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Biomedical subjects

Antje Mueller

Publications and source records attributed to Antje Mueller.

10 recordsLinked to original sources
PubMed2006

Beta-(1-->3)-D-glucan modulates DNA binding of nuclear factors kappaB, AT and IL-6 leading to an anti-inflammatory shift of the IL-1beta/IL-1 receptor antagonist ratio.

BACKGROUND: Beta-1-->3-D-glucans represent a pathogen-associated molecular pattern and are able to modify biological responses. Employing a comprehensive methodological approach, the aim of our in vitro study was to elucidate novel molecular and cellular mechanisms of human peripheral blood immune cells mediated by a fungal beta-1-->3-D-glucan, i.e. glucan phosphate, in the presence of lipopolysaccharide (LPS) or toxic shock syndrome toxin 1 (TSST-1). RESULTS: Despite an activation of nuclear factor (NF) kappaB, NFinterleukin(IL)-6 and NFAT similar to LPS or TSST-1, we observed no significant production of IL-1beta, IL-6, tumor necrosis factor alpha or interferon gamma induced by glucan phosphate. Glucan phosphate-treated leukocytes induced a substantial amount of IL-8 (peak at 18 h: 5000 pg/ml), likely due to binding of NFkappaB to a consensus site in the IL-8 promoter. An increase in IL-1receptor antagonist (RA) production (peak at 24 h: 12000 pg/ml) by glucan phosphate-treated cells positively correlated with IL-8 levels. Glucan phosphate induced significant binding to a known NFIL-6 site and a new NFAT site within the IL-1RA promoter, which was confirmed by inhibition experiments. When applied in combination with either LPS or TSST-1 at the same time points, we detected that glucan phosphate elevated the LPS- and the TSST-1-induced DNA binding of NFkappaB, NFIL-6 and NFAT, leading to a synergistic increase of IL-1RA. Further, glucan phosphate modulated the TSST-1-induced inflammatory response via reduction of IL-1beta and IL-6. As a consequence, glucan phosphate shifted the TSST-1-induced IL-1beta/IL-1RA ratio towards an anti-inflammatory phenotype. Subsequently, glucan phosphate decreased the TSST-1-induced, IL-1-dependent production of IL-2. CONCLUSION: Thus, beta-1-->3-D-glucans may induce beneficial effects in the presence of pro-inflammatory responses, downstream of receptor binding and signaling by switching a pro- to an anti-inflammatory IL-1RA-mediated reaction. Our results also offer new insights into the complex regulation of the IL-1RA gene, which can be modulated by a beta-1-->3-D-glucan.

Bacterial Toxins↗
PubMed2006

Recovery of olfactory function following closed head injury or infections of the upper respiratory tract.

OBJECTIVE: To investigate the outcome of olfactory function in patients with olfactory loss following infections of the upper respiratory tract (post-URTI) or head trauma. DESIGN: Retrospective patient-based study. SETTING: Smell and Taste Outpatient Clinic at a university hospital. PATIENTS: A total of 361 patients (228 women, 133 men) were included. MAIN OUTCOME MEASURES: Olfactory function was assessed using the "Sniffin' Sticks" test battery, which result in a threshold, discrimination, and identification score. The mean interval between first and last visit was 14 months. RESULTS: In comparing the overall threshold, discrimination, and identification scores between the last and first visit, olfactory function improved in 26% of the patients whereas it decreased in 6%. The cause of olfactory impairment had a significant effect on the recovery rate of olfactory function. Within the post-URTI group (n = 262), 32% of the patients improved, but in the posttraumatic group (n = 99) only 10% improved. In patients with post-URTI olfactory loss, a negative correlation was found between age and recovery of olfactory function. In general, the factor "sex" had no significant effect on recovery of smell function. CONCLUSIONS: To our knowledge, the series of patients presented herein is the largest in the literature to date in which standardized testing methods were used to assess the progression of impaired olfaction. It showed that the rate of improvement of olfactory function was significantly higher in patients with post-URTI dysosmia compared with patients with posttraumatic dysosmia. During an observation period of approximately 1 year, more than 30% of patients with post-URTI olfactory loss experienced improvement, whereas only 10% of patients with posttraumatic olfactory loss experienced improvement. Furthermore, age plays a significant role in the recovery of olfactory function.

Adolescent↗
PubMed2006

Extrapyramidal symptoms in Wilson's disease are associated with olfactory dysfunction.

