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Biomedical subjects

G Kahaly

Publications and source records attributed to G Kahaly.

At least 37 records · Page 2Linked to original sources
PubMed1996

T cells and orbital connective tissue in endocrine orbitopathy.

In order to analyse the immunological changes in patients with endocrine orbitopathy (EO) the antigenic character of orbital connective tissue was studied. Counter-stimulation assays of patients' lymphocytes with autologous retrobulbar fibroblasts resulted in a markedly increased lymphocyte proliferation in comparison to incubation with retrobulbar control fibroblasts. Proliferation tests of retrobulbar T cell lines showed significant responses to autologous retro-orbital connective tissue proteins, with molecular weights of 6-10 kD and 19-26 kD. Phenotypic analysis of orbital T cell lines indicates that they consisted predominantly of CD4+ cells. Hyaluronic acid production of orbital fibro blasts following co-cultivation with lymphocytes of EO patients or controls revealed a threefold increased synthesis in patients with EO. Furthermore, distribution pattern of orbital extracellular matrix glycosaminoglycans (GAG) differs in EO patients in comparison to controls. The results suggest the presence of autoreactive T cells directed against antigens of orbital fibroblasts, whose stimulation results in an augmented GAG synthesis in patients with EO.

Connective Tissue↗
PubMed1996

Impaired cardiopulmonary exercise capacity in patients with hyperthyroidism.

STUDY OBJECTIVE: Hyperthyroidism (H) has been implicated as a primary cause of decreased exercise tolerance. To our knowledge, analysis of respiratory gas exchange, an efficient noninvasive method in evaluating cardiopulmonary capacity, has not been performed in patients with H. PATIENTS: Using cardiopulmonary exercise testing, 12 consecutive women with Graves' H were examined and controlled in euthyroidism (E). Eighteen women with E, in whom cardiac catheterization had ruled out heart disease, served as control subjects (C). MEASUREMENTS: The ventilatory anaerobic threshold was determined by means of the V-slope method. Ergometry was performed with patients in a semisupine position using a continuous ramp protocol of 20 W/min. Echocardiography at rest was performed in all patients. RESULTS: In patients with H, heart rate at rest was higher than in patients with E (p < 0.05) and showed a markedly lower increase between rest and anaerobic threshold compared with E patients (p = 0.007) and C (p = 0.009). Work rate was reduced (H, 50% vs E, 70%; p = 0.038). In H patients, the anaerobic threshold occurred at 59.6% of maximal oxygen uptake and 72% in E patients, respectively (p = 0.024). In H patients, the linear regression of the heart rate to oxygen uptake ratio showed a reduced slope in comparison with E patients (p = 0.001) and C (p = 0.004). In patients with H, a reduced tidal volume (p = 0.021) and an increased respiratory rate (p = 0.003) in comparison to patients with E were demonstrated. Echocardiographically, H patients had an increased ejection fraction (p = 0.008) and a higher cardiac index (p = 0.008) in comparison with E patients. CONCLUSIONS: Analysis of respiratory gas exchange showed marked alterations of cardiopulmonary exercise capacity in H patients, which are reversible in E patients. The impaired chronotropic response during exercise might be the primary limiting factor of reduced work capacity in patients with H.

Adult↗
PubMed1996

[Cardiopulmonary involvement in thyroid gland diseases].

Thyroid hormones exercise a direct influence on the lung and myocardium. It has been found that at the heart of patients suffering from hyperthyroidism there is an increased production of contractile proteins and a redistribution of myosin Isoenzymes. Reduced efficiency results from the increased oxygen consumption and insufficient adaptation of the heartbeat to stress. Thyroid hormones are responsible for reducing arterial resistance; a higher incidence of supraventricular arrhythmias has been observed. In contrast, the cardiac changes in hypothyroidism are associated with an enhanced deposition of glycosaminoglycan in the myocardium. Besides bradycardia and low voltage there is an increased incidence of pericardial, pleural and peritoneal effusions with high protein content. Patients suffering from hypothyroidism have a higher incidence of atherosclerotic changes. Hypothyroidism is associated with a reduction of the beta-adrenergic receptors, and hence disturbances of rhythm are rare and do not increase even under substitution therapy. Pulmonary involvement in hyperthyroidism is evident from an enhanced respiratory minute volume, a reduced vital capacity, and dyspnoea at rest. In patients suffering from hypothyroidism, hypoventilation reduces the efficiency. Over and above this, myopathic changes of the respiratory muscles have been described. Involvement of thyroid hormones in the maturing of type II pneumocytes and of the surfactant factor has also been under discussion.

Cardiovascular Diseases↗
PubMed1996

[Cardiovascular effects of thyroid hormones].

The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypothyroidism or hyperthyroidism. Triiodothyronine (T3)-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, T3 leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart. The pathophysiologic basis for myxedema is the opposite of that discussed for the hyperthyroid heart. In addition to decreased direct effects of thyroid hormone in cardiac myocytes, indirect effects occur through decreases in peripheral oxygen consumption and changes in hemodynamic parameters. Myofibrillar swelling with loss of striation and interstitial fibrosis occurs on histologic examination of hypothyroid hearts. In addition, accumulation of mucopolysaccharide substances (Glycosaminoglycans) can be demonstrated. On electron microscopic examination, mitochondria show disruption and lipid inclusion. Cardiac papillary muscle obtained from animals with hypothyroidism shows a depression of the force velocity curve and reduced rate of tension development, indicating significant contractile abnormalities. In patients with hypothyroidism, a true enhanced incidence of hypertension (increased peripheral vascular resistance) has been found. In addition, hypercholesterolemia and impairment of fatty acid mobilization are associated with myxedema and present additional risk factors for the development of atherosclerotic cardiovascular disease.

Animals↗
PubMed1995

Prevalence of myxomatous mitral valve prolapse in patients with lymphocytic thyroiditis.

In conclusion, given the cardiac (mitral regurgitation, endocarditis, thromboembolic complications, arrhythmic sudden death) and neurologic (cerebral embolic event) complications of the pathologic forms of MVP, physicians should look carefully for myxomatous involvement of the mitral valve and prolapse in patients with autoimmune thyroid diseases. Patients should be monitored and prophylactic antibiotic treatment recommended when appropriate.

Adult↗
PubMed1995

Autoimmune endocrine ophthalmopathy and retrobulbar antigens.

Endocrine Ophthalmopathy (EO) is based on autoimmune processes that lead to lymphocyte infiltration of the retrobulbar space. In this study, antigenic character of retrobulbar adipose, connective and muscle tissue as well as of cultured fibroblasts and myoblasts were examined. Samples were obtained from EO patients (n = 13, 8 fem., age 26-82 years, median 47 years) undergoing orbital decompression surgery. Retrobulbar and abdominal tissue from 7 controls (4 fem., 48 - 74 y) was investigated, too. Tissues were homogenized and the proteins were separated by SDS-PAGE according to molecular weight. In order to recover the separated proteins in soluble form, an electroelution technique was employed. Twenty-two separated soluble protein fractions were used as antigenic stimuli for autologous peripheral blood mononuclear cells (PBMC) separated by Ficoll gradient centrifugation. Subsequently, the proliferation of T cells was measured by [3H]-thymidine uptake. A marked T cell response to protein fractions with molecular weight of 6 - 10 kD and 19 - 26 kD was detected (p < 0.001). These autoantigens were found readily reproducible in adipose tissue in 8 out of 9 EO patients, stimulation index (SI) to antigen 6 - 10 kD 29 +/- 4.6 (mean +/- SEM); 19 - 26 kD 5 +/- 1.4 and in 3 out of 4 patients using retrobulbar eye muscle tissue (SI: 6 - 10 kD 23 +/- 4.2; 19 - 26 kD 6 +/- 2). Using the proteins of cultured fibroblasts as antigen, the autologous PBMC from 2 out of 4 tested EO-patients also responded (SI: 7 +/- 2; 4 +/- 1.4). Testing cultured retrobulbar myoblasts of an EO patient, a response to the 19 - 26 kD antigen was found only (SI: 8.0). In response to retrobulbar or muscle proteins, PBMC of 2 controls showed also a higher proliferation rate (SI: 16 +/- 3.5; 13 +/- 2.8), whereas, a response to abdominal adipose or muscle proteins (4 controls) was never found. Thus, two orbital antigens reacting with autologous T cells could be demonstrated and may play an important role in the immunopathogenesis of EO. According to these findings, retrobulbar fibroblast antigens are most likely the main T cell targets.

Adipose Tissue↗
PubMed1995

Insulin-dependent diabetes mellitus and glycosaminoglycans.

The influence of diabetic nephropathy on urinary glycosaminoglycan distribution was assessed in 96 patients with insulin-dependent diabetes mellitus (IDDM, 49 female, age: 16 - 64 yrs, median 35; duration of IDDM: 0 - 43 yrs, median 13 yrs) in comparison to 103 healthy controls (57 female, 17 - 82 yrs, median 40 yrs). Glycosaminoglycan concentration of 24 h urine samples was determined by means of precipitation with cethylpyridinium chloride and potassium acetate in ethanol followed by a colorimetric test with carbazole. A marked difference (p = 0.0008) in urinary glycosaminoglycan excretion between patients (19.0, 12.4, 35.6 mg/24 h, median, 25th, 75th percentile) and controls (15.8, 10.4, 21.6 mg/24h) could be detected. In patients with insulin-dependent diabetes mellitus of longer duration, glycosaminoglycan excretion was increased (<10 years: 17.3, 10.8, 30.5 mg/24 h; > 10 yrs: 23.3, 16.0, 39.1 mg/24 h; p = 0.03). Furthermore, diabetic patients with manifest nephropathy and retinopathy exhibited a significantly higher glycosaminoglycan excretion compared to patients without nephropathy (40.8, 23.3, 42.2 versus 18.2, 11.4, 31.0 mg/24 h, p = 0.005) or retinopathy (31.9, 16.6, 41.6 versus 17.6, 11.2, 26.7 mg/24 h, p = 0.009). Thus, the results of this study demonstrate a close relationship between diabetic nephropathy and the renal glycosaminoglycan excretion.

Adolescent↗
PubMed1995

Role of octreoscan and correlation with MR imaging in Graves' ophthalmopathy.

Since the identification of somatostatin receptors on lymphocytes, orbital infiltration with mononuclear cells in Graves' ophthalmopathy has provided a rationale for receptor imaging with the radiolabeled somatostatin analog Octreotide. In 40 patients with Graves' ophthalmopathy and 10 controls, 110 MBq indium-Octreotide were administered i.v., and scans were performed at 4 and 24 h after injection. An uptake ratio between the orbits and the brain was determined. In 20 ophthalmophathy patients, magnetic resonance imaging (MRI) of the orbits was performed and the T2 relaxation time was measured within the rectus muscles. Compared to controls (4 h Octreotide uptake: median 6.0 counts/pixel/MBq, orbit/brain ratio 5.6), ophthalmopathy patients showed a 2- to 3-fold increased uptake (15.8 counts/pixel/MBq vs controls p = 0.0032; ratio 12.6, vs controls p = 0.003). When considering patients with active disease only, a higher uptake was registered (16.8 counts/pixel/MBq vs controls p 0.0048, ratio 15.6 vs controls p = 0.0006). Untreated patients showed a markedly higher uptake (23 counts/pixel/MBq) compared to patients receiving steroid therapy (12.6, p = 0.001). MRI of the orbit revealed a correlation between T2 relaxation time of the eye muscles and orbital uptake of Octreotide (p < 0.001).

Adult↗
PubMed1995

Response to methimazole in Graves' disease. The European Multicenter Study Group.

OBJECTIVE: A variety of regimens continue to be used in the treatment of Graves' disease with antithyroid drugs. We have investigated the factors which determine the initial response to methimazole (time until euthyroidism is achieved) in Graves' disease. PATIENTS: Five hundred and nine patients with Graves' disease in different European countries with normal and subnormal iodine supply. Patients were randomized to treatment with either 10 or 40 mg of methimazole per day for one year, with levothyroxine supplementation as required to maintain euthyroidism. Investigations were carried out before treatment and at 3 and 6 weeks and 3, 6, 9 and 12 months. MEASUREMENTS: Response was assessed by serial measurements of serum thyroid hormones. TSH receptor antibodies, thyroid autoantibodies and urinary iodide excretion were measured centrally. Twenty-minute thyroid uptake was measured by standard techniques. Data were collected and analysed centrally. Standard techniques as well as a stepwise logistic regression model were used to examine the relations between methimazole dose, age, goitre size, presence of endocrine eye signs, thyroid hormone levels, urinary iodide excretion, thyroid uptake, index of disease severity (Crooks), presence of TSH receptor antibodies and duration of the hyperthyroid phase. RESULTS: Within 3 weeks, 40.2% of patients responded to 10 mg of methimazole and 77.5% responded within 6 weeks. The corresponding figures for 40 mg of methimazole were 64.6 and 92.6%. Significant associations were found between duration of hyperthyroidism and the following variables: goitre size, urinary iodide excretion, methimazole dose, presence of TSH receptor antibodies (TBIAb), index of disease severity (Crooks) and pretreatment thyroid hormone levels. Response to methimazole was delayed in patients with large goitres, iodine excretion of > or = 100 micrograms/g creatinine, high pretreatment thyroid hormone levels, elevated levels of TBIAb and treatment with only 10 mg of methimazole. In the 10-mg group, 46% of patients were euthyroid within 3 weeks when urinary iodide was < 50 microgram/g of creatinine, and only 27% when iodide was above 100 micrograms/g. By stepwise logistic regression, the main factors for the response to methimazole were daily dose, pretreatment T3 levels, and goitre size. CONCLUSION: Methimazole dose, pretreatment serum T3 levels, and goitre size are the main determinants of the therapeutic response to methimazole in Graves' disease, at least in areas comprising low, subnormal and normal iodine supply.

Adult↗
PubMed1995

[The Müller-ectomy in endocrine orbitopathy].

Thyroid ophthalmopathy frequently causes significant upper- and lower-eyelid retraction. This is not only cosmetically disfiguring, but also causes the cornea to be exposed so that a lid-correcting procedure becomes necessary. We used the Mueller ectomy technique with mechanical disinsertion of the levator muscle of the upper eyelid, as described by Putterman et al. in 1972, and operated on ten patients with thyroid ophthalmopathy. By means of the Mueller ectomy and mechanical disinsertion of the levator muscle of the upper eyelid, the eyelid was lowered by 5.0 mm compared with the preoperative findings (measured as the distance between the edge of the upper eyelid and the center of the pupil). In 3 cases the postoperative result was a temporal upper eyelid flare that required operative correction in one case; in one case a ptosis resulted postoperatively. Transconjunctival Mueller ectomy with mechanical disinsertion of the levator muscle of the upper eyelid gives good cosmetic and functional results in patients with significant upper-eyelid retraction. The transconjunctival approach avoids external scar formation and leaves the external lid structures intact so that a revision can be performed by an external lid incision.

Adult↗
PubMed1995

[Imaging of metastases from thyroid carcinomas using 111In-pentetreotide scintigraphy].

There is little experience with imaging of thyroid carcinoma tissue by somatostatin receptor scintigraphy. Our case report describes an acromegalic patient, in whom 111In pentetreotide scintigraphy did not only demonstrate a receptor-positive pituitary tumor but also visualized metastases from a papillary thyroid carcinoma which had no correlate in radioiodine scintigraphy carried out under hypothyroid conditions. The possible role of this radiopharmaceutical in dedifferentiating thyroid carcinoma is discussed for its usefulness in tumor localisation and its predictive value for the outcome of an octreotide therapy.

Female↗
PubMed1995

Indium-111-pentetreotide scintigraphy in Graves' ophthalmopathy.

UNLABELLED: The radiolabeled somatostatin analog 111In-pentetreotide can sensitively demonstrate somatostatin receptor-positive localizations in diseases where activated lymphocytes play a role. Lymphocyte infiltration of retrobulbar tissue in Graves' ophthalmopathy is the rationale of receptor imaging with radionuclide-coupled 111In-pentetreotide. METHODS: Forty patients with Graves' ophthalmopathy, 5 patients with orbital myositis and 10 control subjects were included in this prospective study. Indium-111-pentetreotide (110 MBq) was intravenously injected and SPECT images were obtained at 4 and 24 hr after injection. The scans were analyzed by a region of interest technique. An uptake ratio between the orbits and the brain was determined. RESULTS: Compared to controls (4-hr 111In-pentetreotide uptake: median 6.0 counts/voxel/MBq, orbit-to-brain ratio 5.6), ophthalmopathy patients showed two- to threefold increased uptake (15.8 counts/voxel/MBq versus controls p = 0.0032; ratio 12.6 versus controls p = 0.003). When considering patients with active disease only, even higher uptake was registered (16.8 counts/voxel/MBq versus controls p = 0.0048, ratio 15.6 versus controls p = 0.0006). Untreated patients showed markedly higher uptake (23 counts/voxel/MBq) compared to patients under steroid therapy (12.6, p = 0.001). In myositis, high uptake (20 counts/voxel/MBq) was also registered. CONCLUSION: In contrast to controls, ophthalmopathy patients showed markedly increased orbital accumulation of labeled 111In-pentetreotide. This sensitive nuclear medicine technique could possibly select those patients who might benefit from treatment with immunosuppressive agents and/or octreotide.

Eye↗
PubMed1995

[Cardiovascular parameters in transient hypothyroidism].

Cardiovascular manifestations are a frequent finding in hypothyroidism. Thus, blood-pressure measurements, longtime electrographic monitoring, and spiroergometry were examined in 20 patients with transitory hypothyroidism. In the patients with thyroid carcinoma, total thyroidectomy was performed. Measurements were made in hypothyroidism and after TSH-suppression with L-thyroxine. Thirty-five patients in whom intracardiac catheter examination ruled out cardiopulmonary disease served as controls. Cardiopulmonary exercise was done by bicycle exercise testing. In transitory hypothyroidism an increase of diastolic blood pressure was found at rest (p = 0.02) and during exercise (p = 0.002), which was reversible after T4-therapy. Compared to the controls diastolic blood pressure in hypothyroidism was increased at rest (p = 0.014) and during exercise (p = 0.005). ECG-monitoring showed a day-night difference in heart rate in hypothyroid patients and after therapy. The mean heart rate (74 vs. 88 beats per minute; p = 0.0006), the minimal (p = 0.0062) and the maximal heart rate (p = 0.0016) during the day were decreased in hypothyroidism compared to euthyroidism. There were no atrioventricular blocks in transitory hypothyroidism and no increase of ventricular or supraventricular premature beats after high-dose T4-treatment. Spiroergometry showed no change in ventilation and an increased growth in heart rate (p = 0.021) associated with good working capacity in hypothyroid patients. Heart rate at rest (p = 0.004) and at the anaerobic threshold (p = 0.03) were decreased in transitory hypothyroidism.

Adult↗
PubMed1994

Immunohistochemical staining of retrobulbar adipose tissue in Graves' ophthalmopathy.

An increase of retrobulbar adipose tissue has been shown by imaging techniques in patients with Graves' ophthalmopathy (GO). Immunohistochemical staining was applied to investigate the involvement of different retrobulbar (especially adipose) tissue components in the autoimmune process of the disease. Cryostat sections from retrobulbar tissues of 15 GO patients and 11 controls were analyzed with a battery of monoclonal antibodies against CD2, CD4, CD8, CD11a, CD19/22, CD25, CD54, CD57, CD68, C3b, HLA-A, B, C, and HLA-DR. In contrast to controls, the retrobulbar adipose tissue showed an increase of HLA-DR expression, an activation of intercellular adhesion molecule I (ICAM-1, CD54), as well as a marked infiltration of activated T-cells (especially CD4) and macrophages (CD68), whereas a positive staining for interleukin-2 receptors (CD25), T-cells (CD2), B-cells (CD19/22), complement factors (C3b), and LFA-1 (CD11a) was present only in a few patients' specimens. Staining for natural killer cells (CD57) was negative in fat tissue of patients and controls. The perimuscular connective tissue sections of GO patients showed an accumulation of T-cells (CD4/CD8), an enhanced display of ICAM-1, LFA-1, HLA-DR-positive cells, and B-cells. Retrobulbar muscle tissue of GO patients exhibited an increase of CD4, CD8, CD54, CD68, and HLA-DR-positive cells, located in the intramuscular connective tissue, exclusively. In conclusion, the present study underlines the involvement of retrobulbar adipose tissue in the immunopathogenesis of Graves' ophthalmopathy.

Adipose Tissue↗
PubMed1994

Plasma glycosaminoglycans in endocrine ophthalmopathy.

