ISSN:0891-6934    

DOI:10.3109/08916939209014628

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

It has been suggested recently that autoimmunity could be regarded as a physiological response of the normal immune system to autoantigens caught up in an inflammatory response to viral or bacterial antigen expressed in the target tissue. Other theories to explain autoimmunity include molecular mimicry whereby a viral or microbial hapten similar to an autoantigen initiates the production of autoantibodies that cross react with an autoantigen, with a subsequent immune response reacting with autologous cell structures which are homologous with the particular microorganism. There has also been a suggestion that there may be a genetic abnormality of the target cell which is necessary for the initiation of autoimmune thyroid disease. The present review examines these proposals and provides evidence against an antigen-driven origin for autoimmune thyroid disease (AITD). Currently, there is no valid evidence for viral involvement, and likewise the evidence for molecular mimicry as an initiating factor does not hold up to scrutiny. While a genetic abnormality of the thyrocyte may be important in certain animal models of AITD, in the human there is no evidence for such an abnormality. Evidence that AITD is derived from a disturbance of immunoregulatory mechanisms has been documented elsewhere and would appear to be the most appropriate explanation for these disorders. The immunoregulatory disturbance itself may be related to an abnormality of the mechanism of specific antigen (i.e. normal autoantigen) presentation to appropriately induce T lymphocytes and that theory will require further illumination.

ISSN:0891-6934    

DOI:10.3109/08916939209014629

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

We review here our analyses of hTcR V gene activity within the thyroid glands of patients with autoimmune thyroid disease. Our data, based on thyroid aspiration specimens, indicate that early in the onset of Graves' disease there is a marked restriction in both hTcR Vαandβgene families utilized by intrathyroidal T-cells. Later, however, and as seen in surgical thyroid specimens from patients with long term disease, there appears to be a loss of Vβrestriction for unclear reasons. In contrast, patients with Hashimoto's thyroiditis are usually diagnosed later in the natural history of the disease and appear to show much less hTcR V gene family restriction. The mechanisms driving the use of few and many hTcR V genes within the thyroid gland are likely to be complex and may reveal important insights into disease pathogenesis.

ISSN:0891-6934    

DOI:10.3109/08916939209014630

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

In order to analyze T cell epitopes of human thyroid peroxidase (TPO), 60 peptides based on the sequence of TPO were synthesized and used as antigens in a peripheral blood mononuclear cell (PBMC)-proliferation assay. PBMCs were obtained from 19 patients with Graves' disease, 19 patients with Hashimoto's thyroiditis, and 24 normal subjects. Significant proliferation of PBMC to these peptides occurred only among the autoimmune thyroid disease (AITD) patients, whereas normal subjects did not respond to any of the peptides with a stimulation index over 2. Many peptides induced isolated positive responses and eight produced stimulation of PBMCs from multiple patients on comparison to control PBMC responses. To confirm the significance of reactivity to the peptides PBMCs from four patients were studied on two occasions, and the proliferative responses found to be reproducible. Four peptides, designated according to the amino acid sequence as pi 10-129, p211-230, p842-861, and p882-901, stimulated patients' PBMCs in a dose-dependent manner. The optimal concentration was 10μg/ml. An anti-HLA-DR monoclonal antibody directed against a mono-morphic determinant of the DR molecule was able to block the responses. A significant correlation was found between the PBMC responses to these peptides and responses to microsomal antigen (McAg)ZTPO. These data suggest that four peptides corresponding to the amino acid sequences 110-129, 211-230, 842-861 and 882-901 are T cell epitopes of TPO.

ISSN:0891-6934    

DOI:10.3109/08916939209014631

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

We studied the role of cytokines and immune regulation in thyroid tissue from patients with Graves' disease. Immunohistochemistry showed that the thyroid glands are characterized by an aberrant expression of HLA class II antigens on thyrocytes, generation of new blood vessels and infiltration of mononuclear cells. We demonstrated that CD4+memory cells were more frequent in thyroid glands from Graves' patients than were CD4+naive cells. The intrathyroidal T cells demonstrated an enhanced expression of the adhesion molecules LFA-1, CD2, VLA-4 and VLA-5, and vascular endothelial cells of capillaries and thyroeytes in thyroid glands reacted with anti-ICAM-1 monoclonal antibody. The adhesion molecules and HLA antigens on both vascular endothelial cells and thyrocytes were regulated by inflammatory cytokines. These results suggest that circulating lymphocytes migrate into thyroid tissues and that memory T cells are retained in the thyroid tissues by cellular interactions with thyrocytes or with extracellular matrix.

ISSN:0891-6934    

DOI:10.3109/08916939209014632

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Using a rapid (whole blood lysis) single laser microfluorocytometric technique that permitted the simultaneous analysis of two monoclonal antibody surface markers tagged with different fluorescent dyes, the intrathyroidal (IT) and peripheral blood (PB) activated [Ia+=DR+] T-lymphocyte CD3+subsets and [F(ab′)2+] B cells were studied in hyperthyroid patients with Graves' disease (GD) before and after 1-4 months of propylthiouracil (PTU) therapy. IT lymphocytes were obtained by serial fine needle aspiration. In untreated patients a marked quantitative (≈<10 fold) increase in activated (Ia+CD3+) T-lymphocytes as well as CD4+and CD8+subsets, for IT compared to PB sites, was found. The percentages of Ia+CD4+and Ia+CD8+within Ia+CD3+were not significantly different between the two sources of T cells. F(ab′)2+. B cells were significantly increased (≈2-3 fold) in IT compared to PB. In hyperthyroid GD patients, PTU therapy induced rapid and specific changes within the Ia+CD3+subsets, namely a reduction in the Ia+CD4+subset and an increase in the Ia+CD8+subset, resulting in a marked decrease in the Ia+CD4+/Ia+CD8+ratio. These changes occurred in association with a reduction in serum T4 and T3 concentration. No significant changes could be detected within the total (predominantly non-activated) CD3+, CD4+or CD8+lymphocyte subsets within PB and only a small decrease in the CD4+/CD8+ratio was demonstrated in IT, following PTU treatment.The feasibility of measuring intrathyroidal Ia+CD3+T-lymphocytes subsets and B cells in GD patients has been established utilizing fine-needle aspirates and a rapid whole blood lysis and two-colour monoclonal antibody labelling, single laser, microfluoreocytometric technique. These studies also demonstrate that, since the numbers of intrathyroidal activated la+T-Iymphocytes and B cells are greater than those in peripheral blood, the acute therapeutic effects of PTU on Ia+CD3+T subsets and B cells in Graves+hyperthyroidism are more clearly demonstrated by studies from IT rather than PB samples.

ISSN:0891-6934    

DOI:10.3109/08916939209014633

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Human TSH receptor (hTSH-R) gene and RNA transcripts were analyzed by Southern and Northern blots in patients with various thyroid disorders, and in tissue cell lines. A 1.4 Kb cDNA encoding the extracellular human TSH-R domain was used as a probe. Southern analysis revealed two constant bands of 11.0 and 5.0 Kb (hTSH-R) in the thyroid and human white cell samples studied, regardless of the disease process. Northern analysis showed a predominant band at about 4.4 Kb in the thyroid tissues but not in non-thyroid tissue or cell lines tested. There were no gene rearrangements or abnormal transcripts in Graves' disease or multinodular goiter samples. In contrast, the labelled cDNA TSH-R probe did not bind to RNA isolated from 1 of 2 papillary cancer samples. A portion of the unique area of the h-TSH receptor (approximately nucleotides 1100-1230) was directly sequenced in thyroid glands from patients with Graves' disease, multinodular goiter, and differentiated thyroid cancer. No mutations or polymorphisms were identified in these samples, as compared to normal thyroid or control placenta, although further definition of sequence variation in other areas of the TSH receptor, as well as in more samples, needs to be performed. The present study indicates the normal patterns of DNA and RNA hybridization in a variety of thyroid tissues and disease states, and demonstrates that pathologic thyroid samples, with the possible exception of thyroid cancer, were not associated with specific nucleotide abnormalities in the unique area of the TSH receptor that was studied.

ISSN:0891-6934    

DOI:10.3109/08916939209014634

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Although it is well-established that TSH activates a cAMP-dependent pathway in the thyroid follicular cell leading to thyroid hormone synthesis and release, the present review provides new evidence that TSH also activates a non-cAMP-dependent signal transduction system. This cascade involves phosphoinositide (PI) turnover, diacylglycerol accumulation and protein kinase C (PKC) activation. Activation of this pathway leads to an inhibition of differentiated thyroid functionin vitro.Recent evidence suggests that TSH can activate both pathways via a single transcription unit. Unlike TSH, TSH-receptor antibodies may selectively activate cAMP with no effects on PI turnover. In contrast, preliminary studies suggest TSH-blocking antibodies may activate PKC. PKC may be an important mediator of TSH and, possibly, thyroid autoantibody action.

ISSN:0891-6934    

DOI:10.3109/08916939209014635

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Evidence has been presented to support the idea that iodine plays an important role in autoimmune thyroiditis. Excessive amounts induce thyroiditis in genetically susceptible animal strains, while intrathyroidal depletion of iodine prevents disease in strains susceptible to severe thyroiditis. While the mechanisms by which iodine promotes thyroiditis is unknown, several hypotheses have been proposed. (1) T and/or B cells may react specifically to iodinated portions of thyroglobulin (Tg) so that severe iodine depletion renders Tg non-immunogenic. (2) A defect in the iodine processing machinery in thyroid epithelial cells of a susceptible person or animal may, in the presence of iodine, result in elevated levels of oxygen or iodine radicals, which could damage membrane lipids or proteins. (3) Defective iodine processing may result in the iodination of lipid or proteins (other than Tg) which could act either as immunogens or polyclonal activators.

ISSN:0891-6934    

DOI:10.3109/08916939209014636

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939209014637

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor