[Sarcoidosis. Critical review on immunology in sarcoidosis and serum angiotensin converting enzyme in sarcoidosis (author's transl)].
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Clinical Enzyme Tests↗
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Elevation of angiotensin-converting enzyme in granulomatous lymph nodes and serum in sarcoidosis: clinical and possible pathogenic significance.
A statistically highly significant elevation of serum ACE was found in a group of 58 patients with sarcoidosis (serum ACE was elevated in 34% of patients), as compared with normal controls and patients with tuberculosis and various other common diseases. The results suggest that serum ACE is a useful aid for the diagnosis of sarcoidosis when elevated, but that a normal value does not rule out the condition and may occur in more than one-half of monitored patients. There is a trend to diminution of serum ACE with increasing duration of disease with or without steroid therapy, perhaps correlating with the total body mass of active granulomas, as indirectly suggested in preliminary data by correlation of serum ACE with serum globulin in 16 sarcoidosis patients. It is not yet clear whether there is any significant steroid effect on serum ACE, but a significant number of patients on steroid therapy for more than 2-4 yr have elevated serum ACE values, which in some instances are extremely high. There was a 12-fold elevation in ACE to specific activities generally exceeding those of normal lung in granulomatous lymph nodes of 14 patients with sarcoidosis, suggesting that sarcoid granulomas may be actively synthesizing ACE and resulting in elevation of serum ACE. Extensively fibrotic sarcoid lymph nodes had normal or slightly elevated ACE, suggesting that obliteration of granulomas in sarcoid lymph nodes diminishes their ACE content and that this obliteration may be related to the tendency to diminution of serum ACE with time. ACE was not elevated in one tuberculous lymph node or in experimental granulomas, suggesting that elevation of ACE may have some specificity for the granuloma of sarcoidosis rather than being a characteristic of all granulomas. The catalytic and physical properties of ACE in serum and lymph nodes in sarcoidosis were generally similar to normal ACE with respect to pH activity, modulators, polyacrylamide-gel electrophoresis, and Sephadex G-200 gel filtration. However, sarcoid lymph node ACE appeared to be more heat labile than normal lung or lymph node ACE, suggesting the possibility that an abnormal ACE may be present in sarcoidosis. If an abnormal enzyme is indeed present, it might be coded for by a host gene that is not normally expressed or a nonhost gene or it might be a normal ACE that has been altered. No ACE activity was found in circulating white blood cells in sarcoidosis or in control subjects, suggesting that circulating white blood cells may not contain the epithelioid cell precursor or that ACE synthesis (or less likely, uptake) may be turned on at a later stage in the transformation. Lysozyme activity was also elevated in sarcoid lymph nodes. Serum ACE and serum lysozyme were significantly positively correlated in 16 sarcoidosis patients, suggesting a relationship between the two...
Granuloma↗
Localization of the immune response in sarcoidosis.
Pulmonary sarcoidosis is an interstitial disease characterized by granulomas within the lung parenchyma, anergy to a variety of skin tests, and decreased numbers of circulating T-lymphocytes. To evaluate the effector cell populations present at sites of disease in patients with active pulmonary sarcoidosis, inflammatory and immune effector cells were isolated from lung via bronchoalveolar lavage and compared to comparable cell populations from the peripheral blood of the same patients and similar cell populations of normal subjects and patients with idiopathic pulmonary fibrosis. Patients with sarcoidosis had a marked increase in the percentage of T-lymphocytes in the lung despite a significant peripheral blood T-lymphocytopenia. In addition, many of these T-lymphocytes demonstrated surface marker characteristics associated with lymphocyte activation, and they spontaneously secreted leukocyte inhibitory factor. In contrast to patients with sarcoidosis, normal subjects and patients with idiopathic pulmonary fibrosis had similar percentages of T-lymphocytes in lung and blood, and there was no evidence for T-lymphocyte activation. Analysis of lymphocytes in uninvolved marrow from 7 of 8 patients with sarcoidosis revealed proportions of T-lymphocytes similar to those in the marrows of normal subjects and patients with idiopathic pulmonary fibrosis. In comparison, one patient with sarcoidosis had large numbers of T-lymphocytes in bone marrow, but only in areas where there were granulomas in the marrow. These studies suggest that: (1) the alveolitis of pulmonary sarcoidosis is characterized by large numbers of activated T-lymphocytes, and (2) there is an anatomic localization of the immune response in sarcoidosis in that analysis of uninvolved tissues such as peripheral blood may not reflect local immune responses at sites of granuloma formation.
