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J Müller-Quernheim

Publications and source records attributed to J Müller-Quernheim.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pharmacological modulation of the IFNgamma-induced accessory function of alveolar macrophages and peripheral blood monocytes.

OBJECTIVE AND DESIGN: Although alveolar macrophages (AM) are poor accessory cells, alveolar macrophages of patients with sarcoidosis or tuberculosis show an elevated accessory function indicating that the accessory function (AF) of AM can be upregulated. MATERIALS AND METHODS: We examined whether the AF of AM and peripheral blood monocytes (PBM) can be increased by interferon-gamma (IFNgamma) and whether immunomodulating drugs like cyclosporine A, cyclophosphamide, dexamethasone, and ambroxol are able to modulate the accessory function and the expression of accessory molecules. RESULTS: IFNgamma increased the AF of AM and PBM up to 309 +/- 122% and 152 +/- 25%, respectively (p < 0.02, unstimulated control = 100%, in all cases). In alveolar macrophages this increase is most efficiently prevented by cyclosporine A (31 +/- 13%), followed by cyclophosphamide (64 +/- 20%) and dexamethasone (66 +/- 20%). In monocytes the IFNgamma-induced increase in accessory function is prevented only by cyclosporine A (17 +/- 7%) and dexamethasone (59 +/- 9%). Cyclosporine A was also the most effective drug downregulating the expression of accessory molecules (CD54, CD58, CD80 and CD86). CONCLUSIONS: In summary, the accessory function of alveolar macrophages and monocytes is upregulated by IFNgamma and can be controled by immunomodulating drugs.

Aged↗
PubMed1999

Analysis of differentially regulated mRNAs in monocytic cells induced by in vitro stimulation.

Macrophages are known to be effector cells in several granulomatous disorders. However, little is known about granuloma-associated up- or downregulation of genes in these cells. Differential display reverse transcription polymerase chain reaction (DDRT-PCR) is an attractive method for the detection of differentially expressed genes. Although this method entails a number of drawbacks, its application to rare and limited amounts of clinical samples is still convenient. In this study, we introduce a screening procedure for detecting differentially regulated sequence tags in samples of patients suffering from granulomatous diseases. We applied DDRT-PCR in a multiple and complex comparison of expressed sequence tags in response to various granuloma-associated stimuli. The histiocytic cell line U937 was used as a model. The cells had been stimulated with granuloma-associated agents such as Mycobacterium tuberculosis, BeSO4, lipopolysaccharide, or HgS and unspecific stimuli such as phorbol myristate acetate, phytohemagglutinin, Zymosan, and Latex. Comparative analysis of 2237 sequence tags obtained from 55 primer combinations revealed 22.4% differentially amplified PCR products. Notably, only 8.0% of the differentially expressed sequence tags showed an association restricted to in vitro cultivation in the presence of M. tuberculosis, lipopolysaccharide, BeSO4, and/or HgS, while 1.0-1.9% of the tags were altered exclusively as a consequence of stimulation with one of the granuloma-associated agents. Our data provide evidence that this strategy may function as a preselection for appropriate primer combinations to discover sequence tags which could be specifically associated with granulomatous disorders. This approach could shorten laborious screening, save consumption of valuable and rare samples, and could reduce the number of false-positive results.

Cell Line↗
PubMed1999

Bronchoalveolar lavage cell profiles in Wegener's granulomatosis.

Pulmonary involvement due to Wegener's granulomatosis (WG) can present radiologically either as diffuse infiltrates or as nodular and linear opacities. Clinical experience suggest that these radiological patterns are associated with different bronchoalveolar lavage (BAL) cell profiles, but this has not been examined formally. We compared the BAL cell profile in eight WG patients with diffuse infiltrates on chest X-ray, indicative of highly active pneumonitis, with corresponding findings in 37 patients with nodular, linear and focal low-attenuation infiltrates on high-resolution computed tomography (HRCT) which reflected low-grade, mainly interstitial disease. A control group was composed of 11 patients with pulmonary sarcoidosis. Diffuse infiltrates occurred in association with high systemic disease activity and featured a neutrophilic BAL profile in the presence of generally normal BAL lymphocytes. HRCT findings suggestive mainly of interstitial disease were associated with either a lymphocytic BAL cell profile or a normal cell pattern. Patients with a lymphocytic cell profile generally had a preferential elevation of CD4+ cells in the BAL in the presence of a normal CD4/CD8 ratio in the blood. This was a common feature of WG and pulmonary sarcoidosis. In conclusion, highly active pneumonitis and pulmonary disease of low or moderate activity in WG are associated with disparate BAL cell profiles. It remains to be examined whether the preferential elevation of CD4+ cells in the latter condition reflects a common pathogenetic role of this subset of cells in WG and pulmonary sarcoidosis.

Aged↗
PubMed1999

Analysis of the Kveim-Siltzbach test reagent for bacterial DNA.

The sarcoid spleen-derived reagent for the Kveim-Siltzbach test (KST) elicits a sarcoid-specific, granulomatous, cutaneous response used to establish the diagnosis of sarcoidosis. In the context of the ongoing discussion of a bacterial cause of sarcoidosis we asked the question whether bacterial DNA could be found in the KST reagent. For this purpose two different KST reagents, an identical preparation from a normal spleen, and a native sarcoid spleen were analyzed by polymerase chain reaction (PCR) employing universal primers detecting conserved DNA sequences coding for bacterial ribosomal 16S RNA. Neither KST reagents, the control preparation, nor the spleen yielded a positive signal, indicating that the preparations are free of bacterial contamination. Because the KST reagent elicits granuloma, these results do not support the hypothesis of a bacterial cause of sarcoid granuloma.

Conserved Sequence↗
PubMed1999

Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen.

In a few patients with chronic sarcoidosis, prolonged, unacceptably high doses of corticosteroids are required to achieve symptomatic relief. In these cases, a corticosteroid-sparing drug might be administered to allow long-term treatment without the adverse effects of corticosteroids. This study examines azathioprine as a prednisolone-sparing treatment. In an open study, the course of 11 patients with chronic sarcoidosis was analysed. In an induction phase, 2 mg azathioprine x kg body weight (BW)(-1) x day(-1) in combination with 0.6-0.8 mg prednisolone x kg BW(-1) x day(-1) were administered with prednisolone being reduced to 0.1 mg x kg BW(-1) x day(-1) within 2-3 months. This was followed by a 21-22-month maintenance phase with 2 mg azathioprine x kg BW(-1) x day(-1) and 0.1 mg prednisolone x kg BW(-1) day(-1). Clinical parameters and immunological findings of bronchoalveolar lavage (BAL) were analysed. All patients had significant symptomatic relief and improvements or resolutions of physiological, serological and radiographic findings without suffering from serious adverse effects. Nine of 11 patients completed therapy after 19-26 months, and 2/11 patients terminated therapy after 8 and 12 months, respectively. Eight patients had remissions lasting 4-73 months. Three relapses occurred after 8, 18, and 22 months. During the induction phase, BAL cell composition changed and their activity in terms of cytokine release was suppressed. This preliminary study suggests that azathioprine may be effective as a corticosteroid-sparing agent in long-term therapy of sarcoidosis, but a much larger study is necessary to give the definitive answer.

Adult↗
PubMed1999

Age-related decrease in accessory cell function of human alveolar macrophages.

BACKGROUND: Suboptimal function of an aged immune system may significantly contribute to morbidity and mortality in the elderly. In contrast to lymphocytes, only little is known about changes of cells from the monocyte/macrophage lineage. Especially the changes of their accessory function, which are necessary for optimal T cell stimulation are controversially discussed. METHODS: We measured the accessory function of monocytes (PBM) and alveolar macrophages (AM) and correlated their accessory function with the age of the patients. RESULTS: We found a significant decrease in accessory function of AM with the age (rs = -0.5, P < 0.006) but not of PBM (rs = -0.4, P > 0.1). Additionally, we found a significant decrease in the percentage of AM (rs = 0.3, P < 0.005) and an increase in the percentage of lymphocytes (rs = 0.3, P < 0.02) in the bronchoalveolar lavage. No correlations could be found with other lavage parameters or with unstimulated in vitro TNF-alpha, TGF-beta, and IL-6 release of bronchoalveolar lavage cells; however, in stimulated BAL-cell cultures we found a weak but significant correlation between TNF-alpha release and the age (rs = -0.3, P < 0.02). CONCLUSIONS: Impairment of accessory cell function of alveolar macrophages may contribute to an increased risk of pulmonary infection of elderly persons.

Adult↗
PubMed1999

Different cytokine patterns correlate with the extension of disease in pulmonary tuberculosis.

The relative amounts of different pro- and anti-inflammatory cytokines released at the site of infection by bronchoalveolar lavage (BAL) cells may influence the presentation of tuberculosis. To investigate this hypothesis the in situ release by BAL cells of the following cytokines was measured and correlated with the chest X-ray findings of 43 patients with pulmonary tuberculosis: interleukin (IL)-8, macrophage inflammatory protein-1alpha (MIP-1alpha), IL-6, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interferon-gamma (IFN-gamma), IL-2, IL-4 and IL-5. The release of IL-8 and IL-6 decreased with the progression of the disease, while the release of MIP-1alpha was increased in patients with advanced tuberculosis. The release of TNF-alpha and TGF-beta did not differ between patients with or without cavitary lesions. The Th1 (IFN-gamma and IL-2) and Th2 (IL-4 and IL-5) cytokine release exhibited a gradual increment with the advance of tuberculosis. Thus, our data provide evidence that a Th0 cytokine pattern is predominant at the site of pulmonary tuberculosis. In conclusion, immunoparalysis status could not be observed in our patients with severe tuberculosis.

Bronchoalveolar Lavage Fluid↗
PubMed1999

[Diagnosis of chronic berylliosis].

The diagnostic value of the lymphocyte transformation test (BeLT) and the intracutaneous skin test with berylliumsulfate was addressed in 13 patients with chronic berylliosis, and 15 individuals with occupational exposure. Additionally, patients with sarcoidosis (n = 21), tuberculosis (n = 14) and healthy controls (n = 25) were tested with BeLT and yielded negative results. In chronic berylliosis the BeLT was positive in 10/13. In 3/13 the BeLT was negative, but the skin test positive. 6/15 exposed individuals exhibited a positive BeLT. The time course of the skin test differed markedly between the individual berylliosis patients. Typical granulomas were present in 4/10 cases. In 9 exposed individuals BeLT tested negative. Additionally, skin tests were negative in 7 exposed patients, however, unspecific skin reactions were observed in 3 cases. The diagnostic value of Beryllium IT requires further investigation. At present, BeLT appears to be a suitable test to prove beryllium sensitisation.

Adult↗
PubMed1999

[Serum adenosine deaminase as a parameter for activity in sarcoidosis].

UNLABELLED: Adenosin deaminase (ADA) is an enzyme of purine metabolism and reflects the involvement of the cellular immune system. The ADA serum levels were tested in 130 healthy blood donors, and in 98 patients (pts) with sarcoidosis; 59 pts with active and 39 pts with inactive sarcoidosis. These two patient groups were separated into treated and untreated; the active group was divided into an acute onset group (12 pts) and a group with chronic disease (47 pts). The disease activity was determined on the basis of clinical symptoms, chest x-ray and lung function tests. ADA was compared to angiotensin converting enzyme(ACE), neopterin (NPT), and soluble interleukin-2 receptor (sIL-2 R). ADA activity was measured colorimetrically according to a method of Giusti with slight modifications. ACE was determined by a commercial kit by Fujerbio, Japan. NPT and sIL-2 R were evaluated by commercial enzyme-linked immunosorbent assays. The ADA activity in controls was 18.8 +/- 3.8 U/I (mean +/- SD), the upper normal serum range (mean +/- 2SD) was established at 26.4 U/I. Serum ADA levels in the group with active sarcoidosis (33.5 +/- 14.3 U/I, p < 0.0001) were significantly higher than those in healthy controls and in inactive disease (19.6 +/- 5.8 U/I, p < 0.0001). Sensitivity and specificity were: ADA 75%/92%, ACE 49%/85%, NPT 78%/74%, sIL-2 R 81%/57%. CONCLUSION: Our findings demonstrate that the course of the disease can be monitored by measurement of the serum ADA. In comparison to the other parameters, measurement of the serum ADA indicates a greater discrimination between active and inactive disease.

Acute Disease↗
PubMed1998

Soluble intercellular adhesion molecule 1 (sICAM-1) in bronchoalveolar lavage (BAL) cell cultures and in the circulation of patients with tuberculosis, hypersensitivity pneumonitis and sarcoidosis.

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in inflammatory diseases. It is believed that its soluble form (sICAM-1) might be a serum parameter of inflammatory activity with possible relevance in granulomatous disorders. To evaluate this role we measured sICAM-1 by ELISA in serum and shedding of this molecule by BAL cells in patients with granulomatous lung diseases (pulmonary tuberculosis (TB), hypersensitivity pneumonitis (HSP), pulmonary sarcoidosis (PS), and controls). Serum concentrations of sICAM-1 in patients with TB (496.9 +/- 49.7 ng/ml), with HSP (636.5 +/- 85.9.8 ng/ml), and with PS (588.3 +/- 72.2 ng/ml) were significantly increased compared to controls (275.7 +/- 33.1 ng/ml). Spontaneous release of sICAM-1 by BAL cells differed among patient groups (TB: 9.3 +/- 1.7; HSP: 17.5 +/- 1.4; PS: 9.7 +/- 1.5 ng/ml), however, exceeding that of controls significantly (3.8 +/- 0.6 ng/ml). No correlations between the circulating level and the shedding of this molecule by BAL cells were observed within the groups. Significant correlations between serum sICAM-1 and serum tumor necrosis factor alpha (TNFalpha) level were observed in patients with HSP and TB. Kinetic cell culture experiments with BAL cells revealed a dissociation in sICAM-1 shedding and TNFalpha release. After stimulation rapid upregulation of both molecules (5 h) was followed by a cessation of TNFalpha production at 28 h. sICAM-1 shedding, however, was maintained over 2 days. Our results evidence that the circulating pool of sICAM-1, as well as the shedding of this molecule by BAL cells reflect the activity of cells in the inflammatory processes of granulomatous diseases.

Adult↗
PubMed1998

HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis.

Numerous reports on the familial occurrence of sarcoidosis, on regionally different prevalences and on its associations with genetic polymorphisms point to the existence of predisposing genes. We have started to establish a collection of DNA from families with two or more sarcoidosis patients for the purpose of genetic linkage and association studies. In this report we present HLA class II genotypes of affected first-degree relatives from 17 families, including eight instances of affected parent and offspring, six sib pairs, and three sib triplets. Genotyping for HLA-DQB1 revealed an over-representation of DQB1*0603 and DQB1*0604 among alleles shared by affected first degree relatives. The same was found for HLA-DPB1*0201 (Glu69 positive). However, none of the sib triplets had any of these alleles in common.

Family↗
PubMed1998

Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity.

It has been shown that interleukin 8 (IL-8) is increased in bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF) and there is increasing evidence that it is involved in the pathogenesis of this disease. To date, no data are available as to whether IL-8 is elevated in sera of IPF patients. We obtained sera from 42 patients with IPF and 20 healthy controls at time of BAL. From 20 of 42 patients with IPF and 12 of 20 controls BALF was available, enabling us to measure IL-8 in serum and BALF of the same time point. IL-8 was significantly elevated in serum (54.7 +/- 7.5 pg/ml, p < 0.0001) and BALF (715.7 +/- 112.4 pg/ml, p < 0.0001) of patients with IPF compared with controls (IL-8 in serum, 5.2 +/- 0.8 pg/ml; IL-8 in BALF, 67.3 +/- 9.7 pg/ml). We observed a significant positive correlation between IL-8 levels in BALF and percentage of BALF neutrophils (p < 0.001) and between serum IL-8 and BALF IL-8 levels (p < 0.005) in patients with IPF. Consequently, the serum IL-8 level correlated positively with the percentage of BAL neutrophils (p < 0.01), indicating that it may reflect the degree of neutrophilic alveolitis in IPF. Furthermore, the serum IL-8 level showed a negative correlation with important indicators of impairment of lung function (DL(CO), TLC, VC) and PaO2. In conclusion, we were able to demonstrate that the degree of neutrophilic alveolitis in IPF is reflected by increased serum levels of IL-8 and we suggest that the serological assessment of IL-8 may provide a useful parameter for clinicians in monitoring patients with IPF.

Anti-Inflammatory Agents↗
PubMed1998

Sarcoidosis: immunopathogenetic concepts and their clinical application.

Our understanding of the immunopathogenesis of sarcoidosis has been advanced by studies of bronchoalveolar lavage cells. Activated macrophages and T-cells have been identified in different compartments of the sarcoid lung and the characteristics of the activation suggest that the cells become activated in the course of a normal immune response. The immune cells communicate via a cytokine network and the measuring of cytokine levels yields subgroups of sarcoidosis patients with different courses of the disease indicating different states of activation of the disease-mediating immune cells. The causative agent of sarcoidosis has not yet been identified; however, some of the described mechanisms can be clinically applied either to detect patients at risk of deterioration or to develop new therapeutic strategies. Using these approaches methotrexate, pentoxifylline and thalidomide have been identified as drugs which effectively suppress sarcoid inflammation and the serum level of soluble interleukin-2 receptors has been delineated to be a serum marker of sarcoid inflammation. Furthermore, analysing the pulmonary cytokine network in sarcoidosis will yield new staging parameters possibly supplying prognostic information and guiding therapeutic intervention.

Adrenal Cortex Hormones↗
PubMed1998

[Limits of beryllium detection with laser microprobe mass spectrometry (LAMMS)].

Search for beryllium (Be) in tissues or urine in suspected beryllium disease is often disappointing due to inferior sensitivity of the methods employed. We evaluated the clinical use of laser microprobe mass spectrometry (LAMMS) for measurement of Be and detected the metal to a minimum concentration of 1 microM. We then investigated the biological relevance of this concentration. We looked at the alveolar macrophages in 7 patients subsequent to an incubation period of 24 h as well as peripheral blood mononuclear cells (PBMNC) and various cell lines with and without addition of beryllium sulfate (BeSO4). We also investigated skin biopsies of two patients 28 days after intracutaneous injections of BeSO4 (beryllium skin testing) and alveolar macrophages of A/J mice at various time intervals after a beryllium sensitisation protocol and a single intratracheal injection of BeSO4 (maximum interval: 15 weeks). Be was not defectable in native patient alveolar macrophages (AM), but in 6 of 7 cases after coincubation with BeSO4. There was no significant Be signal in any analysed PBMNC sample or cell line--even after coincubation with Be--or in the skin probes. Murine AM, however, had incorporated significant amounts of Be, which were detectable until the end of the experiments 15 weeks later. We conclude that concentrations of Be in acute disease (here, inoculation of Be in mice) exceed 1 microM and are thus detectable by LAMMS. On the other hand, concentrations in chronic processes (in this cosar, skin testing) are below the detection limits of LAMMS. Further results suggest compartmentalisation of the immune processes induced by Be because the alveolar macrophages were able to incorporate Be while PBMNC were not and because AM--at least in the animal experiments--seem to store Be intracellularly.

Adult↗
PubMed1998

Serum markers for the staging of disease activity of sarcoidosis and other interstitial lung diseases of unknown etiology.

Immunopathogenic mechanisms in sarcoidosis, idiopathic pulmonary fibrosis, and pulmonary manifestations of collagen-vascular diseases maintain an alveolitis which may lead to irreversible organ damage. The classical parameters used in the management of pulmonary involvement of these disorders are chest X-ray and pulmonary function test which do not gauge alveolitis but rather pulmonary impairment. From the immunopathogenesis several serological parameters have been delineated estimating different aspects of inflammatory processes. Cytokines, soluble cytokine receptors, metabolites, enzymes, extracellular matrix components, soluble adhesion molecules, and other serum components have been evaluated to serve as serological markers of alveolitis. The mechanisms gauged by these markers, and their clinical usefulness are discussed in this review.

Biomarkers↗