摘要:

The enzyme glutamate decarboxylase (GAD) is considered one of the major Beta cell antigens in Type 1 diabetes mellitus. The GAD autoantibody (GAD-AAb) prevalence in newly diagnosed Type 1 diabetic patients has been described up to 80%, depending on the detection method used. The aim of this study was to evaluate a simple, specific, and sensitive radioimmunoassay (RIA) method for detection of AAb against both isoforms of the enzyme, GAD65and GAD67, in a cross-sectional study using sera from newly diagnosed Type 1 diabetic patients and in a longitudinal study using sera from prediabetic patients and individuals at risk of developing the disease. The125I-labelled full-length human recombinant proteins of GAD65and GAD67expressed in SF9 cells were used as the antigen source. The prevalence of GAD65-AAb in newly diagnosed Type 1 diabetic patients was found to be 73% (112/153), in contrast to 19% (14/72) of GAD67-AAb. Only one patient produced AAb restricted to GAD67. Furthermore, GAD65-AAb could also be detected in 73% (11/15) of prediabetic patients (up to 122 months before clinical manifestation of the disease), whereas only 27% (4/15) of them were positive for GAD67-AAb. In the group at risk of developing Type 1 diabetes, these prevalences were 77% (10/13) and 46% (6/13), respectively. In all GAD67-AAb-positive patients investigated in the longitudinal study, AAb to GAD65were detectable. In 47% of patients positive for both GAD65-AAb and ICA, the GAD65-AAb appeared by up to 46 months before the occurrence of ICA was detected. The data illustrated that GAD65is the main immunogenic isoform of the enzyme in the preclinical and clinical stages. The RIA detecting AAb against this isoform may facilitate the screening for individuals at risk of developing the disease.

ISSN:0891-6934    

DOI:10.3109/08916939409009534

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

The SmN, protein is closely related to the constitutively expressed SmB and SmB’autoantigens and can also act as a target for human autoimmune sera. In contrast to the single gene encoding SmB and SmB’which is expressed in all tissues, the distinct gene encoding SmN is expressed at high levels only in brain and heart tissue. We show that the SmN gene is transcribed at significantly elevated levels in peripheral blood mononuclear cells (PBMCs) from SLE patients compared to normal controls. In contrast no significant elevation in transcription of the genes encoding SmB/B’or the Ul-associatcd 70kD RNP autoantigen is observed in these patients. The elevation in SmN gene transcription in patient PBMCs does not result however, in enhanced levels of the SmN protein in the PBMCs of these patients. The significance of transcriptional and post-transcriptional processes in regulating the expression in SLE patients of SmN and other autoantigens is discussed.

ISSN:0891-6934    

DOI:10.3109/08916939409009535

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+T lymphocytes expressing the activation molecule interleukin-2 receptor (p55αchain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25+CD4+cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3±0.2 to 0.5±0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45RA+CD4+cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25+CD4+cells and a reciprocal increase in CD45RA* CD4 * cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration.

ISSN:0891-6934    

DOI:10.3109/08916939409009536

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

A microcytotoxicity assay has been used to determine the cytotoxic activity of anti-heart antibodies which we have previously shown to be present with greater frequencies and reactivities in patients with dilated cardiomyopathy (DCM) than in patients with ischaemic heart disease (IHD). Serum samples from 45 patients with DCM and 43 patients with IHD were screened against Wl, a transformed human fetalcardiac cell line and also against EA.hy 926, an endothelial and IBR3, a fibroblast cell line. In the presence of complement, sera from 28 (62%) DCM patients showed killing of the Wl cell line as compared to sera from 13 (30%) of IHD patients (p< 0.005) and 3 (15%) of normal individuals. In contrast, only 1 patient with DCM showed killing of the endothelial cell line and 1 patient with IHD showed killing of the fibroblast cell line. These results provide evidence for a complement-dependent, antibody-mediated mechanism of damage to cardiac myocytes which may contribute to the pathogenesis of DCM.

ISSN:0891-6934    

DOI:10.3109/08916939409009537

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

It has been shown that cationic anti-DNA antibodies have nephritogenic potential in murine models of lupus nephritis. More recently, we have reported that there is a close relationship between the presence of circulating cationic anti-DNA antibodies and the development of lupus nephritis in humans, and that the cationic anti-DNA antibodies bind to heparan sulfate, a major glycosaminoglycan in glomerular basement membrane, much better than neutral anti-DNA antibodies. This suggests that cationic anti-DNA antibodies of the IgG class may be responsible for development of nephritisin vivoin patients with systemic lupus erythematosus. In this study, we first studied reactivity of anti-DNA antibodies with a panel of glycosaminoglycansin vitrousing ELISA methods, and found that anti-DNA antibodies cross-react with dextran sulfate, hyaluronic acid and chondroitin sulfate. The reactivity and selectivity of dextran sulfate with anti-DNA antibodies was confirmed byin vitroimmunoadsorption of the patient's sera with dextran sulfate-fixed column; incubation of auto-antibody-positive sera with dextran sulfate cellulose column removed anti-DNA, but not anti-RNP, anti-Sm, anti-SSA and anti-SSB antibodies from the serain vitro.Of note is that dextran sulfate cellulose column adsorbed exclusively, if not all, cationic anti-DNA antibodies in their sera. Nonspecific binding of total immunoglobulins as well as total proteins to the column was marginal. It has been suggested that cationic anti-DNA antibodies in sera of patients with refractory lupus nephritis could be efficiently removed by apheresis using dextran sulfate column.