Adult↗
[Cholinergic bronchial reactivity in patients with sarcoidosis].
The acetylcholine aerosol test was used for testing 65 patients suffering from sarcoidosis for cholinergic bronchial hyperexcitability. Among 46 patients with stage I and stage II sarcoidosis there was only one female patient where the acetylcholine aerosol test gave positive results; however, it was not possible to establish a relationship between bronchial hyperexcitability and sarcoidosis. In two other patients with stage III sarcoidosis, where the acetylcholine aerosol test also gave positive results, there obviously was a close relationship between bronchial hyperexcitability and sarcoidosis. It is considered that positive acetylcholine aerosol test results might be interpreted as being indicative of stage III sarcoidosis. It should be noted in this connection that the third or fibrotic stage of sarcoidosis was characterized by a very much smaller number of cases showing positive acteylcholine aerosol test results than are, in general, observed for those forms of tuberculosis which are accompanied by more or less widespread fibrous processes taking place in, and causing major alterations to, the lungs and which may be described as chronically hematogenously disseminated, fibrocavernous, and cirrhotic forms of pulmonary tuberculosis. Also discussed in detail are the possible reasons for this different behavior.
Acetylcholine↗
Histological and histochemical pattern of phytohemagglutinin (PHA) skin test in patients with sarcoidosis.
Phytohemagglutinin (PHA) is a non-specific stimulant of blastogenic transformation and proliferation of T-lymphocytes in vitro. This material has been used for detection of a reduced lymphoblastic transformation in vitro and, as a skin test, for providing information in the evaluation of cellular immunodeficiency in man (BLAESE et al. 1973). As in sarcoidosis the immunological features are "depression of delayed-type hypersensitivity suggesting T-cell anergy and raised serum immunoglobulins suggesting B-cell overactivity", the authors used PHA skin test in comparison with patients with tuberculosis and M. Hodgkin. PHA positive reactions recorded at 72 hrs. were in 95% for sarcoidosis, 90% for tuberculosis and 5% for M. Hodgkin. But the histological and histochemical investigation of cutaneous biopsies demonstrated three significant differences at 72 hrs. in untreated patients with sarcoidosis compared to the material of tuberculosis patients: formation of lymphatic pseudo-follicles, an increased number of arteriovenous anastomoses and appearance of C-mucopolysaccharide (a histochemical marker of connective tissue in sarcoidosis). There were in sarcoidosis, unlike tuberculosis, blast cells, plasmocytes and a number of lymphocytes at 72 hrs. It is difficult for the authors to explain the different behaviour of the PHA skin test in sarcoidosis and tuberculosis. The appearance of the C-mucopolysaccharide might be a result of the raised serum level of IgM in patients with sarcoidosis.
Glycosaminoglycans↗
Serum angiotensin-converting enzyme (SACE) in sarcoidosis and other granulomatous disorders.
