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At least 19 recordsLinked to original sources
PubMed1998

Pre-autoimmune thyroid abnormalities in the biobreeding diabetes-prone (BB-DP) rat: a possible relation with the intrathyroid accumulation of dendritic cells and the initiation of the thyroid autoimmune response.

Thyroid autoimmune reactions start with an accumulation of mainly dendritic cells in the thyroid. There is increasing evidence that, apart from being antigen-presenting cells, they are also able to control the growth and hormone synthesis of neighbouring endocrine cells. The questions thus arise: are dendritic cells accumulating in the pre-autoimmune thyroid in response to an altered proliferative or metabolic activity of thyrocytes, and do cytokines, monocyte chemoattractants, or both, have a role in their accumulation? We have investigated these questions in thyrocytes of the biobreeding diabetes-prone (BB-DP) rat in relation to the start of the intrathyroid accumulation of dendritic cells--that is, at about 9 weeks of age. BB-DP rats and Wistar rats (controls) were studied from 3 to 20 weeks of age. Hyperplastic goitre development was studied by assessing the thyroid weight and by measuring the number of thyrocyte nuclei per 0.01 mm2 thyroid section. In addition, the in situ expression of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), monocyte-chemotactic protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were studied by immunohistochemistry. The in vitro proliferative capacity of BB-DP and Wistar thyrocytes was measured by tritiated-thymidine ([3H]TdR) and bromodeoxyuridine (BrdU) incorporation into reconstituted, TSH- and non-TSH-stimulated, cultured thyroid follicles. Further in vitro studies consisted of measurement of the production of thyroxine (T4), triiodothyronine (T3), thyroglobulin, IL-6, TNF-alpha and MCP-1 by the thyroid follicles. BB-DP rats developed a small hyperplastic goitre between the ages of 9 and 12 weeks. The in vitro proliferative rate of thyrocytes isolated from hyperplastic BB-DP thyroids was significantly lower than that of Wistar thyrocytes. This phenomenon also occurred in follicles isolated from BB-DP rats before hyperplastic goitre development, which produced significantly less T4, but more T3, than did Wistar follicles of the same age. At the time of and after hyperplastic goitre development, BB-DP follicles exhibited altered metabolic behaviour and produced significantly more T4, but equal amounts of T3 compared with both Wistar follicles of the same age and follicles of younger BB-DP rats (both under basal conditions and TSH-stimulated). In vitro IL-6 production by these BB-DP thyroid follicles was also increased. There was no noteworthy difference in production of thyroglobulin and MCP-1 between BB-DP and Wistar follicles at any age. TNF-alpha was not produced by BB-DP or Wistar thyroid follicles. Immunohistochemistry revealed the expression of IL-6 by both BB-DP and Wistar thyroid follicle cells at all times of sampling. MCP-1 and TNF-alpha were expressed only when infiltrates were present in BB-DP thyroids (restricted to leucocytes, ages > 18 weeks). Modest ICAM-1 expression was restricted to large blood vessels in both BB-DP and Wistar thyroids; in the case of infiltrates (BB-DP rat) alone, high ICAM-1 expression was found on blood vessels and leucocytes in these infiltrations. At the time of intrathyroidal dendritic cells accumulation, BB-DP rats develop a small hyperplastic goitre. At that time there is also in vitro evidence for a shift to a higher production of thyroxine and IL-6 from thyrocyte follicles. The in vitro proliferation rate of BB-DP thyrocytes is, however, abnormally low (both in the pre- and hyperplastic period). Similar pre-autoimmune thyroid growth abnormalities have been described in another animal model of thyroid autoimmune disease, the obese strain chicken.

Animals↗
PubMed1986

The differences of susceptibility of the target thyroid gland to autoimmune thyroiditis and of antigenicity of thyroid gland for induction of experimental autoimmune thyroiditis.

By using a recently developed method for producing thyroiditis in mice consisting of implantation of a fresh thyroid gland into the peritoneal cavity or under the capsule of the kidney with subsequent injection of lipopolysaccharide, differences were shown in susceptibility of the target thyroid gland to autoimmune destruction and in antigenicity of the thyroid gland for induction of experimental autoimmune thyroiditis. Using recombinant congenic mice, the H-2 haplotypes of the target thyroid gland were found to be as important as those of the immune system in development of autoimmune thyroiditis. On the other hand, the H-2 haplotypes of the thyroid gland are unimportant for induction of autoimmune thyroiditis.

Animals↗
PubMed1989

Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: thyroid follicular cells produce interleukin-1 alpha and interleukin-6.

Cytokine production was studied in thyroid tissue from patients with Graves' disease, Hashimoto's thyroiditis and non-toxic goitre. The expression of interferon gamma, tumour necrosis factor alpha and beta, interleukin-1 alpha and beta, interleukin-6 and platelet-derived growth factor A chain was assessed by slot-blot analysis of the respective mRNA in freshly isolated tissue samples. All seven cytokines were detected in patients of all groups. Although the respective mRNA levels were, in general, higher in thyroid autoimmune disorders, this appeared to relate to the degree of the lymphocytic infiltration of the thyroid gland at the time of surgery. Purified thyroid follicular cells expressed high levels of interleukin-1 alpha and interleukin-6 mRNA and when established in primary culture, purified thyroid follicular cells from Graves' disease as well as non-toxic goitre produced interleukin-1 alpha and interleukin-6 bioactivity spontaneously. In the case of interleukin-1 this could be further augmented by addition of lipopolysaccharide to the thyroid follicular cell cultures. These results demonstrate that the lymphocytic infiltrate found in autoimmune and non-autoimmune thyroid disorders is associated with cytokine production. Additionally we have shown that intrathyroidal cytokine production is not restricted to thyroid-infiltrating mononuclear cells, but may also involve thyroid follicular cells both in vivo and in vitro. The cytokines produced by thyroid follicular cells may have an important role in stimulating autoantigen specific T cells in vivo as both interleukin-1 and interleukin-6 facilitate T cell activation.

Adult↗
PubMed1996

[Clonal B-cell reaction in Sjögren disease and Hashimoto autoimmune thyroiditis].

Autoimmune diseases are defined as specific, adapted immune reactions against self-antigens. These antigens were attacked by activated, autoaggressive T-Cells in most cases. However, since introduction of the MALT concept it became clear, that particularly in the autoimmune diseases of the MALT specific subpopulations of B-cells play an important role. In this study, the B-cells in the thyroid gland of 40 patients suffering from Hashimoto's disease and 25 patients with Sjögrens syndrome and enlargement of the salivary glands were immunophenotyped and molecular-genetically investigated. The molecular-genetical investigation included PCR based amplification of immunoglobulin heavy chain CDR III region and the T-cell receptor gamma chain (TCR-gamma). By immunophenotyping, in the salivary glands monocytoid B-cells could be identified as intraepithelial effector cells in nearly all cases, whereas in the thyroid gland mostly marginal zone cells in the follicle epithelium were observed. In 13 biopsy specimen from salivary gland, clonal rearrangements of TCR-gamma, and in 9 cases of patients with Sjögren's syndrome JH rearrangements could be detected. Monoclonal TCR-gamma rearrangements were identified in 9/40 patients suffering from autoimmunethyroiditis Hashimoto. In 8/40 thyroid gland biopsies a monoclonal JH-rearrangement could be found. Within 11/25 patients with Sjögren's syndrome and in 23/40 patients with M. Hashimoto polyclonal rearrangements were observed. Within all biopsy specimen of patients with monoclonal rearrangements, lymphoepithelial lesions or lymphoepithelial destructions could be identified immunohistochemically. Additionally, in 2 biopsies from salivary gland and in one specimen from thyroid gland the transition from autoimmune disease into a secondary high grade lymphoma was observed. In 26/40 patients with M. Hashimoto and in 11/25 patients with Sjögren's syndrome the transition in a subsequent low grade B cell lymphoma of MALT-type was found. These results lead to the following conclusions: 1. clonal rearrangements of tumor forming B-cells in both autoimmune diseases investigated can be interpreted as facultative malignant. 2. Intraepithelial B-cells probably are the promotors of the autoimmune process and--in case of clonal evolution and immortalisation--can be regard as causative agent in the development of primary extranodal B-cell lymphoma.

B-Lymphocytes↗
PubMed1985

[Diabetes mellitus type I, thyroid gland autoimmunity, thyroid gland function and HLA status].

In a cross-sectional study sera of 130 children and adolescents with insulin dependent (type I) diabetes were tested for the presence of cytoplasmatic islet cell antibodies (ICA), thyroid microsomal antibodies (TMA) as well as thyroid function (T3, T4, thyrotrophin). 102 of the patients were examined for thyroid enlargement, all patients with TMA were within this group. TMA were found in 15.4%, ICA in 38.5%, the latter decreasing with duration of diabetes. Of the TMA positive sera, 45% were also ICA positive, but only one child out of these was diabetic for more than 5 years. Thyroid enlargement occurred in 33.3%, however in TMA positive patients in 70%, of which one girl suffered from hypothyroidism due to biopsy-proven Hashimoto's thyroiditis, all the other diabetics being euthyroid. There was no sex predisposition. By HLA-typing 40% of TMA positive patients expressed the HLA-DR3 antigen which is said to be responsible for "autoimmune" diabetes, whereas only some of these were ICA positive as well. In our study, no significant association was found between presence or even persistence of ICA and TMA, nor between thyroid autoimmunity and HLA-DR3. Since type I diabetic patients with thyroid autoimmunity are predisposed to develop hypothyroidism with time, less likely also Addison's disease, screening of type I diabetics for thyroid microsomal antibodies should be considered especially in those with thyroid enlargement.

Adolescent↗
PubMed1994

Susceptibility to autoimmune thyroiditis in Down's syndrome is associated with the major histocompatibility class II DQA 0301 allele.

OBJECTIVE: Abnormalities of immune function, including thyroid autoimmunity, are common features of Down's syndrome, and the genetic associations of autoimmune thyroiditis have been extensively studied in otherwise normal patients with thyroid disease. In this study we have examined the HLA associations of autoimmune thyroid diseases in a cohort of adult subjects with Down's syndrome, to see whether they differed from those found in other populations. DESIGN AND MEASUREMENTS: Restriction fragment length polymorphism analysis was carried out in 41 subjects whose thyroid status was assessed by measuring thyroid function and autoantibody titres. The genotypes of subjects with and without hypothyroid autoimmune diseases were compared. SUBJECTS: Forty-one older subjects with Down's syndrome and an average age of 46.6 years under review by the Maudsley Hospital. RESULTS: Hypothyroid autoimmune disease in this study group was clearly associated with a 5.5-kb Taq1 DQA restriction fragment length polymorphism (Pc = 0.013) corresponding to the major histocompatibility (MHC) class II DQA 0301 allele. CONCLUSIONS: In contrast to Hashimoto's thyroiditis and atrophic thyroiditis, there is a strong association between class II genotypes and hypothyroid autoimmune disease in Down's syndrome. This implies a role for a gene or genes on chromosome 21 in the development of autoimmune thyroid disease.

Alleles↗
PubMed1990

Dendritic cells and class II MHC expression on thyrocytes during the autoimmune thyroid disease of the BB rat.

The BB rat is a well-established model for spontaneous thyroid autoimmune disease. Since antigen presentation in thyroid autoimmunity is still a matter of debate, we studied the presence of antigen-presenting dendritic cells in the thyroid of the BB/O rat during the development of the disease in relation to the presence of other leucocytes and the aberrant expression of class II MHC determinants by thyrocytes. Thyroid glands, as well as thyroid-draining lymph nodes, were investigated in enzyme histochemistry and immune histochemistry. The appearance of anti-colloid antibodies in the circulation at 6 weeks of age was accompanied by an increase in the weight of the thyroid-draining cervical lymph nodes, which contained many anti-thyroglobulin-producing plasma cells. The only noteworthy event in the thyroid gland in this early stage of the disease was an increase in the number of dendritic cells. T cells, B cells, and plasma cells were virtually absent from the thyroid, and thyrocytes were invariably negative for class II MHC determinants. Only after 18 weeks of age, when large accumulations of dendritic cells, B lymphocytes, and T lymphocytes were seen in 40% of the BB thyroids, could some class II MHC positive thyroicytes be observed. At this stage the thyroid also contained some anti-thyoglobulin-producing plasma cells. Our observations suggest that dendritic cells play a role in antigen presentation in the early stages of the thyroid autoimmune response.

Animals↗
PubMed1989

Endemic cretinism: possible role for thyroid autoimmunity.

Thyroid atrophy, rather than goitre, is a characteristic feature of myxoedematous cretinism but its cause and nature are unknown. In this study, purified IgG fractions of serum from patients with myxoedematous endemic cretinism inhibited thyrotropin-induced DNA synthesis in guineapig thyroid segments in a sensitive cytochemical bioassay. IgG from patients with euthyroid neurological endemic cretinism or from normal subjects did not inhibit thyroid growth. Furthermore, in myxoedematous subjects, the presence of the thyroid-growth-blocking immunoglobulins showed a positive relation with thyroid atrophy found on ultrasound. These findings provide a pathogenic basis for the variable clinical expression of endemic cretinism.

Adolescent↗
PubMed1987

Intrathyroidal MHC class II antigen expression and thyroid autoimmunity.

The association between MHC polymorphisms and autoimmune thyroid disease has been complicated by the observation of MHC class II antigen expression by the human thyroid gland. It is possible that the MHC associations observed in animal and human population studies may have mechanistic explanations at the level of the thyroid cell. There is evidence for expression of HLA-DR allospecific antigen in both normal and abnormal human thyroid cells, with enhanced expression in patients with autoimmune thyroid disease. Such MHC class II expression appears to be mediated primarily by lymphokine secretion from intrathyroidal T lymphocytes. Thyroid cell HLA-DR antigen participates in activation and amplification of T cells and is likely to be involved in presentation of thyroid antigen to the immune system. The relationship between these immune interactions and the initial events leading to the development of autoimmune thyroid disease remains to be understood.

Gene Expression Regulation↗
PubMed1990

Thyroid autoimmunity and thyroid autonomy.

While it is well established that autoimmune factors are the cause of goiter and hyperthyroidism in Graves' disease, these factors are not yet considered relevant in the development of thyroid autonomy. While an increased overall frequency of anti-Tg and anti-TPO antibodies has been found in moderate iodine-deficient areas, where thyroid autonomy is more frequently observed, there was evidence indicating that thyroid autoimmune phenomena were the consequence rather than the cause of the goiter. Thyroid Stimulating Antibodies (TSAb) have been reported in sera of patients with nodular autonomous goiter, but their pathogenetic relevance is uncertain, since these findings could not be confirmed by others. In our experience TSAb were detected in few cases with multinodular nontoxic goiter and were always associated with anti-TG and anti TPO antibodies, indicating that these patients have the nodular variant of Graves' disease. Besides TSAb, Thyroid Growth Stimulating Antibodies (TGAb) have been detected by different techniques in several goitrous conditions, including Graves' disease and sporadic or endemic nontoxic goiter. The precise nature of TGAb remains to be clarified, and particularly the relationship between TGAb and TSAb is still a matter of controversy. However, data indicating that TGAb cannot be dissociated from TSAb in Graves' sera suggest that these antibodies can be regarded as a sufficient pathogenetic agent for the development of both goiter and thyroid hyperfunction in Graves' disease. The relevance of TGAb in euthyroid goitrous conditions is uncertain, since conflicting results have been reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed1988

Human autoimmune thyroid disease: cellular and molecular aspects.

We have reviewed the impact of cellular and molecular biology on our understanding of the immune system and thyroid autoimmune disease and presented the evidence that MHC, TCR and immunoglobulin genes are involved in susceptibility to such disease. At the level of the target thyroid epithelial cell, the identification of the genes for Tg and TPO (the microsomal antigen) using recombinant DNA techniques are evidence of dramatic progress. On the humoral side of the immune response, the investigation of restricted clonality is still hampered by the technical difficulties in obtaining immortal B cell lines producing thyroid antigen specific high affinity IgG antibodies, although the advent of tools to sequence the immunoglobulin V genes from small quantities of DNA will overcome this difficulty (e.g. by polymerase chain reactions). T cells have also begun to be characterized both phenotypically, thanks to the advent of ever better characterized monoclonal antibodies, and functionally at the clonal level, thanks to refinement of cell culture techniques. Future studies in this area will also need to focus on cell immortalization and maintenance of antigen-specific responses although, major strides in the direct sequencing of the TCR are taking place and investigation of T cell receptors in antigen-specific T cells should be feasible. MHC associations with thyroid autoimmune disease, as studied by analysis of RFLP patterns, have not significantly improved already established serological HLA associations and direct MHC gene sequencing will be required. Analysis of the organ-specific regulation of MHC class II gene expression has led to a better understanding of the functional role of MHC class II genes in thyroid autoimmune disease at the target cell level. Such studies have pointed out important local immune responses within the thyroid gland but have not yet provided the initiating factor or factors for human autoimmune thyroid disease in genetically susceptible individuals.

Antigens↗
PubMed1987

Dendritic cells in autoimmune thyroid disease.

Dendritic cells form a morphologically distinct class of cells characterized by shape, reniform nucleus, absent to weak acid-phosphatase activity and strong Class II MHC determinant positivity. Functionally they are the most efficient cells in antigen presentation to T-lymphocytes which indicates their role in the initiation of an immune response. Using immunehistochemical techniques we studied the presence of dendritic cells in normal Wistar rat and human thyroids, in thyroids of BBW rats developing thyroid autoimmunity and in Graves' goitres. Dendritic cells could be identified in all thyroids studied and were positioned underneath the thyrocytes in between the follicles. Skin dendritic cells travel via lymphatics to draining lymph nodes, thus forming an antigen presenting cell system. It is likely that a similar cell system exists on the level of the thyroid for dendritic cells have also been detected in thyroid draining lymph nodes. In normal thyroid tissue of both human and rat dendritic cells were relatively scarce. During the initial phases of the thyroid autoimmune response in the BBW rat (before the appearance of Tg-antibodies in the circulation) numbers of thyroid dendritic cells increased. Intrathyroidal T-helper cells, B-cells or plasma cells could not be found. The thyroid draining lymph node contained large numbers of plasma cells. During the later stages of the thyroid autoimmune response in the BB/W rat (after the appearance of Tg-antibodies in the circulation) and in Graves' goitres dendritic cells were not only present in high number, but 20-30% were seen in contact with now-present intrathyroidal T-helper lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1998

IL-10 expression in thyroid glands: protective or harmful role against thyroid autoimmunity?

IL-10 is a cytokine which not only suppresses cellular immunity but also stimulates the humoral response. In certain animal models of autoimmunity, IL-10 exerts a protective effect against autodestruction. This study was to ascertain whether there could be a role for IL-10 in human autoimmune thyroid disease. Total RNA was extracted from snap-frozen thyroid blocks from surgical specimens. Five 'normal', five multinodular, six Graves and two Hashimoto thyroids (one euthyroid and one hypothyroid) were studied. Approximately 7 microg of total RNA from each gland were reverse transcribed with oligo-dT primers. Pre-plateau semiquantitative polymerase chain reaction (PCR) was performed with specific IL-10 primers. PCR products were run on a 1-5% agarose gel, blotted onto a N-hybond nylon membrane, hybridized with a specific internal probe labelled with gamma-32P-ATP and autoradiographed. Statistical analysis of densitometric values showed significantly higher IL-10 levels in the autoimmune than in the non-autoimmune glands. In situ hybridization and immunohistochemistry showed that the IL-10 message was located within the infiltrating lymphomononuclear cells. Histological analysis revealed that the autoimmune thyroids with the highest IL-10 levels were characterized by relevant degrees of B and T cell infiltration and also exhibited the greatest percentage of spontaneous HLA class II expression on thyrocytes. IL-10 and neutralizing anti-IL-10 antibodies were not able to regulate in vitro spontaneous or interferon-gamma (IFN-gamma)/phytohaemagglutinin (PHA)-induced HLA class II on thyrocytes. We conclude that in active autoimmune thyroiditis, in addition to the well documented production of Th1 cytokines, Th2-related lymphokines can be detected simultaneously. It can be envisaged that in this condition the role of IL-10 might be directed to the stimulation of B cell proliferation and antibody production rather than to the suppression of proinflammatory cytokine release.

Adult↗
PubMed1994

A high iodine intake in Wistar rats results in the development of a thyroid-associated ectopic thymic tissue and is accompanied by a low thyroid autoimmune reactivity.

Evidence is accumulating that dietary iodine intake is an important modulator of autoimmune thyroid reactions. To study this role of iodine intake further, female Wistar rats were kept on an enriched iodine diet (EID, iodine intake 100 micrograms iodine/day) for a period of up to 18 weeks. Control rats were either on a normal iodine diet (NID, iodine intake 7 micrograms iodine/day) or a low iodine diet (LID, 2 days of 1% KClO4 followed by iodine-deficient drinking water/pellets). During the first 6 weeks of the EID rats developed a thyroid-associated ectopic thymic tissue (50-57% of the animals on EID versus 7-14% of NID rats and 0% of LID rats). This thyroid-associated ectopic thymic tissue showed a similar histology (cortex and medulla) and a similar marker pattern as normal rat thymus concerning TdT expression (positive cells in the cortex) and CD4/CD8 positivity (double-positive cells in the cortex, single-positive cells in the medulla). The excessive iodine diet also resulted in a lowered thyroid autoimmune reactivity as compared to the NID and LID, viz. (1) in a lower incidence of anti-colloid antibodies in serum (12.5% positivity in EID rats versus 36% in NID and 60% in LID rats at 18 weeks) and (2) lower numbers of intrathyroidal lymphoid cells, viz. lower numbers of dendritic cells and lower numbers of CD4 and CD8 positive lymphocytes. It is hypothesized that the development of the thyroid-associated ectopic thymic tissue in the EID rats is related to their low thyroid autoimmune responsiveness; the tissue might play a role in tolerance induction to thyroidal autoantigens.

Animals↗