[Immunotherapy of multiple sclerosis].
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Biomedical subjects
Publications and source records attributed to G Edan.
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OBJECTIVE: To determine the optimal duration of antithyroid drug treatment by monitoring serum thyroid stimulating antibody values in patients with Graves' disease. DESIGN: Prospective longitudinal trial of patients with Graves' disease followed up for 24 months after withdrawal of treatment. SETTING: Tertiary referral centre. PATIENTS: A total of 64 consecutive patients with untreated Graves' disease, eight of whom were subsequently excluded. Fifty six patients completed the study. INTERVENTIONS: All patients were treated initially with carbimazole 40 mg, then with decreasing doses that maintained a euthyroid state. Treatment was scheduled to continue for 18 months but was withdrawn earlier if serum thyroid stimulating antibody became undetectable. END POINT: Serum values of thyroid stimulating antibody (assayed by stimulation of human thyroid cells in vitro) and thyroid hormones and thyroid state every three months during treatment and afterwards every six months for 24 months. MEASUREMENTS AND MAIN RESULTS: In 44 patients serum thyroid stimulating antibody became undetectable during treatment and treatment was withdrawn (median duration of treatment nine months, range 3-18 months). In 12 patients the antibody could be detected during 18 months of treatment. Among the first group of 44 patients initial values of the antibody before treatment were significantly lower than in the second group of 12 patients (median 225% (range 138-1236%) v 570% (250-1480%), p less than 0.001); the incidence of relapse was also lower (41% v 92%, p less than 0.001); and among those who did relapse the disease free interval after treatment was longer (median 12 months v 1 month, p less than 0.001). Moreover, the initial median serum values of thyroid stimulating antibodies were not related to the occurrence of relapse or remission as these did not differ between patients who did and did not have a relapse (median 267% (range 139-1480%) v 220% (range 138-1236%). CONCLUSION: Monitoring of serum thyroid stimulating antibody was a good guide to the duration of treatment as it allowed the treatment period to be considerably shortened in a large group of patients with no loss of efficiency.
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Cultures of human thyroid follicles embedded in collagen gel were performed to investigate certain functional properties under bovine thyrotropin (TSH) stimulation. Follicles obtained from normal glands responded to increasing concentrations of TSH administered on day 4 in culture and for 3 days by increased amounts of cyclic AMP (cAMP), thyroglobulin (Tg) and triiodothyronine (T3) and by decreased levels of thyroxine (T4). Effect was maximal at 2000 microU/ml TSH (cAMP) or 200 microU/ml (Tg, T3, T4). When methimazole or propylthiouracil (PTU) were added, the T3 levels decreased. Follicle lumens contained a periodic acid-Schiff substance which was identified by immunoreaction as Tg. Thyroid follicles obtained from Graves' disease glands gave modified results with an earlier and intensified T3 response and no increase in Tg. These data show that (1) Tg and T3 are secretory products of functional follicles giving a cAMP-mediated response to TSH. (2) The detected T3 also derives from T4 5'-deiodination inhibited by PTU. (3) Intensified T3 response in Graves' follicles is probably due to enhanced conversion of T4 to T3.
The involvement of humoral immunity mechanism in etiology of Graves' disease was observed for the first time in 1956. Twenty years later cellular auto-immune dysfunction was also described. To day, there is evidence for suppressor T cell deficiency and decrease in T suppressor lymphocytes in Graves' disease and cell mediated immunity might be one of the most important point in the pathogenesis of Graves disease. For the future, cellular auto-immune dysfunction might be used to predict the evolution of the disease and to choice the best therapeutic scheme.
We compared 609 haplotypes carrying the idiopathic hemochromatosis allele with 475 control haplotypes. Four haplotypes were more frequent in hemochromatosis: A3, B7 (actually A3, CW., B7, Bfs, DR2); A3, B14 (actually A3, CW., B14, BfF, DRW6); A11, B35; and A11, B5. The linkage disequilibrium for A3, B7 and A3, B14 (and probably also for A11, B5) was undeniably stronger in hemochromatosis than in controls. Two haplotypes--A3, B12 and A3, B15--were more frequent in hemochromatosis, without linkage disequilibrium. Four haplotypes in linkage disequilibrium in hemochromatosis--i.e., A2, B12; A1, B8; A9, B7; and A29, B12--were also found to have the same frequency and strength of linkage in controls. The dual observation (1) that haplotypes carrying A3 without either B7 or B14 were highly significantly more frequent in hemochromatosis than in controls and (2) that haplotypes carrying B7 or B14 but not A3 had the same frequency in hemochromatosis and controls led to the formal conclusion that only A3 is an independent marker for the hemochromatosis allele, B7 and B14 being involved only owing to the haplotypic mode of marking; the hemochromatosis allele can thus be mapped closer to locus A than to locus B. Our findings fit well with the hypothesis that the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.
We compared the activities of thyroid-stimulating antibodies (TSAb) measured in cultures of human thyrocytes and the values for thyrotropin-receptor antibodies (TRAb) as measured with a commercial kit based on use of radiolabeled receptors. Sera were obtained from patients with Graves' disease before, during, and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). We found a significant correlation between the measurements of these two antibodies in patients: before treatment (r = 0.74, p less than 0.01, n = 44), after three months of treatment (r = 0.76, p less than 0.01, n = 21), and during relapse after the drug was discontinued (r = 0.64, p less than 0.01, n = 19). In all three situations, our TSAb technique was more sensitive than the TRAb method. We conclude that, even though the TRAb technique is simpler and quicker, this commercial kit is too insensitive to replace measurement of TSAb in fresh human thyrocyte cultures for management of drug therapy of patients with Graves' disease.
In order to assess the previously reported association of HLA-linked idiopathic haemochromatosis with idiopathic refractory sideroblastic anaemia (IRSA), the prevalence of HLA-A3 antigen in a group of 22 patients with IRSA was compared to that observed in healthy controls and in patients with homozygous idiopathic haemochromatosis and to that calculated for a population heterozygous for idiopathic haemochromatosis. The prevalence of A3 in patients with IRSA (0.23) was quite similar to that observed in controls (0.29) and significantly different from that observed in homozygous (0.73; P less than 10(-5] and heterozygous (0.57; P less than 10(-3] haemochromatosis. Serum iron, transferrin saturation, serum ferritin and liver iron concentration showed no difference in IRSA patients with or without A3. It is concluded that there is neither systematic association between the haemochromatosis allele and IRSA nor systematic implication of such an allele in the development of iron overload observed in IRSA.
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A case is presented of sarcoid myopathy in which radiogallium was seen to accumulate in the sites of muscle involvement. Uptake of the radiotracer disappeared following institution of corticosteroid therapy. The exceptional nature of this case contrasts with the high frequency of biopsy evidence of sarcoid muscle disease but is consistent with the rarity of clinical evidence of sarcoid granulomas in muscle. Gallium-67 imaging can be used to determine the extent of muscle involvement and, through evaluation of uptake intensity, the degree of disease activity before and after treatment.
The distribution of B- and T-lymphocyte subpopulations was studied in peripheral blood of 45 patients with untreated Graves' disease and 45 sex- and age-matched healthy controls. Blood samples were taken at the same hour in all subjects. The following tests were performed: HTLA and E (AET) for relative T-lymphocyte count, complement receptor (EAC) and surface immunoglobulins (IgS, IgG, IgM, IgA, kappa, lambda) for relative B-lymphocyte count. In 23 subjects of each group the subpopulations of T-lymphocytes were defined by their reactivity with monoclonal antibodies OKT8 (T-suppressor cells) and OKT4 (T-helper cells). Compared with the control group, patients with Graves' disease showed a decrease in the number of T-lymphocytes (HTLA: P less than 0.05: EAET: P less than 0.001) a decrease in T-suppressor cells (P less than 0.01), and no significant difference in B-lymphocytes and T-helper cells. Thus, the main lymphocyte characteristic in Graves' disease is a decrease in the relative value of T-cells, specifically affecting T-suppressor cells.
Two hundred and seventy-four patients with hemochromatosis and 1005 controls were HLA-typed, and HLA haplotypes were determined for 163 patients and 123 controls. The increased frequency of antigen A3 and haplotypes A3, B7 and A3, B14 in patients with hemochromatosis was confirmed. After correction for the space taken up by A3, a significant increase in All was found. This increase could not be explained by cross reaction between A3 and All. All showed a phenotype association and a haplotype link with Bw35. The genetic significance of this increased All frequency is discussed.
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We studied iron overloading and HLA genotype in two families with overt forms of idiopathic haemochromatosis in two successive generations. In each family the spouse of the patient with overt haemochromatosis in the first generation had clinical and laboratory signs of moderate iron overload and a HLA haplotype A3, B14 and A3, B7 respectively--which is frequently associated with the haemochromatosis gene. This specific HLA haplotype had been transmitted to the second generation patient with overt disease, which thus could be considered as having received a haemochromatosis gene from each parent. Although the finding of cases of overt disease in successive generation firstly suggests a dominant transmission the genetical analysis of these families lead to further strong argument in favour of recessive inheritance of idiopathic haemochromatosis.
HLA A and B antigens were determined in two groups of patients: 38 patients with idiopathic hemochromatosis (IH) and 22 patients with iron overload accompanying alcoholic liver disease (AH). As previously described, HLA A3 and HLA B14 antigens appeared more frequently in the IH group (76.3 and 28.9%, respectively) than in a control group of 204 subjects (27 and 3.4%). In the AH group the frequency of A3 (22.7%) and B14 (13.6%) was not significantly different from that observed in controls. The frequency of A3 was significantly lower in the AH group than in the IH group (P less than 0.001). On this basis a clear difference appears between the two conditions with iron overload, and genetic analysis of the results rules out the hypothesis that AH would be a heterozygous form of IH exposed by alcohol.