Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human T cells recognize self and foreign antigens when such antigens are processed into small peptides and bound to molecules coded for by genes of the HLA region on chromosome 6. The part of the T-cell surface which is responsible for such recognition is a set of molecules coded for by a variety of genes and known as the T-cell-receptor complex. In animal models, T cells are able to transfer autoimmune thyroiditis and T cells have, therefore, long been implicated in the etiology of human autoimmune thyroid disease (AITD). Information gained from the study of intrathyroidal T cells and thyroid antigen-specific T-cell clones has shown that in patients with Graves' disease, mainly helper T-cell clones have been obtained, whereas in autoimmune (Hashimoto's) thyroiditis cytolytic T-cell clones may be predominant. Such thyroid antigen-specific T cells have now been shown to recognize one or other of the three major thyroid-specific antigens; thyroglobulin, thyroid peroxidase, or the TSH receptor and efforts are currently in progress to characterize the T-cell epitopes of these major thyroid autoantigens. Recent findings of restricted T-cell receptor V gene use amongst intrathyroidal T cells confirm the primary role of T cells in human thyroid autoimmune processes leading to AITD. However, the mechanisms whereby such autoreactive T cells escape deletion and anergy, and how they become activated, remain uncertain. There is compelling evidence that the thyroid cell itself, by expressing HLA molecules, and presenting antigen directly to the T cells, may initiate disease, perhaps after an external insult.
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PMID:T cells and human autoimmune thyroid disease: emerging data show lack of need to invoke suppressor T cell problems. 138 61

Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 caucasian patients with Graves' disease, 63 caucasian patients with Hashimoto's thyroiditis, and 65 caucasian controls. RFLP analysis was carried out on genomic DNA, using probes for DR beta, DQ alpha, DQ beta, DP alpha, DP beta, T-cell receptor TCR alpha, and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR)alpha, DP alpha and -beta, and -beta, and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves' disease, as reported previously by others, but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ, DR, or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ alpha, DP, TCR, or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX alpha RFLP was observed in Graves' disease, but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX alpha, rather than a specific abnormality in Graves' disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed, the involvement of other genes or haplotypes could not be established.
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PMID:Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes. 167 60

We have studied by flow cytometric analysis the antigen specific activation of CD4+ (helper/inducer) T lymphocytes by purified human thyroid peroxidase (TPO). Peripheral blood mononuclear cells were obtained from 26 patients with Graves' disease (GD), 16 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), and 14 normal subjects (N). Cells were cultured for 7 days in the presence or absence of TPO at final concentrations of 3, 30, and 300 ng/mL. When harvested, cells were reacted with an FITC-conjugated anti-CD4 and a PE-conjugated anti-HLA-DR murine monoclonal antibodies. The percentage of HLA-DR+ CD4+ cells (activated CD4+ cells) was determined by a flow cytometer. In the absence of TPO, CD4+ cells had been activated without any specific stimulant. This is known as the autologous mixed lymphocyte reaction (AMLR). In the AMLR, CD4+ cells from GD and HT were less activated compared to those from NG and N. Results of TPO-specific activation were expressed as an incremental increase of activated CD4+ cells (II) (percentage of activated CD4+ cells cultured with TPO minus percentage of activated CD4+ cells cultured without TPO). II of N, GD, HT, and NG were 0.37 +/- 0.21, 2.20 +/- 0.45,** 2.0 +/- 0.66,* and 0.35 +/- 0.27 (mean +/- SEM), respectively (**p less than 0.01; *p less than 0.05 vs N). When patients were further subdivided, the highest mean II was found in patients with hyperthyroid GD (p less than 0.01), followed by euthyroid HT (p less than 0.05) and euthyroid GD (p less than 0.05), however there was no significant difference between hypothyroid HT and N. In conclusion (1) AMLR reactivity of CD4+ cells from GD and HT was impaired, (2) however, CD4+ cells from both GD and HT were significantly more induced by TPO compared to N, and (3) this induction depends, in part, on the in vivo thyroid status.
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PMID:Studies of CD4+ (helper/inducer) T lymphocytes in autoimmune thyroid disease: demonstration of specific induction in response to thyroid peroxidase (TPO) in vitro and its relationship with thyroid status in vivo. 168

The intrathyroidal distribution and cell surface location of HLA-A,B,C and HLA-DR antigens was studied in polarized thyroid follicle cells from Graves' (n = 11) and normal (n = 3) thyroid tissue, using light and electron microscopy. Cryosections and isolated, open follicle segments were incubated with monoclonal antibodies against HLA-A,B,C and HLA-DR antigens and with patient sera containing autoantibodies against the microsomal antigen/thyroperoxidase. Immunoreactivity for HLA-A,B,C and HLA-DR on isolated thyroid follicle cells was frequently detected in Graves' disease, but absent in normal glands. There was a large variation in the immunolabelling between follicles as well as between different glands. Both HLA-A,B,C and HLA-DR immunoreactivity were detected on the apical and the basal surface of the follicle cells. Microsomal antigen/thyroperoxidase immunoreactivity was restricted to the apical cell surface. In contrast to normal tissue, HLA-DR positive cells with a dendritic or macrophage-like morphology were frequent in Graves' tissue. These cells adhered directly to the basal surface of isolated follicle segments. We conclude that HLA antigens are, unlike thyroid-specific plasma membrane constituents, expressed in a non-polarized manner at the surface of the follicular epithelium. These observations might have implications on the immune recognition of thyroidal autoantigens in Graves' disease.
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PMID:Non-polarized cell surface expression of HLA-A,B,C and HLA-DR antigens in Graves' thyroid follicle cells. 175 24

The inheritance of autoantibodies to thyroglobulin and thyroid peroxidase (thyroid microsomal antigen) has been reevaluated with newly developed ultrasensitive assays that depend on the direct interaction between antibody and radiolabeled antigen. In a study of 16 families with autoimmune thyroid disease, autoantibodies to thyroid peroxidase (TPO) were found to be inherited as a dominant Mendelian trait in females with reduced penetrance in males. Similar results were obtained with thyroglobulin (Tg) autoantibodies. Genetic linkage analysis of the loci for TPO and Tg autoantibodies with 28 polymorphic serological markers (including HLA and Gm allotypes) was carried out in 9 families. LOD scores for some serological markers (such as Gm) were uninformative, but linkage with other markers, notably the HLA antigens -A, B, -DR, -DQ, and BF on chromosome 6, could be excluded. Further studies using a comprehensive panel of gene probes to analyze DNA from families with autoimmune thyroid disease should permit the localization of the gene cluster responsible for regulating the ability to produce autoantibodies to TPO and Tg in man.
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PMID:Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. 230 28

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.
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PMID:Human autoimmune thyroid disease: cellular and molecular aspects. 307 47

The prevalence of circulating autoantibodies against thyroperoxidase (mic-TPO) was determined in 3,000 healthy blood donors (age range: 23 to 60 years) from the Hamburg area. Of the blood donors, 153 (5.1%) were found to have high titer of mic-TPO (> 350 IU/ml). Only two autoantibody positive subjects (0.06%) were chemically hyper- and hypothyroid, respectively. Analysis of HLA-DR specificities revealed that HLA-DR specificities DR3 and DR5 were significantly increased when compared to controls (n = 1,863). Comparison of the autoantibody-positive probands with a group of disease controls, i.e., Graves' patients and patients with lymphocytic thyroiditis, revealed a higher prevalence of HLA-DR3-positive HLA haplotypes in the disease controls when compared to autoantibody positives. Individuals with a mic-TPO level greater than 2,000 IU/ml were almost exclusively found to have one HLA-DR3 or HLA-DR5 positive HLA haplotype. We conclude that a high prevalence of high-titer mic-TPO can be found in healthy blood donors. Circulating signs of thyroid autoimmunity were associated with HLA specificities also found to be associated with autoimmune thyroid diseases.
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PMID:HLA-DR3 and HLA-DR5 confer risk for autoantibody positivity against the thyroperoxidase (mic-TPO) antigen in healthy blood donors. 848 24

