Biomedical subjects
Publications and source records attributed to J Müller-Quernheim.
In sarcoidosis a compartmentalized activation of the immune system exists which yields clinical parameters of disease activity. By means of the spontaneous interleukin-1 and tumor-necrosis-factor-alpha release the same phenomenon could be demonstrated for the macrophage/monocyte system.
Serum sIL-2-R levels were measured in 28 sarcoidosis patients at multiple time points before, during, and after therapy, with a mean follow-up time of 10.2 +/- 5.2 months, and the results compared with the clinical activity of the disease. Before therapy, 20 out of 24 episodes with active disease exhibited elevated levels of sIL-2-R (918 +/- 362 U/ml). In inactive disease after tapering off corticoid therapy the sIL-2-R levels were 453 +/- 274 U/ml. Disease activity under therapy also correlated with sIL-2-R serum levels. 23 out of 29 episodes with signs of activity under therapy had elevated sIL-2-R levels (808 +/- 409 U/ml). Only three of 28 patients in whom disease activity ceased after therapy had been initiated had raised sIL-2-R levels (mean: 401 +/- 140 U/ml). These results demonstrate that the activity of pulmonary sarcoidosis is reflected accurately by the serum levels of sIL-2-R, suggesting that the course of the disease can be monitored by this approach.
Current concepts of the immunopathogenesis of sarcoidosis favor a central role of activated, interleukin-2 (IL-2) producing helper T-cells at sites of inflammation. Normally, activated T-cells release IL-2 and express IL-2 receptors (IL-2R). IL-2R+ cells, however, are not uniformly found in patients with clinically active disease. To determine whether the lack of IL-2R+ cells is caused by a dysregulation of the IL-2R gene or by the mode of T-cell activation in pulmonary sarcoidosis, we quantified IL-2 and IL-2R m-RNA transcripts, IL-2 release, and IL-2R surface protein in peripheral blood lymphocytes of patients with sarcoidosis and normal control subjects before and after in vitro stimulation as a function of time. Additionally, we determined the percentage of IL-2R+ bronchoalveolar lavage (BAL) and peripheral blood lymphocytes in our study population and evaluated the in vivo transcriptional activity of the IL-2R gene. In peripheral blood lymphocytes, maximal IL-2R mRNA accumulation is found between 6 and 24 h, and maximal accumulation of IL-2 mRNA is found between 24 and 48 h. No differences emerged between normal subjects and patients with sarcoidosis. In six of 19 patients, we observed elevated numbers of IL-2R+ BAL lymphocytes and found IL-2R mRNA in those cells. These results are in accordance with the concept of a compartmentalized T-cell activation in sarcoidosis, resulting in IL-2 and IL-2R positive BAL cells and quiescent peripheral blood lymphocytes.
Interstitial lung diseases are characterised by chronic inflammatory processes in the lower respiratory tract, parenchymal cell injury and progressive fibrosis of the alveolar structure. Oxygen radicals are claimed to be a major cause of the tissue damage in the lung. We evaluated the spontaneous and stimulated oxygen radical release of bronchoalveolar lavage (BAL) cells in 35 patients with sarcoidosis and 17 patients with IPF. In comparison with the control in both diseases the spontaneous as well as the stimulated oxygen radical release of the BAL cells is markedly increased. In IPF alveolar macrophages produce the buk part of radicals (84%). Due to their low percentage and in spite of a higher activity on a per cell basis the contribution of neutrophils to the total radical burden is only marginal. In sarcoidosis there is a positive correlation between the oxygen radical release of AM and the CD4/CD8 ratio of BAL lymphocytes. Our results demonstrate that the clinical activity of sarcoidosis and IPF is reflected by the oxygen radical release of BAL cells.
The T cells of NZB mice become hyperreactive after stimulation with minor histocompatibility (MIH) antigens. This hyperreactivity has previously been demonstrated only for cytotoxic T cells of NZB, although there was some evidence for an increase of their T-helper cell activity facilitating the response. Here we report a quantitative analysis of T-cell help and help of T-cell subpopulations against autologous, MIH, and H-2 antigens in a limiting dilution assay. After stimulation of NZB T cells with autologous and H-2 antigens, the T-helper cell frequencies did not differ from that of normal mice. After stimulation with MIH antigens however, Lyt 1+2+ T-cells of NZB showed a higher response than those of BALB/c origin. The same difference was seen after prestimulation with ConA or the specific antigen. This demonstrates that NZB-helper cells are more easily activated by weak antigenic differences, and it is possible that this contributes to the prevalence of autoimmune disease in this strain.
Pulmonary sarcoidosis is a granulomatous disorder characterized by the accumulation of activated helper/inducer T-lymphocytes in the lower respiratory tract, a process thought to be central to the pathogenesis of the disease. Because cyclosporine, a fungus-derived cyclic peptide, has specific inhibitory effects on T-lymphocyte activation, it should suppress activated sarcoid lung T-cells, and thus it should theoretically be an ideal therapeutic agent for sarcoidosis. This was confirmed in vitro: the addition of cyclosporine to T-cells recovered from the lungs of patients with active sarcoid suppressed the spontaneous release of interleukin-2 (IL-2) and monocyte chemotactic factor by these cells and inhibited their exaggerated spontaneous replication. In contrast, the oral administration of conventional doses (10 mg/kg/day) of cyclosporine to eight of these patients over a 6-month period was not accompanied by suppression of sarcoid lung T-cell activation. On the average, the spontaneous release of IL-2 and monocyte chemotactic factor, the proliferation of lymphocytes, and the number of helper/inducer T-cells present in the lungs of these subjects remained elevated and similar to their pretherapy values. Consistent with this lack of effect on sarcoid lung T-cell activation, no improvement in lung function was observed over the trial period. Thus, although cyclosporine is effective in vitro in suppressing the exaggerated activation of sarcoid lung T-cells, it does not do so in vivo, suggesting this agent will not be useful in the therapy of active pulmonary sarcoidosis, at least when administered in a conventional fashion.
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Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown etiology. Macrophage dysfunctions are claimed to be involved in the pathogenesis. We investigated phagocytosis and oxidative metabolism of alveolar macrophages in a case of pulmonary alveolar proteinosis. These cells phagocytize normally and phagocytizable stimulants cause a normal oxidative burst. In response to the membrane signals phorbolmyristate acetate and aggregated immunoglobulin, however, no stimulated turnover of the oxidative metabolism can be observed. A 40-kD protein found in the lavage fluid mediates this macrophage-inhibiting effect. This phenomenon may contribute to the frequent opportunistic infections seen in PAP patients. It can be concluded from our data that the high frequency of infections with opportunistic species in these patients can be reduced by therapeutic bronchoalveolar lavage. By this procedure the abnormal macrophage-suppressing protein can be washed out of the lung at an early stage of the disease.
Active pulmonary sarcoidosis is characterized by the alveolar accumulation of activated helper T lymphocytes that are spontaneously releasing IL 2 and proliferating at an enhanced rate. In this regard, sarcoidosis represents a "model" human disorder to test in vivo the known in vitro action of corticosteroids on suppressing the activated IL 2 gene. Comparable groups of patients with active sarcoidosis were prospectively evaluated with no therapy or treated with corticosteroids. Over 3.2 +/- 0.4 mo, the untreated group had no significant change in spontaneous lung T cell release of IL 2 or spontaneous proliferation. In contrast, over the same period, the treated group had marked reduction of spontaneous lung T cell release of IL 2 and proliferation (p less than 0.01, all comparisons before therapy). Furthermore, Northern analysis of lung T cell RNA before therapy demonstrated IL 2 mRNA transcripts, whereas no IL 2 transcripts were observed during therapy. These observations are consistent with the concept that directly, or indirectly, corticosteroids are capable of suppressing the IL 2 gene in activated T lymphocytes in vivo.
