摘要:

We examined the influence of the K+channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-y secreting cells (IFN-γsc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10-5M-10-6M and pinacidil at concentrations of 10-5M-10-7M enhanced the proliferative response to both BPM and PHA. The number of IFN-y sc was suppressed by the K+channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-y sc than of cultures with low numbers of BPM-reactive IFN-γsc. The applied K+”channel openers are primarily acting on ATP-sensitivc K+channels, which have not been found in T cells so far. The drugs may, therefore, excert non-selective effects on conventional voltage-and/or Ca+ +-dependent channels of T cells.A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects.

ISSN:0891-6934    

DOI:10.3109/08916939409009524

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls(Pc<0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%,Pc<0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.

ISSN:0891-6934    

DOI:10.3109/08916939409009525

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rhematoid factor (RF) idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease.Serial sera were obtained from 25 subjects who developed RA and 25 RF-positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies.Expression of the three RF-associated idiotypes was found in both the subjects who developed RA and those who did not. The amount of idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiidiotypes overlapped, with 4C9 appearing to mark a broader spectrum of RF than 6B6.6.Thus, even in an inbred and genetically predisposed population, the RF-asssociated antiidiotypes studied here did not identify a dominant idiotypic response and were no better markers for the development of RA than was RF itself.

ISSN:0891-6934    

DOI:10.3109/08916939409009526

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Our previous studies showed that 54 kD and 48 kD tubular basement membrane (TBM) proteins were the major form of the target antigen involved in anti-TBM antibody-mediated tubulo-interstitial nephritis in humans. In those studies, we isolated the 54 kD glycoprotein (named gp54) from collagenase-digested bovine TBM. NH2-terminal amino acid sequencing indicated that gp54 represented a newly defined glycoprotein. In this study, we further characterized the target antigen, using mouse monoclonal antibodies to gp54 and polyclonal anti-gp54 peptide antibody. Two monoclonal antibodies (H79 and H80) were established, and they reacted, by immunofluorescence, predominantly with the proximal TBM of humans, rabbits, and Wistar, Sprague-Dawley, and Brown-Norway rats, but not with that of Lewis rats. They were also fixed by blotting intensely to the 54 kD component and weakly to the 48 kD component of collagenase-digested human TBM.In vivotransfer of H79 to Wistar rats showed extensive linear binding of mouse IgG to the TBM and the basal membrane of the small intestine; however, no pathologic changes were seen by light microscopy. The anti-gp54 peptide antibody reacted with both the 54 kD and 48 kD TBM components of human TBM. mRNA was prepared from rabbit kidneys, and fractionated to enrich mRNA encoding the 54 kD and 48 kD peptides. Onin vitrotranslation experiments with the mRNA fraction, the 54 kD and 48 kD peptides were immunoprecipitated with anti-gp54 antibodies. These findings indicate that the 54 kD and 48 kD components are encoded with different mRNA, but that they share the same antigenic epitope. It is likely that they are structurally related and exist as isoforms.

ISSN:0891-6934    

DOI:10.3109/08916939409009527

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

PBC is a cholestatic liver disease of unknown etiology with autoimmune features that is often associated with other autoimmune diseases. We analyzed peripheral blood T-cell subsets in patients groups with PBC (n = 11), non-PBC hepatobiliary disease (n = 11) and an age and sex matched control group (n = 11) by two color FACS-analysis. Seven out of eleven PBC patients exhibited markedly lowered and nearly undetectable levels of y8 T-cells (<0.8%). None of the individuals in the non-PBC hepatobiliary disease (HBD) gkroup or the normal control group had y8 values below 1%. The other four individuals in the PBC group hadγδvalues within the normal range. Overall, the PBC group had a statistically significant, lowered mean percentage ofγδT-cells (L.50%) as compared to the hepatobiliary disease group (3.76%) and the control group (4.22%, p = 0.01). The percentages of CD4+and CD8+andαβTCR+CD4-CD8−double negative cells in PBC patients did not differ from the control group. PBC patients with normalγδcell counts did not differ from the PBC group with lowγδvalues in autoantibody titers, liver tests or treatment of the disease. As a possible cause for the observed decrease ofγδT-cells three sera of PBC patients with low y8 T-cell counts were screened by single color, indirect immunofluorescence for antibodies toγδT-cell enriched lymphocytes, but no differences to control sera were observed. In conclusion, we describe what appears to be a disease-specific but inexplicable marked decrease inγδT-cells in the peripheral blood of a group of patients with PBC. The possible role of aγδ-specifjc superantigen in the pathogenesis of the disease is discussed.