In Hashimoto's thyroiditis, the humoral component is manifest by autoantibodies to thyroid peroxidase (TPO). Epitopic 'fingerprinting' of polyclonal serum TPO autoantibodies has been facilitated by the molecular cloning and expression as Fab of a repertoire of human TPO autoantibody genes. To investigate whether TPO autoantibody fingerprints are (i) stable over long periods of time (approximately 15 years), and (ii) inherited, we studied a cohort of nine patients with juvenile Hashimoto's thyroiditis and 21 first degree relatives of four of these patients. Fingerprints were determined by competition between four selected FAB and serum autoantibodies for binding to 125I-TPO. Regardless of titre, the TPO epitopic profile was stable in 10/12 individuals whose TPO autoantibody levels were sufficient for analysis on two or three occasions over 12-15 years. Although the TPO epitopic fingerprint profiles in two families raised the possibility of inheritance, overall the data from all four families did not reveal an obvious pattern of genetic control. In no family was the TPO epitopic fingerprint associated with HLA A, B or DR. In conclusion, TPO autoantibody epitopic fingerprints are frequently conserved over many years. Studies on additional families are necessary to establish whether or not the epitopic profiles of TPO autoantibodies are inherited.
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PMID:Thyroid peroxidase autoantibody epitopic 'fingerprints' in juvenile Hashimoto's thyroiditis: evidence for conservation over time and in families. 860 16

In 157 new onset IDDM (104 men, 53 women, ages 10-39 yr) anti-thyroid peroxidase anti-bodies (anti-TPO) were assayed with a specific immunological test. Values greater than 100 U ml-1 were considered positive. Seventeen per cent of the patients were positive (32% of the women versus 10% of the men, p < 0.001). Eighty-five per cent of the anti-TPO + patients have a positive titre of islet-cell antibodies (ICA > or = 12 JDFU) versus 64% of the anti-TPO-patients (p < 0.05). When patients were subdivided in a young (10-25 yr) and an older age group (26-39 yr) this association was also true for ICA > or = 50 JDFU and valid for insulin autoantibodies (IAA) at low (> or = 0.7%) and high risk (> or = 1.5%) (p < 0.005) in the second group. The median of the TSH concentration was not different between anti-TPO+ and anti-TPO- when the group is considered as a whole. In the anti-TPO+ men (26-39 yr) TSH was however significantly greater (1.55 microU ml-1, range 0.74-8.5 versus 1.4 microU ml-1, range 0.21-3.5, p < 0.0001) when compared to the anti-TPO-men of the same age group. The haplotype HLA DQA1*0301-DQB1*0302 was more frequent in the anti-TPO+ (39%) than in the anti-TPO- (23%) patients (p < 0.02) for the age group 26-39 yr but not for the age group 10-25 yr. The other diabetes susceptibility haplotype DQA1*0501-DQB1*0201 was less frequent in anti-TPO+ patients. In conclusion we suggest that thyroid auto-immunity must be part of the initial screening of IDDM especially when patients are older at clinical onset of the disease.
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PMID:In new-onset insulin-dependent diabetic patients the presence of anti-thyroid peroxidase antibodies is associated with islet cell autoimmunity and the high risk haplotype HLA DQA1*0301-DQB1*0302. Belgian Diabetes Registry. 873 22

The autoimmune thyroid diseases (AITD), encompassing Graves' disease (GD) and Hashimoto's thyroiditis (HT), occur in genetically susceptible individuals. In order to identify the AITD susceptibility genes, we have studied DNA markers in the regions of 8 candidate genes: (1) the HLA region, (2) the TSH receptor, (3) thyroid peroxidase, (4) thyroglobulin, (5) IDDM-4, (6) IDDM-5, (7) Immunoglobulin heavy chain gene and (8) CTLA-4. One hundred and seven subjects from 19 informative families were studied, 14 subjects had GD and 32 subjects had HT. LOD scores were maximized assuming both dominant and recessive modes of inheritance. No linkage was found for any marker in patients with HT. In patients with GD, negative LOD scores were obtained for all the candidate genes, except for markers in the TSH receptor region on chromosome 14q31. Positive LOD scores were found for several markers on 14q31. Marker D14S81 gave the highest score (Z max = 2.05, theta = 0.01) assuming a dominant mode of inheritance and a penetrance of 0.8. These data confirm our previous observations of a lack of a necessary disease locus for AITD in the HLA gene region. Further, the data suggest the presence of an important susceptibility gene on 14q31 but at a considerable distance from the TSH receptor gene.
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PMID:Mapping of a major susceptibility locus for Graves' disease (GD-1) to chromosome 14q31. 914 66


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