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Basil Rapoport - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Peroxidase as an autoantigen
Thyroid, 2007Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Thyroid Peroxidase (TPO) evokes high-affinity, IgG-class autoantibodies [TPO autoantibodies (TPOAbs)] and TPO-specific T cells that are markers of Thyroid infiltration or implicated in Thyroid destruction, respectively. A diverse repertoire of human monoclonal TPOAbs, unparalleled in other autoimmune diseases, provides invaluable probes for investigating antibody epitopes. Human TPOAbs recognize an immunodominant region comprising overlapping A and B domains on conformationally intact TPO. Amino acids recognized by TPOAbs are located in the regions with homology to myeloPeroxidase (MPO) and the complement control protein (CCP) but not in the epidermal growth factor (EGF)-like region. T cells recognize epitopes in the MPO-like region but not in the CCP- or EGF-like regions in humans. Monoclonal human TPOAbs modulate processing of TPO protein to provide peptides for some T cells. A human T cell clone expressed transgenically in mice induces lymphocytic infiltration and hypoThyroidism. This T cell's epitope is only generated by thyrocyte processing of endogenous TPO. Further, intact TPO expressed in vivo is also required for induction of TPOAbs in mice that resemble human autoantibodies. Overall, some TPO-specific T cells and the majority of autoantibodies in humans develop in response to TPO presented by Thyroid cells, rather than to TPO released by damaged thyrocytes.
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why measure thyroglobulin autoantibodies rather than Thyroid Peroxidase autoantibodies
Thyroid, 2004Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Autoantibodies to thyroglobulin (TgAb) and Thyroid Peroxidase (TPOAb) are of immunoglobulin G (IgG) class and have high affinities for their respective autoantigens. Both autoantibodies are markers of Thyroid autoimmunity and they can be measured by a variety of assays. From the clinical perspective, TgAb are less prevalent than TPOAb and less useful than TPOAb for prediction of Thyroid dysfunction. Moreover, TgAb interfere with Tg measurements to monitor metastases in Thyroid cancer. However, increasing evidence suggests that these TgAb provide a surrogate for Tg. In terms of disease pathogenesis, Tg has been suggested to play a role in Graves' ophthalmopathy. Pending further studies, TgAb epitopes could distinguish between individuals who are euThyroid or who have clinical disease. A final, intriguing reason for measuring and characterizing TgAb is the interest these autoantibodies have rekindled in their autoantigen. It is conceivable that Tg polymorphisms, combined with the explosive mix of iodine, TP...
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autoimmune response to the Thyroid in humans Thyroid Peroxidase the common autoantigenic denominator
International Reviews of Immunology, 2000Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Autoimmunity to Thyroid Peroxidase (TPO), manifest as high affinity IgG class auto-antibodies, is the common denominator of human Thyroid autoimmunity, encompassing patients with overt hyper-or hypoThyroidism as well as euThyroid individuals with subclinical disease. The identification and cloning of TPO (the “Thyroid microsomal antigen”) provided the critical tool for analyzing B and T cell reactivity to this major Thyroid autoantigen. In particular, the availability of immunoreactive TPO permitted the isolation of essentially the entire repertoire of human monoclonal antibodies, a feat unparalled in an organ-specific autoimmune disease. These recombinant autoantibodies (expressed as Fab) provide insight into the genes encoding their H and L chains as well as the conformational epitopes on TPO with which serum autoantibodies interact. Analyses of TPO autoantibody epitopic “fingerprints” indicate a lack of epitope spreading as well as a genetic basis for their inheritance. Limited data are available for t...
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the molecular biology of Thyroid Peroxidase cloning expression and role as autoantigen in autoimmune Thyroid disease
Endocrine Reviews, 1992Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:I. Introduction Thyroid Peroxidase (TPO) is the primary enzyme involved in Thyroid hormone synthesis, catalyzing iodide oxidation, iodination of tyrosine residues, and coupling of iodotyrosines to generate the iodothyronines T3 and T4 (1). It is a membrane-bound glycoprotein with a heme prosthetic group. In addition to the pivotal physiological role of TPO, there was strong immunological evidence, even before its molecular cloning, that this enzyme was the elusive “Thyroid microsomal antigen” in autoimmune Thyroid disease (discussed below). The molecular cloning of the complementary DNA for a protein provides powerful new opportunities for studying protein structure and function at an unprecedented level of detail. In t h e past decade, three of the four major Thyroid-specific proteins have been cloned, namely thyroglobulin (TG) (2–4), TPO (see below), and the TSH receptor (5–8). Molecular cloning of the Thyroid iodide transporter may occur soon (9). As might be expected, these advances have been followed...
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a human fab fragment specific for Thyroid Peroxidase generated by cloning Thyroid lymphocyte derived immunoglobulin genes in a bacteriophage lambda library
Biochemical and Biophysical Research Communications, 1991Co-Authors: Stefano Portolano, Pui Seto, Gregorio D Chazenbalk, Yuji Nagayama, Sandra M Mclachian, Basil RapoportAbstract:Abstract A human Fab fragment (SP2) which binds specifically to human Thyroid Peroxidase has been generated by expressing random combinations of heavy and light chain immunoglobulin genes (derived from Graves' Thyroid cDNA) in a bacteriophage lambda library. In common with many serum TPO autoantibodies, the cloned Fab fragment is IgG1 kappa and has a high affinity for TPO (−10 −9 M). On the basis of their nucleotide sequences, the heavy and light chain genes coding for SP2 belong to families VHI, (D), JH3 and VKI,JK2, respectively. These data provide the first characterization at a molecular level of a human Thyroid Peroxidase antibody associated with autoimmune Thyroid disease.
Jan J M De Vijlder - One of the best experts on this subject based on the ideXlab platform.
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molecular analysis of mutated Thyroid Peroxidase detected in patients with total iodide organification defects
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Hennie Bikker, Frank Baas, Jan J M De VijlderAbstract:Wild-type and mutant Thyroid Peroxidase (TPO) was expressed in a Semliki Forest Virus (SFV)-based transient expression system in Chinese hamster ovary-K1 cells. Twenty four hours after transfection proteins immunoreactive with TPO antibodies could be detected on a Western blot. Peroxidase activity was assayed using both the guaiacol and the I3- assay. Addition of hematin was necessary to obtain enzymatic active TPO. Thyroid Peroxidase complementary DNA constructs containing mutations originally found in patients with hereditary congenital hypoThyroidism caused by total iodide organification defects were analyzed using these techniques. In all cases TPO was expressed as shown by Western blotting and immunostaining. Enzymatic activity (measured by guaiacol and iodide oxidation assay) was below the detection level in four out of five mutants. The only mutant yielding TPO with enzymatic activity was G 1858 A (Gly 590 Ser). However, the mutation could affect splicing of TPO messenger RNA, leading to inactive TPO, because it is located at the exon 10/intron 10 border.
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congenital hypoThyroidism caused by a premature termination signal in exon 10 of the human Thyroid Peroxidase gene
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Hennie Bikker, J J J Waelkens, B Bravenboer, Jan J M De VijlderAbstract:The molecular basis of a total iodide organification defect causing severe congenital hypoThyroidism has been elucidated. The defect occurred in a family in which two of five siblings were affected. Thyroid tissue from one patient was available for investigation. The total Thyroid Peroxidase (TPO) messenger ribonucleic acid level was reduced and consisted mainly of the alternatively spliced form of TPO missing exon 10 (TPO-2). No TPO-1 (wild-type) protein was detected by Western blotting. The TPO-2 translation product of a slightly smaller mol wt was present in Thyroid tissue of this patient. TPO activity was absent and thyroglobulin was not iodinated, showing that iodination in vivo did not occur. Denaturing gradient gel electrophoresis and subsequent sequencing revealed in both alleles of the patients a C-->T transition of nucleotide 1708 of the TPO gene, involving a CpG dinucleotide. The mutation introduces a premature termination signal in exon 10 of the TPO gene, preventing the synthesis of enzymatic...
D Maugendre - One of the best experts on this subject based on the ideXlab platform.
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differential evolution of Thyroid Peroxidase and thyrotropin receptor antibodies in graves disease Thyroid Peroxidase antibody activity reverts to pretreatment level after carbimazole withdrawal
Thyroid, 2006Co-Authors: Isabelle Guilhem, Catherine Massart, J Y Poirier, D MaugendreAbstract:In this study, we compared the evolution of Thyroid Peroxidase antibody (TPOAb) and Thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euThyroid and those who had a relapse of hyperThyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge ...
