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Biomedical subjects

M Feldmann

Publications and source records attributed to M Feldmann.

At least 307 records · Page 17Linked to original sources
PubMed1987

Regulation of HLA class II expression and its role in autoimmune disease.

Excessive HLA class II expression is found on the target tissues of the majority of human autoimmune diseases, together with activated (interleukin 2 receptor-expressing) T lymphocytes, suggesting that the target tissues act as antigen-presenting cells for infiltrating autoreactive cells, which in turn produce molecules that maintain class II expression. This vicious cycle has been shown to operate in Graves' thyroiditis, because interferon-gamma (IFN-gamma) induces class II expression on thyrocytes, and thyrocytes expressing class II antigens present their autoantigens to T cells cloned from thyroid tissue of Graves' disease patients. These results led us to consider whether the same mechanisms operate in other autoimmune diseases. In investigations into class II induction in other cell types we found that IFN-gamma is not the only regulator of HLA class II expression and that synergy exists among mediators regulating class II differentially on different cell types. This concept makes it possible to envisage selective diminution of class II antigens on target tissues without loss of class II on antigen-presenting cells. The study of mediators regulating class II expression on cells in vitro led us to ask whether the appropriate regulator molecules are important in disease states. To investigate this question we have developed the use of cDNA probes to analyse the expression of lymphokines, other cytokines, and receptors in small local biopsy samples of tissue from patients with autoimmune diseases. Results obtained so far indicate that mRNAs for many lymphokines are present in synovial fluid cell samples from patients with rheumatoid arthritis.

Autoimmune Diseases↗
PubMed1987

A phenotypically dominant regulatory mechanism suppresses major histocompatibility complex class II gene expression in a murine plasmacytoma.

The expression of major histocompatibility complex (MHC) class II antigens is down-regulated when B cells differentiate into plasma cells. We have studied the mechanism of down-regulation of MHC class II expression in a BALB/c strain-derived murine plasmacytoma cell line, NS1. NS1 cells express MHC class I antigens but not MHC class II antigens. We tested 20 uncloned hybrid cell lines obtained from the fusion of NS1 cells with MHC class II-expressing splenic B cells prepared from CBA, SJL or BALB/c mice. All the hybrid cell lines expressed MHC class I antigens of either or both parental haplotypes but did not express MHC class II. One NS1 X splenic B cell hybrid clone, K3, was used to further validate these results; K3 cells expressed MHC class I but not MHC class II antigens. K3 was fused to the MHC class II-expressing B lymphoma A20, and the seven resulting hybrid cell lines were again found to express MHC class I but not MHC class II antigens. Since NS1 is a subclone of the P3-X63Ag8 murine plasmacytoma, we also tested one P3-X63Ag8 x splenic B cell hybrid, Sp2/0, and two Sp2/0 x splenic B cell hybrids. All were found to express the appropriate MHC class I antigens but did not express MHC class II. Thus, our results suggest that the NS1 plasmacytoma suppresses MHC class II expression by a phenotypically dominant regulatory mechanism. We found that NS1 cells express correctly sized mRNA for the MHC class II genes A alpha, E alpha and the invariant chain. The co-expression of MHC class I protein and I-A and I-E region gene transcripts provides strong evidence that the MHC gene cluster is structurally intact, and that lack of class II expression is due to a genetic regulatory mechanism. The amounts of class II mRNA expressed by NS1 cells were at least equivalent to those found in splenic lymphocytes. Therefore, this regulation must operate post-transcriptionally.

Animals↗
PubMed1987

Antigen-specific T cell unresponsiveness in cloned helper T cells mediated via the CD2 or CD3/Ti receptor pathways.

We have investigated the role of the CD2 protein in the negative regulation of immune function and report that similar to antigen and anti-CD3, the monoclonal anti-CD2 antibodies (T112 and T113) can induce specific unresponsiveness. Antigen and anti-CD2 tolerogenic signals both down-regulated the phenotypic expression of CD3-Ti. In contrast CD2 surface expression was up-regulated after exposure to peptide and down-regulated after anti-T112 and T113 preincubation. However, in both instances interleukin 2 receptor surface levels were increased. These phenotypic changes could only be partly explained by variations in the levels of the transcripts encoding the CD3-Ti and CD2 molecules.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Human T cells from autoimmune and normal individuals can produce tumor necrosis factor.

T cell clones derived from patients with autoimmune diseases were found to be capable of producing tumor necrosis factor (TNF). This was demonstrated by stimulating the clones, in the absence of accessory cells, with antibodies against the Ti/T3 complex and with recombinant interleukin 2 (IL2). Analysis of RNA extracted from these clones showed that TNF mRNA was more abundant than lymphotoxin (LT) mRNA. We also found that TNF protein in the supernatants of these clones was generally more abundant than LT as assessed by using the murine L929 cell assay. TNF production was not limited to T cells from autoimmune individuals, since the T cell tumor HUT78 and T cells purified from the peripheral blood of healthy individuals also made TNF. Unlike the T cell clones, HUT78 produced greater amounts of LT mRNA than TNF mRNA. Induction of TNF mRNA in T cells from healthy individuals displayed a two-signal requirement (phorbol myristate 13-acetate and phytohemagglutinin or OKT3 and phorbol myristate 13-acetate), similar to that described for the induction of the T cell lymphokines IL 2 and interferon-gamma (IFN-gamma). Additionally we found that IL2 alone was sufficient to induce TNF in these cells when they had been precultured with phytohemagglutinin for 7 days to express IL 2 receptors. The cloned T cells we have characterized also produce IFN-gamma which was detected in the supernatants of the clones using a radioimmunoassay. The evidence suggests that T cells can produce TNF and have the potential to deliver by themselves the dual and synergistic signals of TNF/LT and IFN-gamma to target cells, a process which may be of importance in the pathogenesis of human autoimmunity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

New ideas in thyroid autoimmunity.

Endocrine epithelial cells do not normally express human leukocyte antigen (HLA) class II molecules, but do so in a variety of autoimmune diseases. This finding suggests the hypothesis that such inappropriate class II-positive expression may enable these cells to present autoantigens and thus contribute to autoimmune pathogenesis. Indeed, class II-positive thyrocytes can present both exogenous antigenic peptides and intrinsic autoantigens to the appropriate T cells. Class II expression by thyrocytes can be induced by interferon-gamma, and is positively and negatively regulated by thyroid-stimulating hormone and epidermal growth factor, respectively. Furthermore, heterogeneity of thyrocyte class II subregion expression appears to be related to the nature of the inducing stimulus. The complexity of regulatory signals is underlined by findings in type I diabetes: islet beta cells aberrantly express class II in this disease, but class II cannot be induced in normal beta cells by interferon-gamma.

Antigen-Presenting Cells↗
PubMed1987

Enhancement of thyrocyte HLA class II expression by thyroid stimulating hormone.

HLA Class II molecules are expressed by human thyroid epithelial cells (thyrocytes) in thyroid autoimmunity, although these cells are normally Class II-. gamma-Interferon (gamma-IFN) is probably involved in this expression, as suggested by its ability to induce Class II in cultured normal thyrocytes. We have now found that thyroid stimulating hormone (TSH) enhances Class II expression induced in cultured thyrocytes by gamma-IFN, and effects similar to those of TSH were obtained with dibutyryl cyclic AMP. A proportion of thyrocytes also expressed Class II following treatment with TSH or dibutyryl cyclic AMP in the absence of gamma-IFN, but the optimal activity of these mediators then appeared to be dependent upon the occurrence of some pre-existing Class II expression. These findings give insights into how a variety of mediators may influence Class II expression in thyroid autoimmunity.

Autoimmune Diseases↗
PubMed1987

HLA-D subregion expression by thyroid epithelium in autoimmune thyroid diseases and induced in vitro.

Human thyroid epithelial cells (thyrocytes) express HLA Class II molecules in autoimmune thyroid diseases (ATD). Normal thyrocytes do not express Class II, but can be induced to do so by culture with interferon-gamma (gamma-IFN). We have examined HLA-D subregion expression in sections and monolayers of thyroid by indirect immunofluorescence using appropriate monoclonal antibodies. The results indicate that, in ATD, the incidence and intensity of Class II subregion expression by thyrocytes varies between patients, and follows the pattern DR greater than DP greater than DQ. The same hierarchy is observed in cultured normal thyrocytes treated with gamma-IFN: strong induction of Class II, and of DP and DQ in particular, requires relatively high concentrations of gamma-IFN or additional factors such as thyroid stimulating hormone. These findings suggest that HLA-D subregion expression by thyrocytes in on-going ATD is determined by the levels of disease related factors in the affected tissue.

Autoimmune Diseases↗
PubMed1987

Effects of cyclosporin A on expression of IL-2 and IL-2 receptors in normal and multiple sclerosis patients.

The effects of the immunosuppressant Cyclosporin A (CsA) on T cell activation in vivo and in vitro were examined using the monoclonal antibody, anti-Tac, for interleukin 2 (IL-2) receptors and 3.9C2, for a peptide fragment of human IL-2. Peripheral blood lymphocytes (PBL) were stimulated with PHA in the presence of CsA. The expression of IL-2 receptors and production of IL-2 were reduced. PBL from CsA-treated MS patients had significantly lower proportions of Tac+ cells compared with untreated patients. This inhibition was not reflected in the CSF lymphocyte populations from CsA-treated patients and indicates the urgent need for an immunosuppressant drug which can enter the CNS in sufficient concentrations to inhibit local T cell activation.

Cyclosporins↗
PubMed1986

Comparative investigation of the microcirculation in patients with hypertension and healthy adults.

A total of 51 patients with arterial hypertension, 29 of which have renal dysfunction, were examined with regard to patient history, clinically, laboratory analysis and capillary microscopy. Compared to healthy adult patients with hypertension demonstrated a significant increase in the number of capillaries per millimeter of epidermis, while at the same time showing a significantly decreased erythrocyte column diameter. This observation was more pronounced the greater the degree of retinal vascular alteration (fundus hypertonicus). The duration of reactive hyperemia in response to three minutes of ischemia with a spygmonometer cuff was considerably shortened in patients with hypertension. Here as well, an increasing degree of retinal vascular alteration correlated with a decrease in reactive hyperemia to the point of no response at all. The blood fluidity of patients with arterial hypertension was significantly limited. The plasma viscosity as well as the erythrocyte aggregation were significantly elevated. Patients suffering from additional kidney dysfunction had even higher viscosities. There also appeared to be a correlation to the degree of fundus hypertonicus in which the plasma viscosity increased in relation to an increasing degree of retinal vascular alteration.

Adult↗
PubMed1986

Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis. Possible role for microglia in lesion growth.

As there is evidence that in multiple sclerosis T-cell activation occurs in the central nervous system rather than outside, the inflammatory lesion may be extended through antigen presentation by cells at the edge of the plaque. In this study we present an immunocytochemical report on CNS tissue from an active case of MS, with an analysis of the distribution of CD4 and CD8 binding T cells and the expression of class I and II MHC determinants in plaques and white matter. Perivascular cuffs of early lesions, as judged by hypercellularity and minimal demyelination, contained activated T (Tac+) cells, which reacted with an anti-IL-2 monoclonal antibody. Thus sufficient T-cell growth factor would appear to be present to fuel the immune reaction in a growing lesion. The preponderance of T cells of the cytotoxic/suppressor (CD8) phenotype in the CNS parenchyma was found in conjunction with widespread staining of class I MHC antigen, a prerequisite for activity of cytotoxic T cells. Potential antigen presenting cells were demonstrated in MS plaques with a monoclonal antibody against the cytoplasmic, invariant chain of class II MHC. Macrophages and astrocytes, contributed to the staining in the hypercellular plaque border while the distribution of class II+ microglia in white matter suggest they may also be of importance in local antigen presentation.

Adult↗
PubMed1986

Derivation of ganglioside-specific T cell lines of suppressor or helper phenotype from cerebrospinal fluid of multiple sclerosis patients.

In order to investigate the specificity of activated T cells in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), we have cultured cells in the presence of mitogen-free IL-2 but without any antigen. Two T cell lines have been derived and showed specific reactivity to certain purified gangliosides (GM1, GD1a, GD1b and GQ1b). However, responses to other brain and viral antigens were not seen, and neither were T cell lines from peripheral blood lymphocytes (PBL) of normal, MS or other neurological disease patients stimulated by these gangliosides. Release of IL-2 could be detected after incubation of these CSF lines with specific gangliosides. One line exhibited predominantly helper/inducer (T4+) phenotype whilst the other was suppressor/cytotoxic (T8+), and further analysis indicated it could be of the suppressor phenotype. These data may have implications for T cell-induced demyelination in MS.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

HLA-D/DR expression on epithelial cells: the finger on the trigger?

The findings we have described here show a clear association between epithelial HLA-D/DR expression and autoimmunity. Furthermore, the ability of class II+ thyrocytes to present both exogenous antigens and autoantigens indicates an active role for these HLA-D/DR molecules in autoimmune pathogenesis. IFN-gamma is capable of inducing HLA-D/DR expression by thyroid epithelium, but a number of observations suggest the involvement of other inducers as well. Overall, we conclude that epithelial class II expression very probably plays a key role in the propagation and also in possibly the initiation of autoimmune attack. This is in accord with the proposal of a more general relationship between inappropriate or excessive class II expression and pathogenesis.

Antigen-Presenting Cells↗
PubMed1986

Influence of antigen structure on the activation and induction of unresponsiveness in cloned human T lymphocytes.

Using cloned human helper T lymphocytes reactive with a 24 amino acid peptide (p20) of the carboxyl terminal of the HA-1 molecule of influenza haemagglutinin we have investigated the influence of antigen structure on the activation and in the induction of antigen specific unresponsiveness of T cells. For this analysis stereoisomers and structural isomers of p20 have been constructed. P20 in the form of a single loop created by a disulphide based between residue 306 and an additional cysteine at position 330 was able to activate the helper T cells in the presence of accessory cells but unable to induce tolerance. This result suggested that critical residues were prevented from direct interaction with the T-cell receptor and/or the MHC Class II determinants and required processing to expose them. The enantiomer (D-p20) and the inverted sequence (retro-L-p20) which have non complementary side chain topography as compared to the parent peptide neither activated nor tolerized the T cells. Furthermore the retro-D-p20 isomer which has the same side chain topography as L-p20 but with a reversal of amino and carboxyl acid groups also failed to stimulate or tolerize. Therefore T-cell antigen recognition is not determined by side chains alone. The results presented suggest that structure of extrinsic antigen influences T-cell antigen recognition.

Epitopes↗