The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.
NZB mice spontaneously develop autoimmune hemolytic anemia (AIHA). The red blood cell (RBC) autoantigen bound by pathogenic IgG autoantibodies, previously designated "X", was identified by immunoprecipitation. Autoantibody eluted from the RBC of AIHA-positive NZB mice precipitated a 105-kDa antigen that was identical in apparent molecular mass to Band 3, the RBC anion channel protein. Furthermore, the immunoblotted antigen also reacted specifically with BRIC 132, a monoclonal antibody against Band 3. The results, therefore, demonstrate that Band 3 bears autoantigenic epitopes that are important in the pathogenesis of AIHA in the NZB mouse.
Two subpopulation of circulating human T cells forming rosettes with neuraminidase-treated sheep erythrocytes were purified on the basis of the presence of receptors for IgG (TG cells) or for IgM (TM cells), and were shown to have distinguishing morphological and histochemical characteristics. TM cells had the general features of typical small- or medium-sized lymphocytes; most were easily identifiable by distinctive cytoplasmic accumulations, usually one and sometimes two large spots, of nonspecific acid esterase activity. The release of the vesicular contents on short-term culture of TG cells was inhibited by cytochalasin B. Definition of these distinguishing characteristics of TM and TG cells provides a basis for practical enumeration of these functionally distinct subpopulations of human T cells. Some of the TG cells were capable of endocytosis of IgG antibody-coated erythrocytes.
We have previously shown that patients with SLE have significantly lower percentages and absolute numbers of NK(CD3-/CD16+56) cells in their peripheral blood compared with normals. Patients with active disease had very low levels of NK cells and the reduction was also associated with patients who had renal involvement. We have now performed a serial study immunophenotyping 11 patients with SLE and renal involvement using dual colour immunofluorescence and flow cytometry. Patients were tested every three months on an average of three occasions. As a control, nine SLE patients without renal involvement were immunophenotyped for similar intervals; 11 normal controls were also tested. Major lymphocyte subsets (T, B and NK) remained very stable during serial bleeds. However, the NK cell populations were decreased significantly in patients with renal involvement both as percentages (5 +/- 6 vs 9 +/- 5, P < 0.0001) and absolute counts (75 +/- 108 vs 109 +/- 52, P < 0.001) in comparison to non-renal patients. Analysis of disease activity using BILAG score showed an inverse correlation between renal system activity and percentage and absolute number of NK cells (P < 0.002 and 0.01, respectively). In this study we have also analysed a CD8 T cell subset which we have not studied before. We have found a significantly increased percentage of CD38+CD8+ T cells(activated CD8 subset) in patients with SLE in comparison to normal controls. We did not find any association with the CD38+CD8+ T cells and disease activity as measured by BILAG or renal involvement. NK cells are important factors in immunity against virus infections and tumour cells. CD38+CD8+T cells are increased in viral infections. We speculate that the lack of NK cells in SLE patients might have an association with increased CD38 expression.
Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and the production of autoantibodies, some of which (antibodies to dsDNA) are thought to be pathogenic. T helper cells drive the production of autoantibodies and the aim of this study is to characterize phenotypically a subpopulation of T cells (the CD3+ CD4- CD8-, double negative (DN) T cells) previously identified as helping to enhance anti-DNA antibodies in patients with SLE. Data were obtained using FACS staining of DN T cells that had been purified from PBMCs by magnetic bead separation. The percentage of TCR alphabeta+ DN T cells was found to be significantly higher in patients with SLE as compared with controls (P = 0.02), although there was no significant increase in total percentage of DN T cells, which includes TCR gammadelta+ cells. Activation markers HLA-DR and CD69, the costimulatory molecule CD28 and CTLA-4 were all expressed on the surface of a higher percentage of DN T cells in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls (HC). More DN T cells from patients with SLE were of CD45RA phenotype than was found in controls, while CD45RO-expressing cells were reduced. In addition, DN T cells from patients with SLE expressed significantly higher levels of HLA-DR (P = 0.006), CD28 (P = 0.05), CTLA4 (P = 0.03) and CD45RA (P = 0.05) on the cell surface than those from the CD4/8 population. Correlation of expression of the markers measured with various parameters of disease activity and severity showed that high levels of HLA-DR expression correlated with high circulating serum C3 (> 0.9 IU/ml), indicating that an activated phenotype is consistent with severe disease.
Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease that may affect every organ or system in the body. We have shown previously that the TCR alphabeta+ subpopulation of CD3+ CD4- CD8-, DN T cells is expanded in patients with SLE and that double negative T cells express increased levels of activation markers compared both with healthy people and with patients with rheumatoid arthritis, (RA) as autoimmune controls. The aim of this study was to characterize these cells in terms of their ability to produce IL4, a Th2 cytokine, both spontaneously and after mitogen stimulation. It was found that a higher percentage of TCR alphabeta+ double negative T cells from patients with SLE contained IL4 constitutively than did the same population of cells from healthy people or from those with RA. After mitogen stimulation, there was no significant difference in the amount of IL4 produced by each of the three groups. Further study of patients producing high levels of IL4 (about one third of the patients) indicated that they had a lower percentage of alphabeta+ T cells in the double negative compartment than did patients with fewer IL4 containing cells.
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