NZB-mice have a T cell hyperreactivity based on a primary response to minor histocompatibility antigens (MIH) on target cells identical to NZB on the H-2 complex (MHC). We tested the idea that a single MIH difference on MHC identical target cells is sufficient to elicit such a primary response in vitro. Cytotoxic T lymphocyte (CTL) response and activated T-helper cell (THC) frequencies were evaluated. NZB x CBA/J (Mls a/d) and NZB x CBA/Ca (Mls a/b) hybrids, which differ only at the M-locus, were raised. A primary cytotoxic response in the direction Mls b anti Mls d, but not vice versa was observed in vitro. In the assay used no unusual THC frequencies against Mls d could be demonstrated. The results favour cellular hyperreactivity in NZB which can be elicited by a single MIH antigen alone.
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Sarcoidosis is a systemic disorder characterized by the accumulation of large numbers of interleukin 2 (IL 2) releasing helper (Leu-3+) T cells in involved organs. To determine whether the IL 2 gene is activated in sarcoidosis T cells in a systemic manner or only at sites of disease, cells obtained by bronchoalveolar lavage of individuals with active sarcoidosis, inactive sarcoidosis, and normals were evaluated for the spontaneous presence of IL 2 transcripts by using a human IL 2 cDNA probe and Northern analysis of extracted RNA. Freshly recovered lung cells of individuals with active pulmonary sarcoidosis contained 0.85 kilobase pairs (kb) IL 2 mRNA transcripts. In contrast, no IL 2 mRNA transcripts could be detected in fresh autologous blood T cells or in purified autologous blood Leu-3+ T cells, although IL 2 mRNA transcripts were inducible in these cells by phytohemaglutinin/phorbol myristic acetate. The sarcoid lung T cells, however, did not express the IL 2 gene constitutively; when placed in culture with no stimulation and evaluated after 24 hr, they demonstrated down regulation of the amounts of IL 2 mRNA transcripts, despite the fact that they were capable of re-expressing the IL 2 gene and releasing more IL 2 in response to added activation signals. Thus the activation of the IL 2 gene in T cells in active sarcoidosis occurs at the sites of disease and is not a generalized property of T cells throughout the body, and is not sustained if the T cells are removed from the sites of disease. Although the cause of sarcoid is unknown, these observations are consistent with the concept that sarcoid is associated with local stimuli at the site of disease eliciting the Leu-3+ T cell IL 2 gene activation that plays such a critical role in the pathogenesis of this disease.
NZB mice develop an autoimmune disease of unknown etiology. Since the detection of immunoregulatory T-cells it has been speculated that disbalances of these cells may be important in the course of the NZB disease. By utilization of monoclonal antibody defining immunoregulatory Lyt subsets and a FACS IV system we investigated whether differences in the number and/or marker densities of given subsets exist between NZB and the normal reference strain BALB/c. Newborn animals and animals up to 60 weeks of age were tested. No significant difference in the percentages nor in the marker densities of theta+, Lyt 1+, and Lyt 2+ cells was observed at any age or sex, neither in spleen nor in thymus. It is concluded the autoimmune disease of NZB is not influenced by the parameters investigated.
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Alveolar macrophages located on the alveolar surface have contact with air pollutants. We evaluated the dose-dependent effect of nitrogen dioxide exposure on the oxidative metabolism of alveolar macrophages and peripheral blood mononuclear cells by measuring the spontaneous and stimulated reactive oxygen intermediates production. Alveolar macrophages or peripheral blood mononuclear cells were placed on a polycarbonate membrane, which was in direct contact with the surface of a nutrient reservoir. The cells were exposed to nitrogen dioxide during different periods of time, varying between 30 and 120 min at concentrations ranging from 0.1 to 0.5 ppm. Exposure of alveolar macrophages to nitrogen dioxide for 30 min yielded a dose-dependent stimulation of reactive oxygen intermediates generation of 1.7- to 2.9-fold of control. An 120-min exposure to nitrogen dioxide at concentrations between 0.1 and 0.5 ppm resulted in a similar reactive oxygen intermediates production of about 1.9- to 2.2-fold of control at all concentrations tested. The nitrogen dioxide exposure to peripheral blood mononuclear cells yielded identical results. These experiments demonstrate that alveolar macrophages and peripheral blood mononuclear cells become activated by nitrogen dioxide and that concentrations up to 0.5 ppm nitrogen dioxide induce an increase in reactive oxygen intermediates production after 30 to 120 min exposure of the cells.