Serum angiotensin-converting enzyme (SACE) activity was significantly higher in 90 patients with sarcoidosis (55 +/- [S.D.] 23 nmol min-1 ml-1) than in 80 healthy controls (34 +/- 9 nmol min-1 ml-1). Steroid therapy modified SACE activity; 60 sarcoidosis patients who were not being treated with steroids had significantly higher enzyme activities (58 +/- 24 nmol min-1 ml-1) than 30 steroid-treated sarcoidosis patients (40 +/- 19 nmol min-1 ml-1). In 50% of the non-steroid treated sarcoidosis patients SACE activity was more than 2 S.D. above the mean value for the controls. SACE activity was measured in 22 tuberculous patients (38 +/- 14 nmol min-1 ml-1), 20 leprosy patients (34 +/- 9 nmol min-1 ml-1), 31 with primary biliary cirrhosis (44 +/- 20 nmol min-1 ml-1), 26 with inflammatory bowel disease (31 +/- 9 nmol min-1 ml-1), 8 with hepatic granulomatous disease, 5 with Hodgkin's disease, and 2 with schistosomiasis. The combined false-positive rate for these non-sarcoidosis patients was 10%. Serial SACE assays provide useful information on the course of sarcoidosis and response to steroid treatment.
Acute Disease↗
[Sarcoidosis of the skeleton. Review of the literature and case report. (author's transl)].
The frequency of sarcoidosis in the skeleton varies between 3 and 36%. Skeletal sarcoidosis is rare in early stages (Löfgren-syndrom), relatively frequent in late stages. The initial phase is characterized by the formation of miliary non-caseating epitheloid-cell granulomas in the bone marrow. The invasion of the bone marrow may either be tolerated by the bone tissue or it initiates a perifocal osteosclerosis or a osteolysis. Correspondingly the X-ray of the skeleton shows normal structure or focal osteosclerosis or osteolysis. Therefore in the first case the sarcoidosis cannot be identified by X-ray. Most frequent locations are the phalanges of the fingers and toes, less common the stem skelton (skull, vertebrae, pelvis) and very rare the long tubular bones. In most cases the skeletal sarcoidosis is well tolerated. Report of a case of osteosclerotic sarcoidosis of the pelvis of a 39-years old woman with generalized sarcoidosis which was diagnozed four years earlier. The X-rays of the phalanges were normal. The biopsy of the iliac crest shows miliary sarcoid granuloma of the bone marrow and accretion of lamellar bone on the surface of the bone trabeculi with a distinct mosaic pattern. Treatment with steroids during the following five years was ineffective.
Adolescent↗
Angiotensin-converting enzyme in sarcoidosis.
Using a spectrophotometric assay with L-hippuryl-L-histidyl-L-leucine as substrate, s-angiotensin-converting enzyme (SACE) was determined in 85 sarcoidosis patients, 116 healthy controls and 150 patients with various non-sarcoid diseases. The controls showed no sex or age variation and had SACE levels of 24.4 +/- 6.2 U/ml (mean +/- 1 S.D.), giving a normal range (mean +/- 2 S.D.) of 12.0-36.8 U/ml. In contrast, the sarcoidosis patients had SACE values of 38.4 +/- 14.4 U/ml, with the highest values in cases with active sarcoidosis and duration of disease longer than two years (49.0 +/- 12.7 U/ml). A total of 41% of the sarcoidosis patients had elevated SACE, in the chronic active group 85%. Patients with renal failure, Hodgkin's disease and other malignant lymphoma had low SACE, whereas patients with lung cancer and tuberculosis had normal SACE values. Among 266 patients with non-sarcoid diseases and healthy controls, only two had slightly elevated SACE, but so far we have not found SACE above 40 U/ml in other than sarcoidosis patients. An elevated SACE is rather specific in sarcoidosis and seems to be a useful supplement to existing diagnostic measures.
Adolescent↗
Serum angiotensin--converting enzyme (SACE) in sarcoidosis and other granulomatous disorders.
Serum angiotensin-converting enzyme (SACE) activity was significantly higher in 90 patients with sarcoidosis (55 +/- [S.D.] 23 nmol min-1 ml-1) than in 80 healthy controls (34 +/- 9 nmol min-1 ml-1). Steroid therapy modified SACE activity; 60 sarcoidosis patients who were not being treated with steroids had significantly higher enzyme activities (58 +/- 24 nmol min-1 ml-1) than 30 steroid-treated sarcoidosis patients (40 +/- 19 nmol min-1 ml-1). In 50% of the non-steroid treated sarcoidosis patients SACE activity was more than than 2 S.D. above the mean value for the controls. SACE activity was measured in 22 tuberculous patients (38 +/- 14 nmol min-1 ml-1), 20 leprosy patients (34 +/- 9 nmol min-1 ml-1), 31 with primary biliary cirrhosis (44 +/- 20 nmol min-1 ml-1), 26 with inflammatory bowel disease (31 +/- 9 nmol min-1 ml-1), eight with hepatic granulomatous disease, five with Hodgkin's disease, and two with schistosomiasis. The combined false-positive rate for these non-sarcoidosis patients was 10%. Serial SACE assays provide useful information on the course of sarcoidosis and response to steroid treatment.
Adolescent↗
Lymphocyte transformation, rosette formation and behaviour of immunoglobulins in sarcoidosis.
1. Patients with sarcoidosis indicated significant decrease of the mean value of lymphocyte transformation (LT) in all stages and all periods of sarcoidosis. In chronic sarcoidosis the mean value of LT was significantly lower (27.6%) than in the initial active stage I (44.6%) and increased among patients who recovered from sarcoidosis. 2. Patients suffering from sarcoidosis have depressed percentage of T lymphocytes compared to healthy subjects and depressed ability to lymphocytes blast transformation after PHA stimulation. No significant difference exists in the percentage of B cells detected by rosette formation with normal subjects. 3. The mean values of IgG, IgA and IgM in sarcoidosis patients were higher, and became normal after recovery. Levels of immunoglobulins were successively increased according to the stage. An increased IgG level is connected with active phase of the process whereas IgA is more stable but rised.
Animals↗
Pilot study identifying distinct circulating proteomic profiles associated with longitudinal CT-defined fibrotic and inflammatory sarcoidosis.
INTRODUCTION: Pulmonary sarcoidosis exhibits heterogeneous clinical trajectories ranging from self-limited disease resolution to chronic progressive fibrosis, yet reliable biomarkers capable of distinguishing these disease patterns remain lacking. Whether longitudinal CT-defined sarcoidosis phenotypes are associated with distinct circulating molecular signatures remains unknown. METHODS: We performed high-throughput plasma proteomics (SomaScan 11K) in participants with pulmonary sarcoidosis classified into longitudinal chest CT-defined progressive fibrosis, progressive nodular inflammatory disease, or resolving disease trajectories, along with healthy controls. CT phenotypes were assigned based on predefined longitudinal changes in reticulation, traction bronchiectasis, nodular involvement, and mediastinal lymphadenopathy across serial CT scans. One plasma sample per participant was selected from the study visit corresponding to the CT time point at which criteria for the assigned longitudinal phenotype were met. Principal component analysis, hierarchical clustering, pathway enrichment, and correlation-based analyses linking protein expression to quantitative CT features were used to evaluate whether distinct longitudinal CT phenotypes were associated with divergent proteomic signatures. RESULTS: Principal component analysis and hierarchical clustering suggested partial segregation by CT-defined phenotype. Longitudinal CT phenotypes were associated with distinct pathway-level proteomic signatures, with progressive fibrosis enriched for epithelial-mesenchymal transition signaling, and progressive nodular inflammatory disease enriched for mTORC1, MYC, oxidative phosphorylation, adipogenesis, and fatty acid metabolism pathways. Correlation analyses showed coordinated protein-expression patterns associated with fibrotic CT features and mediastinal lymph node enlargement. DISCUSSION: These findings suggest that longitudinal CT-defined fibrotic and inflammatory sarcoidosis phenotypes are associated with distinct pathway-level proteomic signatures. This pilot study provides preliminary proof-of-concept evidence that integrating longitudinal CT imaging phenotypes with plasma proteomics may serve as a framework for future mechanistic studies and biomarker discovery in pulmonary sarcoidosis.