ISSN:0891-6934    

DOI:10.3109/08916939409009538

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Glutamic acid decarboxylase antibodies (GAD65Ab) are common in new onset Caucasian insulin-dependent diabetic (IDDM) patients but it is unclear if this marker is also prevalent in patients of other ethnic backgrounds. We determined antibodies against human recombinant GAD in Japanese diabetic patients using a radioimmunoassay with competition betweenin vitrotranslated35S-GAD65 and non-labelled recombinant human GAD65 (rhGAD65). GAD67 antibodies (GAD67Ab) were similarly analyzed but without antigen competition. In 73 Japanese diabetic patients, GAD65Ab were found in 11/16 (69%) of patients with short-duration (less than 5 yrs) IDDM, 6/23 (26%) with long-duration (5 or more yrs) IDDM and 10/20 (50%) with slowly progressive diabetes. High GAD65Ab levels were associated with concomitant autoimmune diseases (p =0.021). GAD67Ab were found in 4/16 (25%) of patients with short-duration IDDM, 3/23 (13%) with long-duration IDDM and 2/20 (10%) with slowly progressive diabetes. In 14 non-insulin dependent diabetic (NIDDM) patients, GAD65Ab and GAD67Ab were not found (0/14) and 1/50 (2%) healthy controls were positive in either assay. Among the GAD67Ab-positive samples, 8/9 (88%) were also high level GAD65Ab positive, 7/9 (77%) were displaced by an excess of rhGAD65 and the antibody levels correlated (r2= 0.573;p= 0.003). Our data are consistent with a strong association of GAD65Ab also in Japanese IDDM, and suggest that, when present, GAD67Ab are frequently directed to epitope(s) common to GAD65 and GAD67.

ISSN:0891-6934    

DOI:10.3109/08916939409009539

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939409009540

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

The kinetics of potentially autoreactive B-cells were investigated in a double-transgenic model of self-tolerance. Two types of transgenic mice were created for this purpose. In the first the great majority of B-cells expressed the rearranged heavy and light chain genes encoding a high affinity receptor for hen egg lysozyme (HEL), while the second type expressed HEL in either soluble (sHEL) or membrane-bound (mHEL) form. Double-transgenic (Dbl-Tg) mice were produced either by mating the two types of founders or by transferring bone marrow cells from Ig-transgenic (Ig-Tg) donors into irradiated HEL-Tg recipients. The lifespan of B-cells from the Dbl-Tg mice was measured by oral loading with the thymidine analogue, 5-bromo-2′-deoxyuridine (BrdU) for periods varying from three days to six weeks.Experiments in various combinations of Dbl-Tg mice revealed a three-tiered hierarchy of B-cell unresponsiveness, each level of which was characterised by a different B-cell lifespan. Exposure to mHEL led to rapid deletion of B-cclls at an immature stage in their development with a median lifespan of approximately 15 hours. B-cells exposed to sHEL above a critical tolerogenic threshold were not deleted in the bone marrow but migrated to the spleen in an anergic state where they died within three days. If the receptor occupancy of sHEL was below the tolerogenic threshold, B-cells were neither deleted nor rendered anergic (ie were“indifferent”) and had a normal median lifespan of four to five weeks.A number of conclusions were derived from these studies(i) there is a correlation between receptor occupancy by self antigen and B-cell lifespan;(ii) anergy and deletion in self-reactive B-cells appear to be part of a spectrum of unresponsiveness rather than being totally discrete molecular entities;(iii) a lack of T-ccll help in addition to receptor occupancy is a crucial factor in determining the relatively short lifespan of anergic B-cells; and(iv) B-cells from young mice have a higher turnover rate than in adult mice suggesting selection of newly-generated B-cells into the long-lived repertoire; the short lifespan of tolerant self-reactive cells further implies a major role for negative selection in this process.

ISSN:0891-6934    

DOI:10.3109/08916939409009541

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

The initiation of a humoral immune response to a foreign antigen is a complex biologic process involving the interaction of many cell types and their secreted products. Autoimmune diseases, which are characterized by an abnormal activation of the immune system, probably result from the failure of normal self-tolerance mechanisms. The etiology of such illnesses, however, is far from being understood. While there have been extensive studies on the participation of the immune and endocrine systems in autoimmune diseases, few have dealt with nervous system-mediated immunoregulation in such situations. Evidence continues to grow suggesting that nerve growth factor (NGF), first identified for its activity in promoting the growth and differentiation of sensory and sympathetic neurons, may exert a modulatory role on neuroimmunoendocrine functions of vital importance in the regulation of homeostatic processes. Newly detected NGF-responsive cells belong to the hemopoietic-immune system and to populations in the brain involved in neuroendocrine functions. NGF levels are elevated in a number of autoimmune states, along with increased accumulation of mast cells. NGF and mast cells both appear to be involved in neuroimmune interactions and tissue inflammation. Moreover, mast cells themselves synthesize, store, and release NGF, proposing that alterations in normal mast cell behaviors may provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states, including those of an autoimmune nature. This review focuses on these cellular events and presents a working model which attempts to explain the close interrelationships of the neuroendocrinoimmune triade via a modulatory action of NGF.

ISSN:0891-6934    

DOI:10.3109/08916939409009542

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939409009543

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor