Elevated concentrations of soluble interleukin-2 receptors in serum samples and bronchoalveolar lavage fluids in active sarcoidosis

Sarcoidosis is a granulomatous disorder of unknown cause characterized by activation of T-lymphocytes. We here report the use of an enzyme-linked immunosorbent assay for the soluble interleukin-2 receptor (IL-2R) as a measure of T-cell activation in serum samples and bronchoalveolar lavage fluids in 15 patients with active sarcoidosis. The geometric mean (x divided by SEM) value for soluble IL-2R in serum samples from patients with sarcoidosis was 1,110 (x divided by 1.17) versus 224 (x divided by 1.08) U/ml for normal control subjects (p less than 0.001). Detectable levels of soluble IL-2R were present in bronchoalveolar lavage fluids from 10 of 15 patients with sarcoidosis versus only 2 of 36 normal control subjects (p less than 0.001). Levels of soluble IL-2R in serum samples from untreated patients with sarcoidosis correlated with 67gallium lung scanning scores (p less than 0.05) but not with serum angiotensin-converting enzyme concentrations or constituents of bronchoalveolar lavage. In 5 patients, the level of soluble IL-2R in serum samples fell from 1,499 (x divided by 1.20) to 476 (x divided by 1.58) U/ml (p less than 0.05) after 6 wk of successful treatment with corticosteroids, whereas the changes in soluble IL-2R in bronchoalveolar lavage fluids were more variable. These observations suggest that measurements of soluble IL-2R, particularly in serum samples, may reflect disease activity and be clinically useful in the management of patients with sarcoidosis.     

Bronchoalveolar lavage and lung histology. Comparative analysis of inflammatory and immunocompetent cells in patients with sarcoidosis and hypersensitivity pneumonitis

To determine whether bronchoalveolar lavage reflects the histologic aspects of the lung histology in patients with sarcoidosis and hypersensitivity pneumonitis, cells recovered from lavage fluid were compared with tissue sections from transbronchial lung biopsies in 33 patients. The evaluation of cellular types and their topographic distribution in situ was determined by using monoclonal antibodies in combination with immunohistochemical techniques. Cell counts in bronchoalveolar lavage and lung biopsies were significantly correlated both in sarcoidosis and hypersensitivity pneumonitis. In fact, the relative proportions of inflammatory and immunocompetent cells recovered from lavage fluid accurately overlapped those observed in lung tissue sections. However, in patients with more pronounced alveolitis, the frequency of macrophages in tissue sections was higher than that observed in the bronchoalveolar lavage, and the degree of lymphocytes in the lavage was higher than that observed in the corresponding biopsy. Specifically, in these patients the lavage underestimated the amount of macrophages in the lung biopsies and overestimated the number of lymphocytes that were present in the lung parenchyma. This was more evident in patients with hypersensitivity pneumonitis, where the intensity of alveolitis was higher than in sarcoidosis. Our data support the idea that, at least in patients with sarcoidosis and hypersensitivity pneumonitis, bronchoalveolar lavage correctly samples the alveolitis. Discrepancies in patients with very high intensity alveolitis could be due to a more pronounced recirculation of lymphocytes from the parenchyma to the alveolar spaces.     

Flow cytometry analysis of T lymphocytes in sarcoidosis

To examine the immunologic alterations in patients with sarcoidosis we characterized the cell cycle phase of T lymphocytes that were collected from peripheral blood and from bronchoalveolar lavage fluid. T-cell DNA and RNA contents were measured at the single cell level using flow cytometry after staining with the metachromatic fluorochrome acridine orange. T-enriched lymphocyte suspensions were obtained from peripheral blood and from bronchoalveolar lavage in 17 patients with histologically-proved sarcoidosis (10 patients, stage I and 7 patients, stage II) and in 4 patients with acute extrinsic hypersensitivity pneumonitis (AEHP). The percentages of cells in the S + (GS + M) phase in the peripheral blood of the patients with sarcoidosis did not differ from those of healthy control subjects. With bronchoalveolar lavage, however, elevated numbers of T cells in the S + (G2 + M) phase were found in the patients with AEHP and in those with stage II sarcoidosis when compared to patients with stage I sarcoidosis. The cellular RNA content of T lymphocytes from the peripheral blood showed a typical bimodal distribution without difference between patients and control subjects. Conversely, T lymphocytes obtained by bronchoalveolar lavage from patients with AEHP and sarcoidosis had a homogeneous low RNA content which differed from that of T lymphocytes from the blood from that of in vitro phytohemagglutinin-stimulated lymphocytes. These findings provide a new approach to the study of the mechanisms of local T-cell activation in sarcoidosis.     

Increased procollagen III aminoterminal peptide-related antigens and fibroblast growth signals in the lungs of patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by an increased density of inflammatory cells, fibroblasts, and collagen within the lung parenchyma. To gain insights into the mechanisms leading to the increased density of fibroblasts and altered collagen metabolism in the IPF lung, bronchoalveolar lavage fluid from normal subjects and patients with IPF or sarcoidosis was analyzed for (1) the presence of antigenic material related to the aminoterminal propeptide domain of type III procollagen, and (2) fibroblast growth-promoting activity in the extracellular milieu of the lower respiratory tract. Whereas bronchoalveolar lavage fluid (BALF) type III procollagen aminoterminal peptide-related antigen levels in 59 patients with sarcoidosis were similar to the levels of control subjects (p greater than 0.10), 31 patients with IPF had markedly increased levels (12-fold over controls; p less than 0.025, IPF versus controls; p less than 0.01, IPF versus sarcoidosis). Type III procollagen aminoterminal peptide-related antigen levels correlated with an increase in the ability of BALF to stimulate fibroblast proliferation (p less than 0.05). Furthermore, BALF from patients with IPF markedly stimulated human lung fibroblast proliferation in vitro (199% increase, p less than 0.01), whereas lavage fluid from patients with sarcoidosis and from control subjects did not. The enhanced fibroblast proliferation induced by IPF BALF occurred in the absence of serum and exogenous growth factors, suggesting that both competence- and progression-type growth factors were present in the lavage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme in serum and in bronchoalveolar lavage in sarcoidosis

Angiotensin-converting enzyme (ACE) determinations were made in serum and in bronchoalveolar lavage fluid in 20 controls and in 28 patients with sarcoidosis. Serum ACE was significantly higher in patients with active sarcoidosis (54.3 +/- 19.0 SD nmol/ml/ min; n = 24) compared to controls (25.7 +/- 8.2; n = 20) or to patients with inactive sarcoidosis (23.6 +/- 7.3; n = 4). In contrast, ACE in bronchoalveolar lavage fluid was similar in nonsmoking controls (16.4 +/- 7.3 nmol/ml/min/macrophage; n = 8), smoking controls (10.4 +/- 11.9; n = 7); nonsmoking active sarcoidosis patients (16.7 +/- 14.6; n = 10), smoking sarcoidosis patients (17.9 +/- 8.4; n = 6) and inactive sarcoidosis patients (14.5 +/- 8.2; n = 3). Since ACE has been demonstrated by immunofluorescence in mononuclear phagocytes in granulomas, the authors speculate that macrophages recovered by alveolar lavage are not activated and do not reflect sarcoid alveolitis at the tissue level.     

Lung T cells in hypersensitivity pneumonitis

Monoclonal antibodies OKT3 (all T cells), OKT4 (T-helper/inducer), and OKT8 (T-suppressor/cytotoxic) were used to determine surface phenotypes of bronchoalveolar lavage and peripheral blood lymphocytes in patients with chronic hypersensitivity pneumonitis. Similar studies were done in asymptomatic pigeon breeders, patients with sarcoidosis, and nonsmoking controls. Increased numbers of lavage T cells were found in patients with hypersensitivity pneumonitis and sarcoidosis and in asymptomatic pigeon breeders. The predominant T-cell subset in patients with hypersensitivity pneumonitis and in asymptomatic pigeon breeders was T8 +; in contrast, the predominant subset in those with sarcoidosis was T4 +. Peripheral blood T-cell subsets were normal in all groups. Thus, most lung T lymphocytes in chronic hypersensitivity pneumonitis belong to the T8 + subset; the local cellular immune response in hypersensitivity pneumonitis and sarcoidosis are different; and the pattern of alveolitis, as determined by bronchoalveolar lavage, is not the sole determinant of lung impairment after exposure to hypersensitivity pneumonitis antigens.     

Hypersensitivity pneumonitis induced by toluene diisocyanate: sequelae of continuous exposure

A 41-year-old automobile paint sprayer showed the clinical features of hypersensitivity pneumonitis 1 week after he had begun to work with paint materials containing toluene diisocyanate. His symptoms began 6 to 8 hours after exposure to the agent and spontaneously disappeared by the next morning. He had diffuse, fine reticulonodular shadows on a chest roentgenogram and a restrictive impairment of pulmonary function. Immunoglobulin G antibody to toluene diisocyanate-human serum albumin was present in bronchoalveolar lavage fluid and sera: IgA antibody was present only in bronchoalveolar lavage fluid. Also, the patient had sensitized bronchoalveolar lymphocytes to toluene diisocyanate-human serum albumin. The histologic findings suggested hypersensitivity pneumonitis. The results of bronchoalveolar lavage, which was repeated on four separate occasions, showed lymphocytosis and a predominance of suppressor-cytotoxic T cells. The findings from serial determinations of humoral antibodies showed no changes consistent with the results of clinical and laboratory studies. In contrast, blastogenic responses of bronchoalveolar lymphocytes to toluene diisocyanate markedly decreased, and the patient showed clinical improvement despite continued exposure to the agent.     

Functional significance of anti-T-lymphocyte antibodies in sarcoidosis

Pulmonary sarcoidosis is a chronic disorder characterized by the activation of helper/inducer T-cells in the lung without a concomitant increase in suppressor/cytotoxic T-cells. It is known that patients with sarcoidosis have circulating anti-T-cell antibodies, primarily of the IgM class. To evaluate a functional role for these antibodies in enhancing lung helper T-cell processes in pulmonary sarcoidosis, we evaluated serum and lavage fluid of patients with active sarcoidosis for the presence of anti-T-cell antibodies, the T-cell subset specificity of these antibodies, and the possible stimulatory or inhibitory effects of these antibodies on T-cells relevant to the exaggerated helper T-cell processes in sarcoidosis. Indirect immunofluorescence studies demonstrated that sarcoid patients had anti-T-cell antibodies of the IgM type reacting with autologous as well as with nonautologous normal T-cells. IgM recovered in sarcoid lavage fluid also reacted with T-cells, thus demonstrating the autoantibodies at the site of disease. Two-color immunofluorescence and flow cytometry showed that these sarcoid autoantibodies bound to mostly Leu2+ suppressor/cytotoxic T-cells, but also to a small proportion of Leu3+ helper/inducer T-cells. Incubating lymphocytes with sarcoid serum or IgM purified from sarcoid serum did not stimulate T-cell proliferation. Furthermore, when Leu2+ T-cells were stimulated with irradiated allogenic B-cells, increasing concentrations of sarcoid serum had no inhibitory effects on the activation and proliferative response of the Leu2+ T-cells. Likewise, the purified IgM anti-T-cell antibodies had no inhibitory effects on the mitogenic response of Leu2+ T-cells to the anti-T-cell antigen receptor-associated T3 complex antibody OKT3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated Tenascin-C Levels in Bronchoalveolar Lavage Fluid of Patients with Sarcoidosis

Background

Sarcoidosis is a disease characterized by granulomatous lesions involving multiple organ systems. The etiology of sarcoidosis remains unknown, and reliable biomarkers have not been identified. Tenascin-C is an extracellular matrix molecule expressed during wound healing in various tissues. The present study aimed to investigate the role of tenascin-C in sarcoidosis.

Methods

Enzyme-linked immunosorbent assays were used to measure tenascin-C levels in serum and bronchoalveolar lavage fluid (BALF) from 31 patients with sarcoidosis and 15 healthy individuals. Relationships between tenascin-C concentrations in BALF and serum samples and clinical parameters in patients with sarcoidosis were evaluated.

Results

BALF tenascin-C levels were significantly higher in patients with sarcoidosis than in healthy individuals, but serum levels were no different. BALF tenascin-C levels showed positive correlations with serum lactic dehydrogenase levels and the ratio of lymphocytes in BALF. BALF tenascin-C levels were also higher in patients with parenchymal infiltration on chest radiographs than in those without.

Conclusions

The present results demonstrated that the BALF tenascin-C level was correlated with pulmonary infiltrates on chest radiographs in patients with sarcoidosis. Although measurement of serum tenascin-C levels has a limited role and measurement of BALF tenascin-C levels might be impractical, tenascin-C in the lung might play a role in the pathogenesis of sarcoidosis. Further studies are necessary to determine the role of BALF tenascin-C in sarcoidosis.     

Correlation between 25-hydroxyvitamin D3 1 alpha-hydroxylase gene expression in alveolar macrophages and the activity of sarcoidosis

PURPOSE: To demonstrate expression of the 25-hydroxyvitamin D3 1 alpha-hydroxylase (1 alpha-hydroxylase) gene in human alveolar macrophages and measure the correlations among the 1 alpha-hydroxylase mRNA level, the activity of sarcoidosis, and calcium metabolism. SUBJECTS AND METHODS: We examined 7 patients with sarcoidosis and 6 control patients with other pulmonary disorders who underwent bronchoalveolar lavage. Levels of 1 alpha-hydroxylase mRNA were measured by semiquantitative polymerase chain reaction amplification. We measured serum levels of calcium, ionized calcium, parathyroid hormone, calcitriol (1,25-dihydroxyvitamin D3), and 25-hydroxyvitamin D3 to evaluate calcium metabolism. To estimate the activity of sarcoidosis, we measured the cell count, the CD4/CD8 ratio in bronchoalveolar lavage cells, and the serum angiotensin-converting enzyme (ACE) activity. RESULTS: Expression of 1 alpha-hydroxylase was demonstrated in purified human alveolar macrophages. The 1 alpha-hydroxylase mRNA levels in bronchoalveolar lavage cells were fivefold higher in sarcoidosis patients than in control patients (10.8 +/- 3.6 vs. 2.2 +/- 1.4, P <0.003). Among all patients studied, there were significant correlations between the 1 alpha-hydroxylase mRNA level in bronchoalveolar lavage samples and the percentage of alveolar lymphocytes (r = 0.83, P <0.005), the CD4/CD8 ratio (r = 0.77, P <0.02), serum ACE level (r = 0.58, P <0.05), serum ionized calcium level (r = 0.58, P <0.05), and the calcitriol/25-hydroxyvitamin D3 ratio (r = 0.57, P <0.05). In the sarcoidosis patients, a significant correlation was also observed between 1 alpha-hydroxylase mRNA and the percentage of alveolar lymphocytes (r = 0.82, P <0.05). CONCLUSION: There is a correlation between 1 alpha-hydroxylase gene expression in alveolar macrophages with the activity of sarcoidosis and its associated disturbances in calcium metabolism.     

Increased levels of interleukin-18 in patients with pulmonary sarcoidosis

Interleukin-18 (IL-18) has recently been identified as an interferon-gamma (IFN-gamma)-inducing factor, and it plays an important role in T helper 1 (Th1) response. We measured the serum levels of IL-18 and IFN- gamma in 37 patients with pulmonary sarcoidosis and 25 healthy control subjects. We also measured the levels of IL-18 and IFN-gamma in 10-fold concentrated bronchoalveolar lavage (BAL) fluids of 19 patients with pulmonary sarcoidosis and 9 healthy control subjects (all lifelong nonsmokers). The levels of serum IL-18 and IFN-gamma were significantly increased in patients with sarcoidosis. The levels of BAL fluid IL-18 were significantly elevated in patients with sarcoidosis, however, the IFN-gamma levels of the patients and control subjects were all below sensitivity. Serum IL-18 levels significantly correlated with serum IFN-gamma levels and lysozyme activity. The patients positive for gallium-67 ((67)Ga) scan had significantly elevated serum IL-18 levels as compared with those of the negative patients. BAL fluid IL-18 levels significantly correlated with serum IL-18 levels in patients with sarcoidosis, and there was a significant correlation between IL-18 levels and lymphocyte proportions in sarcoid BAL fluids. In patients with sarcoidosis, IL-18 seems to induce IFN-gamma production and IL-18 levels in sera may reflect disease activity of sarcoidosis.     

Chitotriosidase activity in the serum of patients with sarcoidosis and pulmonary tuberculosis

BACKGROUND: Human chitotriosidase is a chitinase selectively expressed by activated macrophages. An increase in chitotriosidase activity was previously described by us in the serum and bronchoalveolar lavage of sarcoidosis patients. OBJECTIVE: The aim of the present study was to analyze serum chitotriosidase activity in a larger number of sarcoidosis patients to verify the reported increase with respect to controls and to compare serum chitotriosidase levels in patients with sarcoidosis and tuberculosis, two granulomatous disorders of different etiology. METHODS: Chitotriosidase activity was measured in the serum of 96 sarcoidosis patients, 15 pulmonary tuberculosis patients and 30 healthy controls. RESULTS: We found significantly higher serum chitotriosidase activity in sarcoidosis patients than controls (p < 0.01) and in sarcoidosis patients than tuberculosis patients (p < 0.01), confirming a striking elevation of chitotriosidase activity (>10 times greater than normal) in pulmonary sarcoidosis patients. This is the first time that chitotriosidase activity has been analyzed in the serum of patients with pulmonary tuberculosis; it was found to be significantly lower than in sarcoidosis patients and not significantly greater than in controls. CONCLUSION: Although the mechanisms leading to the increase in chitotriosidase activity in sarcoidosis are still unknown, this enzyme may be specifically involved in the pathogenesis of the disease. Further studies with a greater number of patients are needed to confirm these results and to determine whether chitotriosidase could be a marker with diagnostic or prognostic value in sarcoidosis.     

Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients.

Scandinavian human leukocyte antigen-DR17-positive (DR17+) sarcoidosis patients are characterised by a good prognosis. They also reveal an accumulation in bronchoalveolar lavage fluid of T-lymphocytes expressing the T-cell receptor V gene segment AV2S3 at disease onset. The authors of this study wished to establish whether AV2S3 T-lymphocyte accumulation changes from disease onset to clinically resolved disease and how this relates to other activity parameters. Bronchoalveolar lavage fluid and serum from nine DR17+ sarcoidosis patients were examined at disease onset and after spontaneous resolution of clinical and radiographical signs of disease. Nine DR17+ patients with lung accumulated CD4+ AV2S3+ T-cells were investigated after clinically recovery. At re-examination the percentage of CD4+ AV2S3+ lymphocytes in bronchoalveolar lavage fluid was normalised (29 versus 5.4%). A significant reduction in lymphocyte percentage (14 versus 4.4%) and a decrease in cellular concentration (179x10(6) x L(-1) versus 111x10(6) x L(-1)) and CD4/CD8 ratio (5.2 versus 2.4) were also seen. In serum, the activity of angiotensin-converting enzyme (24.9 versus 14.0 U x mL(-1)) as well as the levels of neopterin (7.8 versus 5.3 nmol x L(-1)) decreased significantly after recovery. These results indicate that the locally accumulated AV2S3 positive T-lymphocytes in bronchoalveolar lavage are involved in the pathogenic process of sarcoidosis in this patient group.     

Significance of lymphocytosis in bronchoalveolar lavage in suspected ocular sarcoidosis.

Ocular sarcoidosis is frequent in Japan, but in many cases the condition remains undiagnosed in patients with suspected ocular sarcoidosis. Bronchoalveolar lavage (BAL) was performed in order to study the clinical implications of lymphocytosis of BAL fluid in such patients with characteristic ocular manifestations. The subjects included in this study were 39 patients with suspected ocular sarcoidosis. The patients were divided into four types based on high-resolution computed tomography (HRCT) findings; no lung involvement (HRCT-0), bilateral hilar lymphadenopathy (BHL) without lung involvement (HRCT-I), lung involvement and BHL (HRCT-II), and lung involvement and no BHL (HRCT-III). Transbronchial lung biopsy (TBLB) and BAL were conducted after examining serum angiotensin-converting enzyme and serum lysozyme values, skin test for purified protein derivative chest radiograph, HRCT, and gallium scintigram. Twenty patients were histologically diagnosed as having sarcoidosis, and 19 patients remained undiagnosed. Granuloma was identified by TBLB in 19 of 20 patients in type HRCT-II but in only one of 19 patients in types HRCT-0 and HRCT-I (p<0.0001). Lymphocytosis in BAL (>15%) was identified in all patients who showed lung field involvement (type HRCT-II) and in 16 of 19 patients without lung field involvement (types HRCT-0 and HRCT-I). There were 10 patients whose only relevant findings were lymphocytosis in BAL. Among these 10 patients, an increased CD4+/CD8+ ratio (>3.5) in BAL was seen in 60%. The authors conclude that high-resolution computed tomography results yield the same degree of diagnostic accuracy as transbronchial lung biopsy in ocular sarcoidosis suspects. However, bronchoalveolar lavage revealed significant lymphocytosis in patients with negative high-resolution computed tomography results. It should be kept in mind that a diagnostic group of patients with sarcoidosis who manifest ocular involvement and lymphocytosis in bronchoalveolar lavage exists.     

Serial changes in markers of disease activity with corticosteroid treatment in sarcoidosis

Serial changes in various markers of disease activity with corticosteroid therapy were assessed in 12 patients with active sarcoidosis. After six weeks of treatment with 40 mg daily of prednisone, all but one patient demonstrated symptomatic and radiographic improvement. For the entire patient group, there were corresponding improvements in forced vital capacity, from 59.2 +/- 5.5 to 70.5 +/- 5.3 percent of the predicted value (p less than 0.001, Student paired t test), serum angiotensin-converting enzyme levels, from 66.0 +/- 12.1 to 28.2 +/- 4.0 U/ml (p = 0.003), 67gallium lung scanning scores, from 3.6 +/- 0.2 to 0.8 +/- 0.3 (p less than 0.001), serum gamma globulin levels, from 2.40 +/- 0.2 to 1.5 +/- 0.1 g/dl (p less than 0.001), and erythrocyte sedimentation rate, from 26.8 +/- 2.7 to 14.8 +/- 3.0 mm per hour (p less than 0.001). Changes in percent of bronchoalveolar lavage fluid lymphocytes were less impressive (from 28.7 +/- 4.9 to 21.2 +/- 5.1, p = 0.034), but the geometric mean number of bronchoalveolar lavage fluid-IgG-secreting cells decreased from 23,861 to 3,830 (p = 0.013). Serial evaluations in five patients treated with decreasing doses of alternate-day prednisone for an additional 10 1/2 months indicated that changes in 67gallium lung scanning scores corresponded most closely to the clinical course in five of five patients. Determination of serum angiotensin-converting enzyme levels also closely paralleled the clinical course in four of five patients, whereas the other parameters measured were more variable markers of clinical response. However, abnormalities of bronchoalveolar lavage fluid-IgG-secreting cells often persisted in the absence of clinically evident disease, and the percentages of bronchoalveolar lavage fluid lymphocytes were frequently normal in patients who responded subsequently to corticosteroids. Larger prospective studies are warranted to more extensively evaluate various measurements of disease activity, especially bronchoalveolar lavage fluid analysis, in sarcoidosis.     

Serum Clara cell protein (CC16), a marker of the integrity of the air-blood barrier in sarcoidosis.

To test the hypothesis that sarcoidosis is associated with an intravascular leakage of lung epithelium secretory proteins, the occurrence and determinants in serum of sarcoid patients of CC16, a small size and readily diffusible lung-specific protein of 16 kDa secreted by bronchiolar Clara cells, was investigated. CC16 was measured by a sensitive latex immunoassay in the serum of 117 patients with established sarcoidosis and of 117 healthy subjects matched for age, sex and smoking status. Stepwise regression analysis was used to identify extrapulmonary variables of CC16 changes in serum. These changes were then compared with biochemical and cellular parameters in bronchoalveolar lavage fluid (BALF) as well as with the number of CC16 immunostaining cells on bronchial or pulmonary biopsy samples. CC16 concentration in serum of sarcoid patients was significantly increased, compared to their matched controls (25.9 +/- 16.2 versus 13.9 +/- 5.2 microg x L(-1)). In nonsmoking patients without significant renal impairment, CC16 in serum increased with the severity of the chest radiograph and computed tomography changes, and was on average 50-100% higher when parenchymal involvement was present. Sarcoid patients had, however, normal levels of CC16 in BALF and an unchanged number of CC16-immunopositive cells in lung biopsy samples, suggesting that an increased secretion of CC16 in the sarcoid lung is very unlikely, and that the elevation of CC16 in sarcoidosis results from an increased intravascular leakage of the protein across the air-blood barrier. The present study suggests that CC16 in serum might provide a useful tool to noninvasively evaluate the damage and increased permeability to proteins of the air-blood barrier associated with sarcoidosis.     

Plasma matrix metalloproteinase 7, CC-chemokine ligand 18, and periostin as markers for pulmonary sarcoidosis

BackgroundSome patients with sarcoidosis experience worsening of pulmonary lesions. However, no biomarker has been identified that reflects pulmonary disease status in sarcoidosis. We investigated the usefulness of potential markers of pulmonary fibrosis in patients with sarcoidosis.MethodsPlasma matrix metalloproteinase 7 (MMP-7), CC-chemokine ligand 18 (CCL-18), and periostin levels were evaluated in 60 patients with sarcoidosis and 30 healthy controls; bronchoalveolar lavage fluid levels were analyzed in 22 patients with sarcoidosis. To determine the usefulness of these markers, we explored potential correlations between these markers and sarcoidosis clinical characteristics.ResultsPlasma MMP-7, CCL-18, and periostin concentrations were significantly higher in patients with sarcoidosis than those in healthy controls. MMP-7 concentrations in plasma and bronchoalveolar lavage fluid were higher in patients with sarcoidosis with parenchymal infiltration than in those without lung lesions. Moreover, MMP-7 concentration was negatively correlated with pulmonary function.ConclusionAmong these novel biomarkers, MMP-7 most precisely reflected pulmonary sarcoidosis disease status and thus, might be useful for diagnosing and evaluating sarcoidosis, particularly in patients with pulmonary parenchymal lesions.     

Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases.

