The influence of cyclosporin A on the induction of experimental autoimmune thyroid disease in the PVG/c rat.

Using an experimental model of autoimmune thyroid disease we have investigated the influence of cyclosporin A (CyA) on the induction of the disease and its potential ability to prevent disease development. PVG/c rats (n = 80) neonatally thymectomized (day 21) and thence sublethally irradiated were divided into eight groups and received either no CyA or oral CyA (10 mg/kg body weight) for varying periods prior to and during disease induction. Serial serum measurements of thyrotropin (TSH) by radioimmunoassay and anti-thyroglobulin autoantibody by enzyme linked immunosorbent assay showed a progressive rise in untreated animals. The rise in serum TSH levels from 349 +/- 15 ng/ml (mean +/- s.e., normal less than 400 ng/ml) at 7 weeks of age to 526 +/- 61 ng/ml at 11 weeks and 820 +/- 54 ng/ml at 15 weeks was not significantly different in animals treated with CyA for periods ranging from 24 h prior to thymectomy to 7 days post-thymectomy. In contrast animals treated for 28 days post-thymectomy showed significantly lower levels of TSH at both 11 weeks (391 +/- 26; P less than 0.02) and 15 weeks (587 +/- 37; P less than 0.005) as compared with untreated animals. Similar though less dramatic changes were seen in intermediate groups. Autoantibody levels in untreated animals rose from initially undetectable levels to 0.451 +/- 0.07 OD (mean +/- s.e.) at 11 weeks and 0.581 +/- 0.041 OD at 15 weeks. Animals treated for at least 4 weeks after thymectomy with CyA had significantly lower levels of antibody at both 11 weeks (0.213 +/- 0.01; P less than 0.001) and 15 weeks (0.337 +/- 0.03; P less than 0.001) of age. Intermediate groups ranged in antibody levels depending on the duration of CyA treatment. Thyroid gland weight (12.7 +/- 2.4 mg/100 g body weight, mean +/- s.e.) and histological grade of thyroiditis (1.8 +/- 0.4, mean +/- s.e.) in the animals treated with CyA for 4 weeks, assessed when the animals were killed at 15 weeks, were smaller and had less severe thyroiditis than untreated thymectomized and irradiated animals (23.8 +/- 2.8 mg/100 g, P less than 0.02 and 2.9 +/- 0.2, P less than 0.05) killed at the same time. CyA given for long enough during induction of experimentally-induced autoimmune thyroid disease delayed the onset of disease and reduced its severity but could not prevent it given over time courses ranging from 48 h prior to thymectomy to 4 weeks after.(ABSTRACT TRUNCATED AT 400 WORDS)     

Heterogeneity of thyroid autoantigens identified by immunoblotting

Autoimmune thyroid disease in man is commonly associated with autoantibodies against thyroglobulin, microsomes, and the TSH receptor, and the character and specificity of these antithyroid antibodies have been extensively utilized in investigating these conditions. In the present study we have asked whether other thyroid-related antigens exist, against which autoantibodies may be directed. A crude thyroid extract was separated by polyacrylamide gel electrophoresis followed by immunoblotting with serum obtained from patients with Graves' disease or Hashimoto's thyroiditis. Antibodies in sera from patients with Graves' disease and Hashimoto's thyroiditis reacted with many antigenic determinants in immunoblots of the thyroid membrane preparation (2000g supernatant). These determinants were disease specific in that sera from normals and patients with Addison's disease and rheumatoid arthritis did not react, but there was no difference between the patterns of reactivity with Graves' disease or Hashimoto's thyroiditis sera. Thyroglobulin produced two predominant bands of reactivity at 320 and 200 kDa, whereas purified microsomal antigen produced a triplet of bands around 105 kDa, when these preparations were reacted with appropriate autoimmune sera. Nonetheless, some sera produced additional bands with the microsomal antigen blots, indicating that some of the antigens which were detected using crude thyroid membrane remained in the microsome preparation to produce multiple antibody binding reactivities. We were unable to inhibit any of the antibody binding with TSH. Purification of individual thyroid antigens on the basis of their molecular weights should standardize current antibody assays and permit more detailed evaluation of the cellular immune responses in Graves' disease and Hashimoto's thyroiditis.     

The influence of lithium chloride on experimental autoimmune thyroid disease.

Lithium administration is known to be associated with the development of thyroid dysfunction; it also exerts an effect on the immune system. The effect of lithium on experimental autoimmune thyroid disease was studied in female August rats. Following immunization with rat thyroglobulin in Freund's complete adjuvant, lithium chloride was administered i.p. for 30 days to four groups at varying stages of the disease. Control animals received i.p. saline. Anti-thyroglobulin antibody levels (measured by ELISA) were significantly increased in rats given lithium immediately post-immunization (group B) compared to control animals (661 +/- 42 OD vs 448 +/- 68; mean +/- s.e., P less than 0.02). In contrast, animals which received lithium during the spontaneous resolution of the disease (group D) showed a significant fall in anti-TG antibody compared to controls (99 +/- 15 vs 27 +/- 15; P less than 0.001). Anti-TG antibody levels remained undetectable in animals which received lithium but were not immunized. The splenic T cell blastogenic response (as measured following phytohaemagglutinin stimulation) was significantly increased in rats receiving lithium prior to and during immunization (group A) (stimulation index 63.4 +/- 6.9 vs 10.2 +/- 2.4; P less than 0.001). Spontaneous cell proliferation of splenic lymphocytes was decreased in two lithium treated groups (group A P less than 0.005, group C P less than 0.05). There was no alteration in splenic weight or the degree of thyroid lymphocytic infiltration in any of the treated group. Lithium exerted both positive and negative influences on the immune system in rats immunized with thyroglobulin in adjuvant but did not induce autoantibody production in normal rats.     

Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum

Anyone who has been in an endocrine clinic will appreciate that associations exist between autoimmune thyroid disease (AITD) and other autoimmune disorders. However, the full extent of these associations is still not fully appreciated, and new associations are being uncovered which may shed new light on the pathogenic basis for these connections, and the underlying reasons for them are only now becoming understood. This review is based on the British Thyroid Association Pitt‐Rivers Lecture 2010. The first section provides an update on studies which have detailed the strength of various autoimmune disease associations, the second section discusses the environmental and genetic factors which underlie these associations and the final section describes some recently identified, unexpected AITD associations. Unravelling these associations further will illuminate the pathogenesis of autoimmune diseases and offers the prospect of new therapeutic approaches.     

Is there a need to redefine the upper normal limit of TSH?

Mild forms of hypothyroidism--subclinical hypothyroidism--have recently been discussed as being a risk factor for the development of overt thyroid dysfunction and for a number of clinical disorders. The diagnosis critically depends on the definition of the upper normal limit of serum TSH as, by definition, free thyroxine serum concentrations are normal. Cut-off levels of 4-5 mU TSH/l have been conventionally used to diagnose an elevated TSH serum concentration. Recent data from large population studies have suggested a much lower TSH cut-off with an upper limit of 2-2.5 mU/l but application of strict criteria for inclusion of subjects from the general population studies aiming at assessing TSH reference intervals (no personal or family history of thyroid disease, no thyroid antibodies and a normal thyroid on ultrasonography) did not result in an unequivocal upper limit of normal TSH at 2.0-2.5 mU/l. When summarizing the available evidence for lowered upper TSH cut-off values and their potential therapeutic implications there is presently insufficient justification to lower the upper normal limit of TSH and, for practical purposes, it is still recommended to maintain the TSH reference interval of 0.4-4.0 mU/l. Classifying subjects with a TSH value between 2 and 4 mU/l as abnormal, as well as intervening with thyroxine treatment in such subjects, is probably doing more harm than good.