With evidence on the important role of glycosaminoglycans (GAG) in the pathogenesis of endocrine ophthalmopathy (EO) having accumulated, the present study focused on the biochemical assessment of plasma GAG content in 37 EO patients as compared to 20 controls. Glycosaminoglycans were isolated from plasma samples by protein elimination, dialysis, and precipitation with ethanol and cetylpyridinium chloride. Patients (9.71, 5.09, 15.09 mg/100 ml; median, 25th, 75th percentile) exhibited significantly (p = 0.0021) higher plasma GAG levels than controls (4.6, 3.38, 6.8 mg/100 ml). Plasma GAG content was unrelated to age, sex, or antithyroid treatment. However, an even higher level of significance (p = 0.0001) was reached when discriminating between untreated patients with EO of recent onset (14.16, 10.35, 15.51 mg/100 ml) and controls. By contrast, steroid therapy of EO led to values (3.82, 1.85, 6.52 mg/100 ml) indistinguishable from those of the controls. Further statistical analysis of the results, based on a specificity of 95% for the control group, revealed a sensitivity of 91% for patients with untreated EO of recent onset, and a specificity of 100% for patients receiving steroid therapy. In comparison, plasma GAG content was determined in 8 untreated and in 6 treated EO patients by a second method already published. All untreated patients exhibited high GAG levels (median 2.23 mg/100 ml) whereas in treated EO patients normal plasma GAG values (0.17-0.34 mg/100 ml) were found. Follow-up determination of plasma GAG content in 7 patients undergoing steroid treatment unveiled a marked decrease of initially elevated values. These findings correlated well with clinical improvement of thyroid eye disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Somatostatin receptor scintigraphy in endocrine orbitopathy].

Somatostatin receptor scintigraphy with 111In-labeled octreotide proves to be a very sensitive diagnostic tool for evaluation of inflammative activity in endocrine ophthalmopathy (EO). The results of somatostatin receptor scintigraphy (SRS) in 40 patients with EO show a high orbital accumulation of 111In-octreotide in clinically active EO (4 h-median/orbit-brain-ratio: 12.6; controls 4 h-median: 5.8) Patients with clinically inactive EO (4 h-median: 7.1) show a similar orbital accumulation of radioactivity compared to controls. 5 patients with active orbital myositis also revealed an even higher orbital accumulation of radioactivity (4 h-median: 42.3). The diagnostic value of SRS lies in its ability to act as a measure of inflammation and can be useful as an activity parameter when planning therapeutic procedure as well as for EO follow-up. The results in patients with orbital myositis nevertheless do not permit a differential diagnosis with this method. The therapeutic value of 111In-octreotide in Graves' disease has yet to be established.

Adult↗
PubMed1994

Cellular immunity and retrobulbar fibroblasts in Graves' ophthalmopathy.

In Graves' ophthalmopathy (GO), retrobulbar connective tissue is infiltrated by T cells whose role in the pathogenesis of the disease was investigated in the present work. The aims included firstly to characterize subsets of blood lymphocytes and of sessile lymphocytes cloned from a retroorbital tissue specimen. Second, in counterstimulation assays, the ability of patients' T cells to influence cultivated retrobulbar fibroblasts and in turn the enhancement of lymphocyte proliferation by retrobulbar fibroblasts was investigated. Blood lymphocytes of 16 GO patients and 12 controls isolated by density gradient centrifugation and retrobulbar fibroblasts obtained from orbital decompression were alternately exposed to irradiation of 4000 rad (to suppress proliferation of either cell type), then cocultivated for 48 h. Subsequently, the cells (250,000 lymphocytes, 5000 retrobulbar fibroblasts) were incubated with [3H]thymidine for 24 h. A stimulation index representing the degree of proliferation in comparison with a control was determined. Screening of 62 retrobulbar lymphocyte clones by cell-ELISA revealed a CD4/CD8 ratio of 8.2, contrasting with a normal ratio of 2.1 in peripheral lymphocytes (as obtained by FACS analysis). Incubation of patient's lymphocytes with autologous retrobulbar fibroblasts resulted in a markedly elevated stimulation index (9.7) compared to incubation of lymphocytes with retrobulbar fibroblasts from controls (2.5). In another assay, the degree of stimulation amounted to 2.2 vs. -0.8. Retrobulbar fibroblasts were stimulated twice as much by lymphocytes of the same patient compared to retrobulbar fibroblasts from controls. The autologous reactions demonstrated suggest the presence of autoreactive T lymphocytes in GO patients directed against retrobulbar fibroblasts, which, in addition, are stimulated by these lymphocytes.

Adult↗