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SUMMARY Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves’ ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM-1, sVCAM-1 and sELAM-1 in 62 euthyroid Graves’ patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves’ patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM-1 300 [171–575] versus 244 [119–674], P < 0·001; sVCAM-1 457 [317–1060] versus 410 [238–562], P < 0·001; and sELAM-1 61 [19–174] versus 53 [23–118], P = 0·021. Euthyroid Graves’ disease patients without GO had levels similar to controls: sICAM-1 273 138–453), sVCAM-1 386 [260–1041] and sELAM-1 46 [22–118]. Smoking had an independent effect and was associated with higher levels of sICAM-1 and lower levels of sVCAM-1 in both GO patients and controls; sELAM-1 levels were comparable. In the 62 GO patients, sICAM-1 correlated significantly with severity of eye disease (r = 0·40, P = 0·002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM-1 and sVCAM-1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM-1 and decreased sVCAM-1 levels; (ii) independent from smoking, euthyroid GO... [ABSTRACT FROM AUTHOR]

We have reassessed the possible role of the adhesion molecule ICAM-1 in the pathogenesis of thyroid autoimmunity. In order to do that, we have investigated its expression in eight Graves' thyroids both in vivo (i.e. on cryostat sections and on cell suspensions), and in vitro (i.e. on cells cultured in monolayers for 3 days), and the results were compared with those obtained with similar preparations from lour normal glands. On cryostat sections, the expression of ICAM-1, and for comparison that of HLA Class I and Class II molecules, was studied by immunofluorescence (IFL), but the former were also assessed by a distinct immunohistochemical technique. ICAM-I was not detected in thyrocytes in vivo of both normal and Graves' glands, but solely in endothelial ceils and antigen-presenting cells (APC), This selective reaction was confirmed by a four-layer technique using specific markers which identify endothelial cells and thyrocytes. HLA Class II molecules were confirmed to be inappropriately expressed in thyrocytes of Graves' glands, but there was no co-expression of these products and ICAM-I in the same cells. In contrast, ICAM-I appeared de novo in a proportion of Graves' and normal thyrocytes soon after the attachment and spreading of these cells in monolayer cultures (36-48 h). Graves' thyrocytes showed a quantitively higher degree of expression compared with that detected on normal thyroid cells (40-70% versus 12-20%). Under these experimental conditions, the four-layer staining with thyroid microsomal antibodies confirmed that thyrocytes were indeed the positive cells which expressed ICAM-1. Blocking experiments with cultured thyrocytes from two Graves' glands and MoAbs to tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) did not prevent the occurrence of ICAM-1 expression, As a result of our study, we failed to demonstrate that Graves' thyrocytes express ICAM-1 in vivo. The unexpected ease of inducing ICAM-1 on thyroid cells under certain in vitro conditions remains intriguing. The phenomenon could be the simple consequence of a mechanical effect rather than exerted by specific biological processes. Further investigations arc, therefore, needed to establish whether ICAM-1 is really involved in the pathogenesis of Graves' disease. [ABSTRACT FROM AUTHOR]

γ&lembda; T cells are a subset of T cells with unknown function, and restriction of the γ&lembda; T cell receptor (TCR) repertoire has been described in rheumatoid arthritis and multiple sclerosis. Elevated numbers of γ&lembda; T cells have been reported in the peripheral blood and thyroids of patients with Graves' disease. We have carried out flow cytometric analysis on peripheral blood mononuclear cells (PBMC) and intrathyroidal lymphocytes (ITL) from 12 patients with Graves' disease and nine patients with multinodular goitre (MNG), a thyroid disease of unknown etiology. There was no significant difference between the proportion of γ&lembda; T cells in the PBMC of Graves' and MNG patients, nor between the PBMC and ITL populations in either patient group. We have also carried out polymerase chain reaction amplification on RNA prepared from matched PBMC, ITL and the activated (CD25+) subset of ITL using six TCR V λ-family specific primers. Although there were differences in the amounts of each V λ transcript amplified from PBMC and ITL, there was no difference between the two patient groups. No consistent differences were therefore found between the γ&lembda; cell populations in Graves" and MNG patients, arguing against the direct involvement of this T cell subset in the pathogenesis of Graves' disease. [ABSTRACT FROM AUTHOR]

Antibodies against the gram negative enteric bacterium Yersinia enterocolitica have been found in a high proportion of persons with autoimmune thyroid disorders, especially in those with Graves' disease or hyperthyroidism (Shenkman & Bottone, 1981). There is strong evidence that Graves' disease is caused by receptor autoantibodies which mimic the bioeffects of thyroid stimulating hormone (TSH) on the thyroid (Manley. Knight & Adams, 1982). Recently, saturabte binding sites for TSH were demonstrated in Y. enterocolitica under non-physiological conditions (Weiss et al., 1983). We have characterized TSH binding sites on Y. enterocolitica under physiological conditions and studied their interaction with Graves' immunoglobulins (Ig's). Saturable and specific binding of receptor-purified 125I-TSH to lysozyme/EDTA-treated Y. enterocolitica (serotype 03) was demonstrated under both non-physiological and physiological conditions. Scatchard binding plots were linear indicating a single class of binding site (Kd 1 × 10-7 M, maximum of 30,000 binding sites per cell). In the presence of Graves' Ig's the binding of' 125I -TSH to Y. enterocolitica was significantly inhibited. Graves' Ig's also precipitated a protein of relative molecular mass (Mr) 64,000 from Triton-solubilized. 125I -labelled Y. enterocolitica. similar in size to one of the proteins precipitated by Graves' Ig"s from human thyroid membranes. These findings are consistent with the hypothesis that thyroid autoimmunity may be triggered by bacterial infection via a mechanism involving crossreactivity at the level of the TSH receptor. They also suggest that elements of mammalian endocrine systems are highly conserved and have a function in prokaryotes. [ABSTRACT FROM AUTHOR]