It has previously been reported that the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF) was different from that in the tissues of patients with other interstitial lung diseases (ILDs). The aim of this study was to determine whether this difference reflects the amount of MCP-1 in the bronchoalveolar lavage fluid (BALF) or serum of patients with ILD, and whether such a correlation, if it exists, is clinically useful. MCP-1 concentrations in the BALF and sera were evaluated in 86 patients with ILDs including IPF, acute interstitial pneumonia, interstitial pneumonia with collagen vascular disease (IP-CVD), chronic interstitial pneumonia (CIP), bronchiolitis obliterans-organizing pneumonia, sarcoidosis, hypersensitivity pneumonitis, and in 10 normal healthy volunteers who were controls (NC). BALF MCP-1 levels were significantly elevated in the IPF, IP-CVD, CIP and sarcoidosis groups compared with the NC group. The level in the IPF group was significantly higher than that in any other patient group. Serum MCP-1 levels in the IPF, IP-CVD, CIP and sarcoidosis groups were significantly higher than the NC group. No statistical difference was found in serum MCP-1 levels between the IPF, IP-CVD and CIP groups. BALF MCP-1 levels were significantly higher than serum MCP-1 levels in the IPF group and lower than in the IP-CVD and CIP groups. Serum MCP-1 levels correlated with the clinical course of ILD treated with corticosteroid therapy. These results show that measurement of monocyte chemoattractant protein-1 levels in both bronchoalveolar lavage fluid and serum may be helpful in discriminating idiopathic pulmonary fibrosis from other types of interstitial lung disease and that monitoring of serum monocyte chemoattractant protein-1 may be useful for predicting the clinical course of interstitial lung diseases.     

"Sarcoidosis-like" granulomatous disease in patients with common variable hypogammaglobulinemia

Particular attention has been recently dedicated to the development of a sarcoidosis-like form in patients with common variable immunodeficiency (CVI). In sarcoidosis a 5-fold increase in the number of cells in the bronchoalveolar lavage compared with normal controls has been described and the predominance of CD4+ T cells is a common feature. In contrast to patients affected by sarcoidosis or CVI, patients with co-existence of the two diseases had a more favorable prognosis, as progressive pulmonary fibrosis occurred only in a few cases even when persistent alveolar lymphocytosis was present. Moreover, patients presenting with concomitant sarcoidosis and CVI, showed a lower rate of respiratory infections and of the evolution towards bronchiectasies in comparison with patients affected by CVI alone. The clinical evolution observed in our patients was similar with that reported in other studies and confirms their clinical features. One may speculate that the increase in the number of macrophages and T lymphocytes, as suggested by the increased cellularity in the bronchoalveolar lavage of these patients, can produce a peculiar microenvironment characterized by high levels of soluble factors (cytokines). In turn, the latter could be responsible for a more efficacious effector phase of the immune response. This may explain the reduced rate of infectious diseases and consequently of bronchiectasies observed in CVI patients.     

Predictive value of gallium scan, angiotensin-converting enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis

Evaluation of patients with pulmonary sarcoidosis with serum angiotensin-converting enzyme (ACE), gallium scan, and bronchoalveolar lavage (BAL) has proved useful in demonstrating active disease, especially in the lungs. Long-term prognosis based on the results of pretreatment ACE, gallium scan, and BAL has not been previously clarified. We studied 44 patients with initially symptomatic pulmonary sarcoidosis who were begun on steroid therapy after initial evaluation. At 2 years, 21 of 44 (48%) patients still had worsening disease. Of 31 patients who had positive gallium scan pretreatment, 21 (68%) still had worsening disease at 2 years. None of the 13 patients with a negative gallium scan had worsening disease at 2 years (Chi square = 14.2, P less than 0.01). Similar analysis of the pretreatment serum ACE level, percentage of lymphocytes in the BAL fluid, and ratio of T-helper/inducer to T-suppressor/cytotoxic (T4/T8) in the BAL fluid also had some predictive value for worsening disease at 2 years; however, these tests were less sensitive than the gallium scan. In patients with pulmonary sarcoidosis, the finding of a negative gallium scan suggests a small likelihood that disease activity will worsen after 2 years.