configuration of the iron-loaded protein is one, or perhaps the, decisive step in the mechanism for receptor-mediated endocytosis.

Animals↗