Humans↗
Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis.
The level of serum angiotensin-converting enzyme (ACE) was elevated in 15 of 17 patients with active sarcoidosis. Serum ACE was studied to determine the effect of chronic lung disease upon the blood level of an enzyme believed to originate from the lungs. The assay was performed in approximately 200 control subjects and 200 patients with chronic lung disease using hippuryl-L-histidyl-L-leucine as substrate. Enzyme activity greater in male control subjects than in female subjects of comparable age and greater in children than in adults. Serum ACE was significantly reduced in patients with chronic obstructive lung disease, lung cancer, tuberculosis and cystic fibrosis, as compared to control subjects, and was even lower in those receiving corticosteroids. Of greatest interest, however, was that levels in patients with active sarcoidosis not receiving steroids were greater than 2 standard deviations above the mean for the adult control subjects (greater than 11.6 units) whereas levels in patients with sarcoidosis receiving steroids and in those with resolved disease were normal. A survey of subjects with other granulomatous diseases failed to reveal any other condition that was significantly associated with a similar elevation of serum ACE levels. Elevation of ACE levels in sarcoidosis appears to be associated with the active disease process and does not appear to be a familial inherited enzyme abnormality. An assay of serum ACE is a useful tool for regulating therapy in sarcoidosis and for confirming the diagnosis, since it readily distinguishes these patients from others with tuberculosis, lung cancer or lymphoma.
Adult↗
Conjunctival biopsy in the diagnosis of sarcoidosis.
The diagnosis of sarcoidosis with ocular involvement is often difficult and accompanied by a certain measure of uncertainty due to a paucity of additional physical signs. In the ophthalmic literature, it is controversial as to whether biopsy of a clinically normal conjuctiva should be done if sarcoidosis is suspected. Many authors advocate biopsy only in the presence of conjunctival follicles or nodules. However, a positive biopsy from a clinically normal-appearing conjunctiva has been reported. Recently, we saw a patient with bilateral uveitis, evanescent cranial nerve palsies, and other clinical manifestations suggesting central nervous system and ocular sarcoidosis. Random biopsy of a normal-appearing conjunctiva revealed a noncaseating granuloma consistent with sarcoidosis. Since conjunctival biopsy is a simple office procedure with minimal morbidity, this diagnostic tool should be considered for patients with clinically suspected sarcoidosis, even in the absence of conjunctival follicles or nodules.
Adult↗
The specificity and nature of serum-angiotensin-converting enzyme (serum ACE) elevations in sarcoidosis.
Elevation of serum-angiotensin-converting enzyme (serum ACE) in patients with active sarcoidosis was confirmed in a total of 64 subjects with a mean serum ACE of 15.76+/-7.4 units compared with 6.05+/-2.0 units in 194 patients with other types of respiratory disease. Resolution of the sarcoidosis disease state or therapeutic control with adequate doses of corticosteroids (15 mg prednisone daily) brought the elevated serum ACE levels down into the normal range. A longitudinal study of serum ACE activity was found to be an effective way of judging the therapeutic efficacy of various steroid dosage levels. No other disease state involved in the differential diagnosis of sarcoidosis was found to have elevations of serum ACE activity. However, 6 patients with Gaucher's disease did have elevated serum ACE activity that ranged well above the usual level seen even in patients with sarcoidosis. The two diseases could be readily distinguished in the laboratory by elevated serum acid phosphatase activity in most cases of Gaucher's disease. It would appear that detection of elevated serum ACE levels can be a useful procedure for confirming a diagnosis of active sarcoidosis and for judging the therapeutic response.
Adult↗
Value of measuring serum angiotensin I converting enzyme and serum lysozyme in the management of sarcoidosis.
Serum angiotensin I converting enzyme (ACE) and lysozyme have been measured in 23 controls, 115 patients with sarcoidosis, and 64 with other chest diseases. Both enzymes were significantly raised in sarcoidosis. ACE was raised above the normal range in 21 of 72 (29%) patients with definite sarcoidosis and in 17 of 38 (45%) of those who were untreated and seen within one year of presentation. The rise discriminated usefully between those with stable and progressive disease (5% and 62% respectively). Lysozyme was raised in 50 of 72 (69%) patients with sarcoidosis but also in 11 of 54 (20%) patients with other chest diseases. Discrimination between stable and progressive disease was useful only if very high levels were considered. Five patients had serial measurements after treatment with oral steroids and showed a progressive fall in levals of both enzymes, but patients with other diseases also showed a significant fall within the normal range when so treated. Measurement of these enzymes may help in the management of some cases of sarcoidosis, but results require critical interpretation.
Adult↗
Pulmonary and extrapulmonary sarcoidosis in relation to circulating immune complexes: a quantification of immune complexes by two radioimmunoassays.
Serum specimens from 53 patients with pulmonary sarcoidosis were examined for the presence of immune complexes by 2 methods, the Raji cell and the monoclonal rheumatoid factor radioimmunoassays. We found increased concentrations of immune complexes in the sera of 27 patients by one or both techniques. A significant association was found between increased concentrations of immune complexes and stage III sarcoidosis. Seventeen of 23 patients with stage III sarcoidosis and 10 of 50 with stage I or II disease had increased concentrations of immune complexes. Eight of the 10 patients with stage I or II sarcoidosis and increased concentrations of immune complexes had extrapulmonary sarcoid features, such as erythema nodosum, synovitis, or salivary gland enlargements. The size of the immune complex was 15S in one of the patients examined. Concentrations of C4 were normal. The data suggest a possible role of immune complexes in the pathogenesis of pulmonary and extrapulmonary features of sarcoidosis.
Adult↗
[Angiotensin converting enzyem (ACE) - a blood chemistry parameter in the diagnosis of sarcoidosis].
Serum angiotensin converting enzyme (ACE) activity was studied in 50 patients with sarcoidosis (39 active, 11 inactive sarcoidosis), as well as in 50 control patients (34 chronic lung diseases, 9 Hodgkin-disease, 7 rheumatoid arthritis). There is a significant difference (p less than 0.001) of ACE-activity between sarcoidosis patients and controls, and between active (without steroid treatment) and inactive sarcoidosis. Steroid treatment apparently lowers ACE-activity in sarcoidosis, however, without evidence for clinical improvement. Increased ACE-activity was also found in a patient with primary biliary cirrhosis.
Adrenal Cortex Hormones↗
[Diagnostic value of serum angiotensin converting enzyme activity in sarcoidosis (author's transl)].
Serum angiotensin converting enzyme activity was measured in 60 blood donors and 100 patients with sarcoidosis histologically confirmed using a spectrophotometric assay with hippurylhistidylleucine as substrate. Sex related differences in the enzyme activity could not be observed. ACE was found to be markedly raised above the normal range (the mean of the control subjects plus 2 standard deviations) in 53 (58.2%) out of 91 untreated patients. The distribution of the enzyme activities was significantly different as compared to the control group. Nine patients with sarcoidosis receiving steroids had a mean level within the normal range. ACE level in stage II group tended to be more elevated compared to stage I, but this difference was not significant. Extrapulmonary sarcoidosis (with and without pulmonary involvement) appeared to be associated with especially high ACE activities. The distribution of the enzyme activities within the groups of untreated patients failed to reveal statistically significant differences. Therefore it was not possible to determine the clinical state of the disease and to discriminate between the stages (I and II) of sarcoidosis by the measurement of serum ACE level. However as the results suggest serum ACE assays can be a useful aid in diagnosis of sarcoidosis. Further investigations may demonstrate the value of this in vitro method for the clinical management of the disease including prognosis and therapeutic effects.
Adolescent↗