Suppressor cell activity in progressive systemic sclerosis

Prostaglandin-producing suppressor cell activity was significantly increased in patients with progressive systemic sclerosis (p less than .01). No significant differences were found in concanavalin-A induced suppressor T cell activity. Although these results indicate an alteration in immunoregulatory function they may represent a compensatory reaction to a defect in the regulation of fibrogenesis.     

Gastrointestinal function in patients with progressive systemic sclerosis

Summary In 24 patients with progressive systemic sclerosis (PSS) the pentagastrin-stimulated gastric acid secretion was determined to investigate if acid hypersecretion is associated with reflux-oesophagitis — the most common complication to oesophageal involvement in PSS. Gastro-oesophageal reflux was observed in 12, reflux-oesophagitis in 9 and oesophageal mycosis in 8 patients. Gastric acid secretion was increased in 13 (54%) patients and tended to be higher in patients with oesophagitis. Patients with reflux and increased acid secretion seemed to be free from oesophageal mycosis. Bacterial overgrowth and malabsorption are known complications to intestinal scleroderma and these items were investigated using non-invasive methods. Four patients had increased bile acid deconjugation, 3 had increased (¹⁴C)xylose degradation indicating bacterial overgrowth and 7 patients had decreased fat absorption in the triolein breath test. Nutritional status with respect to selenium, folate, cobalamine and fat-soluble vitamins was essentially normal.     

Cytochemistry of human T lymphocyte subpopulations in peripheral blood

With sequential investigation of immunological and cytochemical markers on single cells, T lymphocyte subsets defined by monoclonal antibodies were examined in the peripheral blood of healthy adults. Leu-3a+ T cells (helper/inducer) were 80.0 +/- 6.6% dot positive with unspecific acid alpha-naphthyl acetate esterase (ANAE) and 52.2 +/- 15.8% dot positive with diaminopeptidase IV (DAP IV) staining, as compared to 52.6 +/- 7.6% ANAE and 29.1 +/- 10.9% DAP IV dot positivity in Leu-2a+ T cells (suppressor/cytotoxic). Although these differences were significant (P less than 0.001 and P = 0.002, respectively), the rather high % of dot positivity in Leu-2a+ cells precludes ANAE or DAP IV staining as a simple method for the determination of T lymphocyte subsets. In acid phosphatase staining, no significant difference in focal positivity between Leu3a+ and Leu-2a+ T cell subpopulations was detected (63.3 +/- 10.9% and 52.3 +/- 10.0%, respectively; P greater than 0.1).     

Exocrine pancreatic function in patients with progressive systemic sclerosis

The exocrine pancreatic function was investigated in 16 patients with progressive systemic sclerosis by means of a meal test (Lundh test) and in 9 of the patients by the secretin-cholecystokinin test as well. Gastrointestinal involvement with progressive systemic sclerosis was evaluated by esophageal manometry and by routine roentgenographic series of the small bowel. Fecal fat excretion measurement, the D-xylose absorption test, and a small-intestinal biopsy procedure were carried out. Duodenal juice was cultured and bacterial counts were estimated. One-third of the patients had reduced exocrine pancreatic function, but only four patients had unequivocally a reduction that could be of clinical importance. The results obtained with the meal test were in accordance with the secretin-cholecystokinin test, indicating a preserved capacity for endogenous stimulation.     

Suppressor T lymphocyte function in patients with idiopathic congestive cardiomyopathy

Suppressor T lymphocyte function was examined in 11 patients with idiopathic congestive cardiomyopathy and in 11 age and sex matched patients with a similar degree of heart failure resulting from ischaemic heart disease. Suppressor T lymphocyte function was also assessed in a control population of 11 normal subjects. Suppressor T lymphocyte function was reduced in both groups of patients with heart failure but not significantly, and a wide range of suppression was demonstrated in all groups. These data do not support the hypothesis that there is a defect in T lymphocyte function in patients with congestive cardiomyopathy, but they do suggest that there may be a non-specific reduction in T lymphocyte suppressor function associated with heart failure in general.     

Analysis of lymphocyte subpopulations in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic inflammatory connective-tissue disease of unknown etiology, characterized by fibrosis and microvascular injury in affected organs. It has become clear that the activated cellular-immune system plays a central role in the pathogenesis of SSc. This study analyzes the numbers of lymphocyte subpopulations and their relations with clinical and laboratory manifestations. We studied a group of 42 patients with SSc and a group of 28 matched normal controls by flow cytometry using the lymphocyte cell-surface markers CD2, CD3, CD4, CD8, CD19, CD25, CD45RA, CD56, CD71, HLA-DR, TCR alpha/beta, and TCR gamma/delta. Patients with SSc had similar percentages of CD2+, CD3+, CD3+ CD4+, CD3+, CD8+, CD25+, CD4+ CD45RA+, CD8+ CD45RA+, CD71+ cells, and CD4+/CD8+ cell ratio when compared to normal controls. In contrast, the percentages of TCR gamma/delta cells were significantly lower in SSc patients with diffuse and late-stage disease with pulmonary involvement, muscle involvement, and the presence of anti-Scl-70 antibodies. Patients with diffuse SSc in early- and late-stage disease had significantly increased percentages of HLA-DR in CD4+ and CD8+ cells. Patients with late-stage disease had increased percentages of CD4+ CD45RA+ T-cells. Patients with limited and early-stage disease had smaller percentages of B-cells (CD19+). Patients with diffuse and late-stage disease had smaller percentages of NK-cells (CD56+). These results suggest that T-, B-, and NK-cell alterations may be involved in the onset of the disease, and/or in the perpetuation of disease, and may eventually be useful as a prognostic indicator in selected patient subgroups.     

Increased proto-oncogene expression in peripheral blood T lymphocytes from patients with systemic sclerosis

The expression of c-myc, c-myb, and c-ras proto-oncogenes, determined using RNA hybridization techniques (slot-blot), was significantly increased in peripheral blood T lymphocytes, but not in B cells, from 17 patients with systemic sclerosis with diffuse scleroderma, compared with the expression in normal control subjects. The magnitude of expression of c-myc and c-myb tended to be higher in patients with early, active disease. These results demonstrate an in vivo activation of T cells from systemic sclerosis patients, which may play an important role in the pathogenesis of the disease.     

Chromosome abnormalities in peripheral lymphocytes from patients with progressive systemic sclerosis

Summary Chromosomal abnormalities in cultured peripheral lymphocytes from 14 progressive systemic sclerosis (PSS) patients and 15 normal subjects were examined. No increase was observed in the frequency of chromosome aberrations in PSS patients who had not received any medical treatment. Those who had received medication showed an increased frequency of dicentrics (0.3%) although the frequency was not significantly higher than that for normal subjects. It is not clear, however, whether the increase was due to the hypersensitivity of PSS patients to agents used for therapeutic purposes.     

Defective Epstein-Barr virus specific suppressor T cell function in progressive systemic sclerosis.

Several immunoregulatory defects of Epstein-Barr virus (EBV) induced B cell activation have been described in patients with rheumatoid arthritis (RA), suggesting that EBV may have a role in the pathogenesis of RA. We assessed EBV specific T cell regulation in 20 patients with progressive systemic sclerosis (PSS) and immune to EBV and in 10 control subjects also immune to EBV by comparing the secretion of IgM into supernatants of 16 day cultures of B cells alone and cocultures of B and autologous T cells. In control subjects autologous T cells mediated a significant decrease in the secretion of IgM by B cells at 12 and 16 days of culture. Analysis of individual responses showed the existence of two subgroups of patients with PSS: group I (10 patients) had a suppressor T cell function similar to that of controls; group II (10 patients) had a defective T cell function. Differences in the duration or severity of the disease, the slow acting therapeutic agents, and anti-inflammatory drugs could not account for these subdivisions. These results suggest that several immunoregulatory defects of EBV induced B cell activation exist in different connective tissue diseases.     

Suppressor T lymphocyte function in patients with idiopathic congestive cardiomyopathy.

Suppressor T lymphocyte function was examined in 11 patients with idiopathic congestive cardiomyopathy and in 11 age and sex matched patients with a similar degree of heart failure resulting from ischaemic heart disease. Suppressor T lymphocyte function was also assessed in a control population of 11 normal subjects. Suppressor T lymphocyte function was reduced in both groups of patients with heart failure but not significantly, and a wide range of suppression was demonstrated in all groups. These data do not support the hypothesis that there is a defect in T lymphocyte function in patients with congestive cardiomyopathy, but they do suggest that there may be a non-specific reduction in T lymphocyte suppressor function associated with heart failure in general.     

Cardiovascular function in patients with progressive systemic sclerosis (scleroderma)

Sixteen patients with progressive systemic sclerosis (PSS), including 3 with the "CREST" (calcinosis, Raynaud's, esophageal dysfunction, sclerodactyly, and/or telangiectasias) variant, were evaluated with resting M-mode echocardiography and noninvasive measurements of cardiac output at rest and during submaximal exercise to determine the nature and extent of any cardiovascular impairment. No patient had arterial hypertension, significant renal impairment, clinical evidence of large vessel coronary artery disease, or severe pulmonary dysfunction. The duration of disease was 1 to 12 years (9 to 30 for patients with the CREST variant). Echocardiographic abnormalities included increased right ventricular dimension (3 patients), reduced left ventricular ejection fraction (3 patients), and pericardial effusion (3 patients). Cardiac index (CI) and stroke volume index (SVI) at rest were similar for patients and controls. Patients and controls were exercised to similar heart rates (130 +/- 3 vs 124 +/- 4; p, NS). Total peripheral resistance (TPR) was higher for patients (1123 +/- 81 vs 810 +/- 44 dyn X s X cm-5) and their mean SVI failed to increase significantly compared with sitting rest values (30 +/- 2 vs 35 +/- 3 ml/m2). The control subjects had the expected increase in SVI (36 +/- 2 vs 51 +/- 5; p less than 0.01). Ten patients with an abnormal hemodynamic response to exercise had a normal echocardiographic circumferential fiber shortening (VCF) or ejection fraction (EF) at rest. The data indicate that PSS patients have a greater degree of cardiovascular dysfunction than would be predicted from clinical data and laboratory evaluation of cardiovascular and pulmonary function at rest. Multiple mechanisms, including right and left ventricular dysfunction and abnormal vasoconstrictor activity, are likely to contribute to the reduction in exercise capacity seen in patients with PSS.     

Hashimoto's thyroiditis is associated with peripheral lymphocyte activation in patients with systemic sclerosis

OBJECTIVE: To investigate whether autoimmune thyroiditis [HT] (i.e., a TH1 disease) influences the pattern of peripheral lymphocyte activation in systemic sclerosis [SSc] (commonly regarded as a TH2 disease). Twenty SSc patients, 6 with (SSc+HT+) and 14 without HT (SSc+HT-) and 20 controls were investigated for the intracellular content of IFN-gamma and IL-4 in unstimulated and stimulated (25 ng/ml PMA and 1 microg/ml ionomycin) CD4+ and CD8+ T lymphocytes. Results Under basal conditions the percentages of CD4+IFN-gamma, CD4+IL-4+ and CD8+IFN-gammawere significantly higher in the patients than the control subjects, no significant differences being detectable between the two patient subgroups. Upon PMA stimulation, the 20 SSc patients showed a higher percentage of CD4+IFN-gamma+ and CD8+IFN-gamma+ than the control subjects. In particular, the 14 SSc+HT- patients showed a higher number of CD4+IFN-y+ and CD4+IL-4+ cells, while the SSc+HT+ patients showed higher percentage of CD8+IFN-gamma+ cells. The latter patients showed a reduced percentage of CD4+IL-4+ cells and an increased percentage of CD8+IFN-y+ in comparison with the SSc+HT- patients. Type-1 activation in the peripheral blood of SSc patients has been already pointed out by other authors and ourselves. This study shows that such activation mainly affects SSc patients with coexistent HT.     

Suppressor T lymphocyte function in Graves' disease

To explore suppressor T lymphocyte function in Graves' disease, studies were performed in one group of patients in the hyperthyroid state and in another group in the euthyroid state after treatment. Peripheral blood lymphocytes were cultured for 1-7 days. Pokeweed mitogen (PWM; 1.25 micrograms/ml) was added at the initiation of the cultures or after 24 h. The degree of lymphocyte activation was assessed by measurements of the cellular uptake of [3H]thymidine and expressed in counts per minute (CPM). The suppressor lymphocyte function was estimated by a quotient between the maximum CPM values from cultures with and without preincubation. For the hyperthyroid group (n = 15) the quotient was 1.00 +/- 0.07 (mean +/- SEM), for the euthyroid patient group (n = 21) 1.12 +/- 0.05 and for the healthy control group (n = 21) 1.37 +/- 0.08. There was a significant difference between the quotients for the control group and the hyperthyroid (P less than 0.01) as well as the euthyroid (P less than 0.05) patient group. The quotients for the two groups of patients did not differ significantly. In conclusion, the present study supports the view of a defect in suppressor T lymphocyte function in patients with Graves' disease in the hyperthyroid state and indicates that this defect can persist in the euthyroid state after treatment.     

Long-term immunomodulatory effects of T lymphocyte depletion in patients with systemic sclerosis

We describe 2 patients with rapidly progressing systemic sclerosis that did not respond to conventional therapy, who were treated with a 5-day regimen of T cell-specific antilymphocyte globulin. One patient had deteriorating pulmonary involvement, and the second patient had developed disabling skin disease with multiple ulcers and gangrene. Both patients showed improvement concomitant with almost complete elimination of CD4+ and CD8+ T lymphocytes. Regeneration of peripheral T cells required 60-90 days and was followed by a long-term inversion of the CD4:CD8 ratio. The persistent therapeutic effect in both patients correlated with the lack of CD4+ T cells and the predominance of CD8+ T cells. This suggests a crucial role of T cell immunity in the pathogenesis of systemic sclerosis. In vitro studies of regenerating T cells demonstrated that CD4+ helper/inducer cells were functionally competent. Alterations in the composition of the CD8+ population may explain the prolonged suppression of CD4+ T cells observed during the period of therapeutic benefit.     

Patterns of pulmonary function in smoking and nonsmoking patients with progressive systemic sclerosis

Pulmonary involvement is a prominent feature in systemic sclerosis and a significant cause of morbidity and mortality. A restrictive ventilatory defect is typical and static lung volumes are usually reduced in patients with ILDs. The possibility of obstruction of small airways in progressive systemic sclerosis (SSc) has been suggested by widespread bronchiolectasis and peribronchial fibrosis noted at necropsy. A total of 46 patients with a diagnosis of SSc were retrospectively included in this study. Patients were classified according to their smoking status (never smokers, n = 34 and ex or current smokers, n = 12). Patients were also compared on the basis of the presence or not of an obstructive pattern on spirometry. The purpose of this study was to establish if SSc patients who are smokers have a different pattern of pulmonary function involvement. Our hypothesis was that smoking habit was not the only cause of air trapping and that the existence of small airway involvement secondary to SSc itself cannot be excluded.     

Clinical relevance of determining lymphocyte subpopulations in peripheral blood of patients with rheumatoid arthritis

Blood lymphocytes were determined from 21 patients with seropositive rheumatoid arthritis (RA) in a cross-sectional study with 5 monoclonal antibodies (MAb) of the BL-series. 7 patients were examined with the same MAb over a time period of 14 weeks before and after a prednisolone-pulse therapy. The cross-sectional study showed a significant higher percentage of Ia4+ T-helper/inducer-lymphocytes in RA-patients compared to control persons. The value of Ia4+ T-lymphocytes didn't correlate to the clinical activity of the RA. No significant differences were observed in the helper/suppressor T-lymphocyte ratio. The lymphocyte subpopulations were not significantly different immediately before and after a prednisolone-pulse therapy. The percentage of B-lymphocytes was significantly higher in comparison to the controls 24 h after prednisolone-pulse therapy. An immunomonitoring of the clinical activity and the therapy of RA is not possible with the used MAb.     

Bilateral bronchoalveolar lavage in progressive systemic sclerosis: interlobar variability, lymphocyte subpopulations, and functional correlations.

Bilateral bronchoalveolar lavage (BAL) was carried out in right middle and left upper lobes of 22 nonsmoking females suffering from progressive systemic sclerosis in order to assess interlobar differences and functional correlation of the BAL composition. The patients' age ranged from 20 to 66 years, and the mean disease duration was 10.4 years. The most frequent finding was a mild BAL lymphocytosis (right in 11 of 22 patients; left in 8 of 22), but eosinophilic (right in 11 of 22; left in 5 of 22 patients) and neutrophilic (right in 9 of 22 patients; left in 1 of 22) alveolitis was recognized as well. Differential counts suggestive of alveolitis limited to one of the lavaged lobes were demonstrated in about one fourth of the cases. Including increased cellularity among the criteria of pathological BAL fluid composition, 14% of the subjects showed bilateral BAL results within the normal range. OKT8-positive lymphocytes were significantly increased in 3 patients, but the mean values were not. Total lung capacity, vital capacity, and forced expiratory volume in 1 s correlated inversely with BAL neutrophil (p less than 0.05) and granulocytic (p less than 0.01) differential counts; the strongest, positive correlation was demonstrated regarding the lymphocyte/granulocyte ratios (p less than 0.0005). In conclusion, several patterns of alveolitis as well as a bilaterally normal BAL composition were found in our series; moreover, even if inhomogeneous alveolitis did occur, a single lavage performed in the right middle lobe correctly detected or excluded the presence of an alveolitis in 95% of our patients.     

Peripheral blood T lymphocyte subpopulations in patients with tuberculosis and the effect of chemotherapy

Peripheral blood T lymphocytes and their subsets were determined in 30 patients with pulmonary tuberculosis (15 smear positive and 15 smear negative) and 11 healthy individuals. All patients were assessed clinically, radiologically, bacteriologically and by tuberculin testing, and their lymphocyte counts were repeated after completion of 3 months chemotherapy. The mean ratio of putative helper/suppressor T cell subsets (CD4/CD8) of healthy individuals was 1.8 (range 1.1-2.5). These ratios were independent of tuberculin reactivity and were unaffected by BCG vaccination. In both smear positive and smear negative patients there was a reduction in the total T cell and CD4 counts and an increase in the CD8 count, with a concomitant reduction in the CD4/CD8 ratio. Following successful chemotherapy, the mean CD4/CD8 ratios reverted from 0.82 to 1.57 in smear positive patients and 0.88 to 1.52 in smear negative patients, these being near normal values.