ISSN:0891-6934    

DOI:10.3109/08916939409009528

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Cytokines play an important role in modulating cellular function. The effect of tumor necrosis factor alpha (TNF-alpha) on the metabolism of proteoglycans (PGs) was studied in mouse aortic endothelial cells (MAE). Confluent and exponentially growing cells were labeled with [35S] sulfate and [3H] glycine, and PGs isolated from the secreted, the pericellular, and intracellular pools. TNF-alpha influenced the metabolism of MAE PGs. This effect of TNF-alpha was dependent on the growth state of the cells. Nondividing MAE secrete PGs that have higher net negative charge than PGs from exponentially growing cells. TNF-alpha treatment further increased the net negative charge of PGs secreted from nondividing cells. Treatment of MAE with TNF-alpha caused a substantial decrease in the sulfation of PGs isolated from pericellular pool of nondividing cells, while it had the opposite effect on pericellular PGs isolated from dividing cells. Our results indicate that changes in PGs metabolism induced by TNF-alpha may contribute to the disturbance of vascular endothelial homeostasis associated with vascular injury in a variety of disease states.

ISSN:0891-6934    

DOI:10.3109/08916939409009529

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

A major surge of interest has recently focused upon nitric oxide (NO) as a mediator of autoimmune destruction ofβ-cells in insulin-dependent diabetes mcllitus (IDDM). It has been proposed that insulin producing cells in response to cytokines are induced to produce self destructing amounts of NO, and that endothelial cells or islet infiltrating macrophages may induceβ-cell death by releasing cytotoxic levels of NO within the islet. Recent findings in this field are presently discussed and we conclude that although NO might have a role in rodent IDDM, any putative role of NO in the pathogenesis of human IDDM remains to be clarified.

ISSN:0891-6934    

DOI:10.3109/08916939409009530

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Antinuclear autoantibodies are useful diagnostic markers for systemic autoimmune diseases and as probes for the molecular cell biology of nuclear proteins1. Here, we review a subset of autoantibodies to nuclear and cytoplasmic proteins involved in the cell cycle. We propose a classification of these autoantibodies into S-phase (DNA Synthesis) and M-phase (Mtosis) autoantibodies. S-phase autoantibodies are represented by autoantibodies to PCNA (Proliferating Cell Nuclear Antigen), the auxiliary protein of DNA polymeraseδ. M-phase autoantibodies are represented by autoantibodies to mitotic spindle components viz. centrosomes, condensed chromosomes, centromeres, mitotic spindle proper and intercellular bridge. We have included autoantibodies to nuclear lamins as M-phase autoantibodies as lamins play a key role in reversible breakdown and reformation of nuclear membranes during mitosis. The usefulness of these autoantibodies as diagnostic markers in systemic autoimmune diseases is tempered by their presence in patients with“atypical”autoimmune diseases and in normal individuals. However, as molecular probes, they have proven to be unique and invaluable tools for shedding new light on the workings of the cell cycle.

ISSN:0891-6934    

DOI:10.3109/08916939409009531

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Evidence has accumulated suggesting the existence in humans of polarized T helper (Th) cell subsets, coded as Thl and Th2, with defined cytokine secretion profiles. Immune responses to intracellular bacteria and viruses result in the preferential development of the Thl cell subset. Thl cells express cytolytic activity against antigen-presenting cells and provide helper function for IgM, IgG and IgA synthesis only at low T/B cell ratios. In contrast, Th2 cells develop in response to allergens or helminth antigens, provide help for all immunoglobulin classes, including IgE, and lack cytolytic potential. The cytokine milieu in the microenvironment plays a fundamental role in determining the functional phenotype of the subsequent antigen-specific Thl or Th2 responses.In recent years it has become clear that Thl and Th2 cells play different roles not only in protection against exogenous offending agents, but also immunopathology. Th2 cells are involved in immunopa-thology induced by helminths and are responsible for the initiation and maintenance of allergic disorders. Thl cells seem to be involved in contact dermatitis, acute allograft rejection and organ-specific autoimmunity, such as thyroid autoimmune disorders, diabetes mellitus or multiple sclerosis, whereas less polarized patterns of Th cells are detectable in target organs of patients with rheumatoid arthritis. Sjogren's syndrome or systemic lupus erythematosus.

ISSN:0891-6934    

DOI:10.3109/08916939409009532

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939409009533

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor