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A M Madec

Publications and source records attributed to A M Madec.

34 records · Page 2Linked to original sources
PubMed1989

[TSH receptors].

It is a paradox that thyroidology often initiates new biological concepts but lags behind in the characterization of the molecular mechanisms involved, the latter progressing more rapidly in other systems. The question of the TSH receptor is an illustration of this. This paper reviews the main aspects of the biochemistry and functions of the TSH receptor. It is stressed that the classical biochemical approach has failed in the elucidation of the structure of the receptor which should benefit from molecular biology methodologies. Experimental difficulties in the study of the TSH binding function of the receptor are also described. Functional pathways activated by the receptor are discussed, especially within the frame of current researches on the thyroid growth effect of TSH. Another important feature concerning the TSH receptor is its implication in the physiopathology of Graves' disease. Auto-anti-TSH receptor antibodies are the hallmark the disease and are responsible for the hyperfunction of the gland. Characterization of the antigenic epitopes of the receptor and biological effects of the various anti-TSH receptor antibodies, both natural polyclonal and experimental monoclonal, is also an area of active research. It is hoped that understanding of Graves' disease will benefit from improvement in our knowledge of the TSH receptor structure and functions.

Animals↗
PubMed1988

Blocking anti-thyrotropin receptor antibodies desensitize cultured human thyroid cells.

Stimulating anti-TSH receptor antibodies (TSAb) mimic TSH in the induction of refractoriness in cultured thyroid cells; TSAb and TSH desensitize one another. We investigated whether blocking anti-TSH receptor antibodies (TBkAb) have the same desensitizing effects in cultured human thyroid cells. Prolonged exposure of cells (20 h) to TBkAb followed by antigen-antibody dissociation by an acid wash step was required to induce refractoriness to subsequent stimulation of cAMP accumulation with TSH and TSAb. Cycloheximide prevented this desensitization effect. The cAMP response to forskolin was not reduced in cells pretreated by TBkAb and was increased in cells desensitized by TSH or TSAb. The pattern of the TSH dose-response curves suggested that desensitization by TSH or TSAb involved only a postreceptor mechanism but both receptor and postreceptor phenomena in the case of TBkAb. In conclusion, like TSH or TSAb, TBkAb may induce a homologous desensitization in human thyroid cells which is not mediated by cAMP.

Animals↗
PubMed1988

Monoclonal antibody approach to the relationship between immunological structure and biological activity of thyrotropin.

In order to locate the domains involved in the biological activity of TSH and to get some insight in the relationship between immunological and biological properties of TSH, 24 monoclonal antibodies (mAb) to 11 different antigenic regions of hTSH were tested for both binding to hTSH and inhibition of hTSH stimulation of adenylate cyclase in human thyroid membranes. These mAb were also investigated for binding to bovine TSH (bTSH), and interference with bTSH binding to the receptor and stimulation of adenylate cyclase. Radioiodinated human TSH (hTSH) was incubated with increasing concentrations of mAb. Maximum hTSH binding by the various mAb ranged from 15-75% and was not related to the apparent affinity of the mAb for hTSH. Maximum inhibition by the mAb of hTSH stimulation of adenylate cyclase ranged from 3-92%. As compared to the antigenic map of hTSH, it was observed that mAb reacting with the same antigenic regions might display varying inhibition of hTSH. Nevertheless, it was clearly shown that the most potent inhibitors of hTSH stimulatory activity interacted with epitopes located on the alpha- and beta-subunits or expressed only by holo hTSH. Only 11 of the 24 mAb cross-reacted significantly with bTSH. Seven exhibited the same inhibition of hTSH and bTSH stimulatory activity; the four remaining mAb rather than to inhibit adenylate cyclase stimulation as observed with hTSH, did not interfere or even increased adenylate cyclase stimulation by bTSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

[Biological criteria of isolated Graves' ophthalmopathy].

The diagnostic value of biological tests, especially the thyroid stimulating immunoglobulin (TSI) assay, was studied in 29 patients with endocrine Graves' ophthalmopathy without hyperthyroidism. In 21 patients the presence of biological abnormalities (L-T3 suppression test, TRH test, presence of antithyroid antibodies) indicated that the ophthalmopathy was related to Graves' disease. The remaining 8 patients were free of any biological abnormality. The contribution of the TSI assay to the pathophysiological diagnosis of ophthalmopathy is poor. These immunoglobulins were detected in 12 out of 29 cases, but they were associated with the above-mentioned abnormalities in all but 3 of these 12 cases.

Adolescent↗
PubMed1987

Immunological parameters in Graves' disease: are they useful for indication and monitoring of antithyroid drug treatment?

This paper reviews the available published data on studies of a correlation between the presence or intensity of measurable immunological abnormalities or markers in Graves' disease and the outcome after a course of antithyroid drug. The following parameters are discussed: circulating anti-thyroid-stimulating hormone receptor antibodies; antitubulin antibodies; human lymphocyte antigens, and repartition of T-lymphocyte subsets. At the present time no single parameter has any real practical value for individual patients either to indicate or monitor antithyroid drug therapy. The more useful information remains the anti-thyroid-stimulating hormone receptor level at the end of treatment which, if elevated, is predictive of relapse. Several areas of research, however, appear promising.

Antithyroid Agents↗
PubMed1987

Thyroid stimulating antibody: an index of thyroid stimulation in Graves' disease?

Early (20 min) thyroid radio-iodine uptake (ERU) and thyroid-stimulating antibodies (TSab) were determined in 27 untreated unselected patients with Graves' disease at the time of diagnosis. In 21 subjects the same tests were further performed in parallel during combined carbimazole-L-T3 therapy (mean duration of follow-up: 10.8 +/- 5.8 months; mean +/- SD). TSab was determined by a cAMP-human thyrocyte culture stimulation assay and expressed in microliter-equivalent of a TSab standard/ml (microliter-eq/ml). Before treatment, ERU, ranging from 15 to 54% of the injected dose (normal less than or equal to 8% dose) correlated with serum T3 (r: 0.54; P less than 0.01); TSab, ranging from 6 to 85 microliter-eq/ml was detected in 21/27 patients. There was a significant correlation between ERU and TSab (Spearman rank test: r: 0.57; P less than 0.01). During the first months of treatment, 5 of the 21 patients sequentially studied had undetectable TSab levels throughout the study and in these patients ERU decreased by 57% of its initial value; the remaining 16 subjects were divided into two groups according to ERU changes: in group A (9 patients), initial ERU decreased by 50% or more or the absolute value became less than 20% of the dose and TSab decreased from 10.9 +/- 4.8 microliter-eq/ml to 5.3 +/- 1.6 microliter-eq/ml (P less than 0.01); in group B (7 patients), the fall of ERU was less than 50% or the absolute value remained greater than 20% of the dose and TSab values remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

T lymphocyte subsets at various stages of hyperthyroid Graves' disease: effect of carbimazole treatment and relationship with thyroid-stimulating antibody levels or HLA status.

Markers of autoimmunity in hyperthyroid Graves' disease were studied at various stages of the disease in connection with HLA status. The 148 patients studied were included in a long term prospective evaluation of antithyroid drug treatment. The proportions of total T lymphocytes and OKT4 and OKT8 positive cells in peripheral blood and circulating thyroid-stimulating antibodies were determined before treatment (M0; 46 patients), after 6 (M6; 50 patients), and 18 months (M18; 22 patients) of carbimazole treatment, at relapse (15 patients) and after 2 yr of euthyroidism after drug withdrawal (remission; 23 patients). Twenty-seven patients were sequentially studied between M0 and M6, and M6 and M18. As compared to matched normal subjects, the mean proportion of OKT8 positive cells was significantly decreased in every group of patients, even in those in remission, and the mean OKT4/OKT8 cell ratios were increased in all groups except the patients in remission. However, OKT4/OKT8 cell ratios in individual M0 patients were widely distributed, being normal in 50%. No correlation was found between the proportions of T cell subsets and thyroid-stimulating antibody values, and the two measures varied independently in patients studied sequentially. OKT8 lymphocyte subset was dependent on HLA status. In DR3-positive patients, the mean OKT4/OKT8 cell ratio was high at all stages of the study; in DR3-negative patients it decreased significantly at M18 and was normal in those patients who had a remission. However, in the DR3-positive and -negative groups of patients, the mean OKT4/OKT8 ratios at M0 and at relapse were similar. In conclusion, the proportions of circulating OKT8 positive lymphocytes reflect only poorly the activity of the immune abnormalities in Graves' disease, but do correlate with HLA-DR3 status.

Adolescent↗
PubMed1984

Thyroid stimulating antibodies: an aid to the strategy of treatment of Graves' disease?

In 1976 we initiated a prospective study to specify the usefulness of thyroid stimulating antibody (TSAb) determinations in predicting the outcome of post-antithyroid drug treatment for Graves' disease. This study was carried out on 55 patients, who were either treated for six (n = 16) or 18 months (n = 39) and followed up for an additional two-year period. TSAb was determined on whole serum in 29 patients before and at the end of treatment, and in 26 patients at the end of treatment only. These determinations were carried out using a sensitive and reproducible microassay based on cAMP accumulation in human thyroid cell cultures. Before treatment, TSAb ranging from 170 to 1529% was present in 28/29 patients and reached significantly low levels at the end of treatment whatever its duration. TSAb was undetectable in 24/55 patients at the end of treatment. 8/16 'short-treated' and 18/39 'long-treated' patients remained in remission. As expected, initial TSAb levels had no predictive value. End-treatment TSAb values, when low (less than 350%) or negative did not correlate with later evolution: in these 39 patients, relapse rate was 41%. In contrast, 13/16 patients with end-treatment TSAb greater than 350% relapsed. Relapses tended to occur earlier in patients with the highest TSAb levels. TSAb determined again during follow-up was negative in each of the 18 patients in remission, and positive in 8/10 patients at the time of relapse, whatever its level at the end of the drug course. This study confirms that only end-treatment TSAb levels are predictive of relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

[Detection of thyrostimulating immunoglobulins in whole serum. Value of the culture of human thyroid cells].

TSAb was assayed in whole serum using a human thyroid cell culture system. Sera (20.% final concentration) were added to each well (10(6) cells) at the initiation of the culture. After 48 h of incubation, total AMPc was assayed and results, when significantly different, were expressed as per cent of basal values. Among 67 untreated patients with Graves' disease, TSAb was detected in 64 (95.5%), with activity varying from 135 to 1000%. No correlation was found between TSAb activity and clinical presentation or thyroid hormones levels. None of the 7 patients with Hashimoto's thyroiditis, or of the 12 with simple goiter or of the 25 normal subjects tested was positive. One of the 10 patients with proven toxic adenoma was weakly positive. When compared under the same conditions, activities of whole sera or of corresponding ammonium sulfate precipitates were similar. Reproducibility averaged 15% and 25% within an assay and between assays respectively. Prolongation of incubations for 48 h instead of 2 h markedly increased the sensitivity of TSAb detection. This culture system provides a relatively simple, sensitive and reliable bioassay for TSAb.

Adolescent↗
PubMed1983

Anti-tubulin antibodies in autoimmune thyroid disorders.

The presence of circulating antibodies directed against a cytoskeletal element, microtubules, in patients with autoimmune thyroid disorders, has been studied using pure brain tubulin as antigen. Immune complexes were immunoprecipitated using a goat anti-human immunoglobulin antibody. Twenty sera among 48 (41%) from patients with Graves' disease and nine sera among 16 (56%) from patients with Hashimoto's thyroiditis had increased levels of anti-tubulin antibodies as compared to that of 26 sera from control subjects. Only one serum among 11 from patients with toxic adenoma was positive. Very similar results were obtained using protein A adsorbent to collect immune complexes. Specificity of the tubulin binding activity was ascertained by dilution of the sera and displacement of tracer tubulin by unlabelled pure tubulin from rat or human brain. Anti-tubulin antibody titres were variable; one serum was positive at dilution higher than 1:15,000, a titre similar to those obtained in animals experimentally immunized against tubulin. Binding of labelled and unlabelled tubulin to immunoglobulins from positive sera was strictly competitive. The apparent affinity constant for the binding of tubulin to human anti-tubulin autoantibodies determined on four sera was 0.2-0.6 X 10(9)/M. There was no significant association between anti-tubulin antibodies and anti-microsomal antibodies or anti-thyroglobulin antibodies or thyroid stimulating antibodies. In contrast, only five to six per cent of sera from patients with other autoimmune diseases: lupus erythematosis or pernicious anaemia, had increased levels of anti-tubulin antibodies. In conclusion, tubulin represents a new autoantigen which is expressed rather specifically in autoimmune thyroid disorders and probably independently from the classical thyroid antigens.

Adult↗
PubMed1982

[Thyroid stimulators other than TSH. Classification. Immunoglobulins of Basedow's disease: history, methodology, nomenclature].

Two families of thyroid stimulators can be described besides TSH: a) hormonal factors, b) Graves' IgGs. Hormonal factors include: biogenic amines (catecholamines, histamine, serotonine), prostaglandins E and LH and hCG. The stimulating effect of the latters is expressed only at very high concentration. Thyroid stimulating effect of GH, insulin, cortisol, NGF and FGF is probably ancillary. Thyroid stimulating IgG were first represented by the LATS. Graves' IgGs are currently detected by their interaction with human thyroid tissue in vitro: one either detects thyroid stimulation (cAMP or hormone production) or binding inhibition of LATS or TSH. These various activities are denominated: thyroid-stimulating IgG (TSI) or antibodies (TSAb), or LATS-Protector (LATS-P) or thyrotropin binding inhibitory (TBIA). TBIA IgGs are not necessarily TSI. Thyroid growth stimulatory IgGs (TGI) have also been described as well as TSAb or TGI blocking IgG, that also block TSH effects. Graves' IgGs probably include a mosaic of specificities directed against different parts of thyroid cell surface antigens constituting, or near, the TSH receptor complex. TSI represent only one or a few types of these specificities.

Autoantibodies↗
PubMed1981

Progesterone and insulin-resistance in the pregnant rat. I. In vivo and in vitro studies.

The effects of pregnancy, progesterone treatment and of progesterone added in vitro on insulin-resistance have been assessed in rat adipocytes and hemidiaphragms. In progesterone treated female rats, the steroid antagonized in vivo the hypoglycemic effect of intravenously injected porcine insulin; the same results were obtained when the steroid was injected at the same time as insulin and there was no lag period between its appearance in the blood and its effect on blood glucose levels. Such a rapid effect differs from the generally accepted scheme for steroidal mode of action. The in vitro glucose uptake and oxidation by rat hemidiaphragms or adipocytes, whether or not stimulated by insulin, were decreased during pregnancy and after progesterone treatment of spayed females; the incorporation of [1-14 C]-glucose into glycogen of the diaphragm varied in the same way. However some of these effects were not decreased at 10 days of pregnancy, when progesterone levels only just began to rise. The effect of progesterone on insulin-resistance and glucose metabolism might occur at tissue level. The action of progesterone on adipocyte oxidation of glucose labeled at the C1 and the C6 position suggests that the steroid may act on the pentose cycle.

Adipose Tissue↗