Wilson's disease is a rare autosomal recessive disorder characterized by the accumulation of copper, mainly in the liver and the brain. As copper accumulation in the brain leads to disturbances in basal ganglia function, neurological-type patients typically present with hypo- and hyperkinetic extrapyramidal symptoms, with Parkinsonism being very common. Although there are numerous reports on olfactory deficits in primary neurodegenerative disorders, olfactory function has not been investigated in metabolic disorders presenting with extrapyramidal features. Twenty-four patients with Wilson's disease participated in the investigation. All patients were treated pharmacologically. They comprised patients with liver disease alone (including mild enzyme elevation in asymptomatic individuals; n = 11) and/or neurological symptoms (n = 13) at the time of testing. Twenty-one patients underwent both [18F]fluoro-2-deoxy-D-glucose positron emission tomography ([18F]FDG-PET) and magnetic resonance imaging (MRI). The severity of extrapyramidal symptoms was judged using a clinical score system ranging from 0 (no symptoms) to 3 (severe symptoms). In all patients, psychophysical testing was performed using the Sniffin' Sticks, which involved tests for odor threshold, discrimination, and identification. Results from the present study revealed that Wilson's disease patients with neurological symptoms show a significant olfactory dysfunction compared to hepatic-type patients. Individuals who are more severely neurologically affected also present with a more pronounced olfactory deficit. Of interest, there was no significant effect of long-term treatment with penicillamine on olfactory function. Olfactory function did not correlate significantly with the presence of MRI visible lesions in the basal ganglia or with any regional glucose metabolism as measured by [18]F-FDG-PET. In conclusion, these findings indicate that the underlying pathological alterations with degeneration in the basal ganglia and neuronal loss in association with a marked increase of the copper content in this brain region play a role in the olfactory deficit.

Adult↗
PubMed2005

Reduced olfactory bulb volume in post-traumatic and post-infectious olfactory dysfunction.

The olfactory bulb is a highly plastic structure the volume of which partly reflects the degree of afferent neural activity. In this study, 22 patients with post-infectious olfactory deficit, nine participants with post-traumatic olfactory deficit, and 17 healthy controls underwent magnetic resonance volumetry of the olfactory bulb. Patients presented with significantly smaller olfactory bulb volumes than controls; significant correlations between olfactory function and bulb volume were observed. Patients with parosmia exhibited smaller olfactory bulb volumes than those without parosmia. Findings indicate that smell deficits leading to a reduced sensory input to the olfactory bulb result in structural changes at the level of the bulb. Reduced olfactory bulb volumes may also be considered to be characteristic of parosmia.

Adult↗
PubMed2004

Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages.

Macrophages (MF) are the final host cells for multiplication of the intracellular parasite Leishmania major (L. major). However, polymorphonuclear neutrophil granulocytes (PMN), not MF, are the first leukocytes that migrate to the site of infection and encounter the parasites. Our previous studies indicated that PMN phagocytose but do not kill L. major. Upon infection with Leishmania, apoptosis of human PMN is delayed and takes 2 days to occur. Infected PMN were found to secrete high levels of the chemokine MIP-1beta, which attracts MF. In this study, we investigated whether MF can ingest parasite-infected PMN. We observed that MF readily phagocytosed infected apoptotic PMN. Leishmania internalized by this indirect way survived and multiplied in MF. Moreover, ingestion of apoptotic infected PMN resulted in release of the anti-inflammatory cytokine TGF-beta by MF. These data indicate that Leishmania can misuse granulocytes as a "Trojan horse" to enter their final host cells "silently" and unrecognized.

Animals↗
PubMed2004

Detection of presymptomatic Parkinson's disease: combining smell tests, transcranial sonography, and SPECT.

Olfactory loss is among the early signs of Parkinson's disease (PD). We investigated whether "idiopathic" olfactory dysfunction might relate to signs of nigral degeneration. Olfactory tests were combined with transcranial sonography of the substantia nigra and single photon emission computed tomography (SPECT) imaging. Thirty patients diagnosed with idiopathic olfactory loss participated. Eleven of these patients exhibited an increased echogenicity of the SN in the transcranial sonography. In 10 of these 11 patients, SPECT scans with (123)I-FP-CIT were performed. Median uptake ratios in the basal ganglia were pathological in 5 patients, 2 patients exhibited borderline findings, and 3 patients had normal results. Considering patients with idiopathic olfactory dysfunction, noninvasive transcranial sonography seems to be helpful in identifying patients potentially at risk to develop PD. Longitudinal follow-up studies are necessary to estimate the ratio of patients with dopaminergic cell loss in the basal ganglia who will develop PD in the future.

Adult↗
PubMed2004

Frequency of proteinase 3 (PR3)-specific autoreactive T cells determined by cytokine flow cytometry in Wegener's granulomatosis.

OBJECTIVE: Previous studies have shown proliferation to Wegener's autoantigen, proteinase 3 (PR3). We tested immunogenicity of PR3-derived peptides and determined frequencies of PR3-specific T cells using cytokine flow cytometry in Wegener's granulomatois (WG). METHODS: Peripheral blood T-cell responses were measured after stimulation with previously described PR3-derived peptides. PBMC were stimulated with PR3-derived peptides or control stimuli for up to 10 days. Cells were stained with antibodies against CD4 or CD8, CD69 and intracellular TNF-alpha and analyzed by flow cytometry. PR3-specific T cells were counted as the percentage of CD69(+)TNF-alpha(+)double positive T cells after stimulation. RESULTS: Frequencies of PR3-specific peripheral blood T cells after short-term stimulation (<or=0.4%) were lower compared to frequencies of PR3-specific CD4(+)T cells (0.64+/-0.09%, mean+/-SEM) and PR3-specific CD8(+)T cells (0.65+/-0.18%) after 10 days of stimulation in WG. There were no differences of the frequency of PR3-specific T cells between WG and healthy controls after stimulation with other peptides. The frequency of PR3-specific CD8(+)T cells stimulated with a preferentially HLA-A*0201 binding PR3-peptide sequence was higher compared to the frequency of T cells stimulated with a HLA-B*0702 binding PR3-peptide in one WG patient whose HLA type was known (A2B7). CONCLUSION: Low frequencies of TNF-alpha(+)PR3-specific T cells can be detected in individual WG patients and controls using cytokine flow cytometry. The pattern and time course of cytokine production in response to PR3 peptides needs to be further elucidated. Additional factors such as the influence of proinflammatory or regulatory T cells might be important for the induction of autoimmunity in WG.

Amino Acid Sequence↗
PubMed2002

Heterogeneity of CD4 and CD8+ memory T cells in localized and generalized Wegener's granulomatosis.

Memory T cells display phenotypic heterogeneity. Surface antigens previously regarded as exclusive markers of naive T cells, such as L-selectin (CD62L), can also be detected on some memory T cells. Moreover, a fraction of CD45RO+ (positive for the short human isoform of CD45) memory T cells reverts to the CD45RA+ (positive for the long human isoform of CD45) phenotype. We analyzed patients with biopsy-proven localized Wegener's granulomatosis (WG) (n = 5), generalized WG (n = 16) and age- and sex-matched healthy controls (n = 13) to further characterize memory T cells in WG. The cell-surface expression of CD45RO, CD45RA, CD62L, CCR3, CCR5 and CXCR3 was determined on blood-derived T cells by four-color flow cytometric analysis. The fractions of CCR5+ and CCR3+ cells within the CD4+CD45RO+ and CD8+CD45RO+ memory T cell populations were significantly expanded in localized and generalized WG. The mean percentage of Th1-type CCR5 expression was higher in localized WG. Upregulated CCR5 and CCR3 expression could also be detected on a fraction of CD45RA+ T cells. CD62L expression was seen on approximately half of the memory T cell populations expressing chemokine receptors. This study demonstrates for the first time that expression of the inducible inflammatory chemokine receptors CCR5 and CCR3 on CD45RO+ memory T cells, as well as on CD45RA+ T cells ('revertants'), contributes to phenotypic heterogeneity in an autoimmune disease, namely WG. Upregulated CCR5 and CCR3 expression suggests that the cells belong to the effector memory T cell population. CCR5 and CCR3 expression on CD4+ and CD8+ memory T cells indicates a potential to respond to chemotactic gradients and might be important in T cell migration contributing to granuloma formation and vasculitis in WG.

CD4-Positive T-Lymphocytes↗
PubMed2002

Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis.

To elucidate whether the fraction of CD28(-) T cells within the CD4(+) T-cell population is a major source of Th1-like and proinflammatory cytokine production driving Wegener's granulomatosis (WG) granuloma formation, we analyzed the phenotype and functional characteristics of peripheral blood CD4(+)CD28(-) T cells and of T cells in granulomatous lesions of 12 patients with active WG. Surface markers and intracytoplasmic cytokine and perforin expression were assessed by flow cytometry. Cytokine secretion was measured by enzyme-linked immunosorbent assay. Immunohistological studies demonstrated interferon-gamma and tumor necrosis factor-alpha cytokine positivity attributable to CD4(+)CD28(-) T cells in granulomatous lesions. Peripheral blood CD4(+)CD28(-) T cells expressed CD57, also found on natural killer cells, and intracytoplasmic perforin. They were generally CD25 (interleukin-2 receptor)-negative. CD18 (adhesion molecule beta(2)-integrin) was strongly up-regulated on CD4(+)CD28(-) T cells, whereas only a minority of CD4(+)CD28(+) T cells expressed CD18. CD4(+)CD28(-) T cells appeared as a major source of interferon-gamma and tumor necrosis factor-alpha. In contrast, CD4(+)CD28(+) T cells were able to produce and secrete a wider variety of cytokines including interleukin-2. One-quarter of CD4(+)CD28(+) T cells expressed the activation marker CD25, but they lacked perforin. Thus, CD4(+)CD28(-) T cells appeared more differentiated than CD4(+)CD28(+) T cells. They displayed Th1-like cytokine production and features suggestive of the capability of CD4(+) T-cell-mediated cytotoxicity. CD4(+)CD28(-) T cells may be recruited into granulomatous lesions from the blood via CD18 interaction, and may subsequently promote monocyte accumulation and granuloma formation through their cytokine secretion in WG.

CD28 Antigens↗