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differential evolution of Thyroid Peroxidase and thyrotropin receptor antibodies in graves disease Thyroid Peroxidase antibody activity reverts to pretreatment level after carbimazole withdrawal
Thyroid, 2006Co-Authors: Isabelle Guilhem, Catherine Massart, Jeanyves Poirier, D MaugendreAbstract:In this study, we compared the evolution of Thyroid Peroxidase antibody (TPOAb) and Thyroid-stimulating antibody (TSAb) activities before, during, and after treatment of Graves' disease (GD) with carbimazole. TPOAb and TSAb were measured in sera from 75 patients with GD, during an 18-month block-replace regimen and after drug withdrawal (12, 24, and 36 months). At diagnosis, TPOAb were present in 85% of the patients versus 99% for TSAb. During the treatment, TPOAb values and prevalence significantly decreased, as observed with TSAb. After drug withdrawal, TPOAb levels increased once again to reach the pretreatment values, whereas TSAb remained unchanged. TPOAb values and prevalence at drug withdrawal were not significantly different between patients who remained euThyroid and those who had a relapse of hyperThyroidism. In contrast, TSAb values and prevalence were higher at drug withdrawal in relapse patients. In conclusion, TPOAb and TSAb changes are similar during GD treatment by carbimazole but diverge after drug withdrawal. TPOAb might reflect autoimmune perturbations independently of the clinical status and of the Thyroid-stimulating activity.
Sandra M Mclachlan - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Peroxidase as an autoantigen
Thyroid, 2007Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Thyroid Peroxidase (TPO) evokes high-affinity, IgG-class autoantibodies [TPO autoantibodies (TPOAbs)] and TPO-specific T cells that are markers of Thyroid infiltration or implicated in Thyroid destruction, respectively. A diverse repertoire of human monoclonal TPOAbs, unparalleled in other autoimmune diseases, provides invaluable probes for investigating antibody epitopes. Human TPOAbs recognize an immunodominant region comprising overlapping A and B domains on conformationally intact TPO. Amino acids recognized by TPOAbs are located in the regions with homology to myeloPeroxidase (MPO) and the complement control protein (CCP) but not in the epidermal growth factor (EGF)-like region. T cells recognize epitopes in the MPO-like region but not in the CCP- or EGF-like regions in humans. Monoclonal human TPOAbs modulate processing of TPO protein to provide peptides for some T cells. A human T cell clone expressed transgenically in mice induces lymphocytic infiltration and hypoThyroidism. This T cell's epitope is only generated by thyrocyte processing of endogenous TPO. Further, intact TPO expressed in vivo is also required for induction of TPOAbs in mice that resemble human autoantibodies. Overall, some TPO-specific T cells and the majority of autoantibodies in humans develop in response to TPO presented by Thyroid cells, rather than to TPO released by damaged thyrocytes.
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why measure thyroglobulin autoantibodies rather than Thyroid Peroxidase autoantibodies
Thyroid, 2004Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Autoantibodies to thyroglobulin (TgAb) and Thyroid Peroxidase (TPOAb) are of immunoglobulin G (IgG) class and have high affinities for their respective autoantigens. Both autoantibodies are markers of Thyroid autoimmunity and they can be measured by a variety of assays. From the clinical perspective, TgAb are less prevalent than TPOAb and less useful than TPOAb for prediction of Thyroid dysfunction. Moreover, TgAb interfere with Tg measurements to monitor metastases in Thyroid cancer. However, increasing evidence suggests that these TgAb provide a surrogate for Tg. In terms of disease pathogenesis, Tg has been suggested to play a role in Graves' ophthalmopathy. Pending further studies, TgAb epitopes could distinguish between individuals who are euThyroid or who have clinical disease. A final, intriguing reason for measuring and characterizing TgAb is the interest these autoantibodies have rekindled in their autoantigen. It is conceivable that Tg polymorphisms, combined with the explosive mix of iodine, TP...
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autoimmune response to the Thyroid in humans Thyroid Peroxidase the common autoantigenic denominator
International Reviews of Immunology, 2000Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:Autoimmunity to Thyroid Peroxidase (TPO), manifest as high affinity IgG class auto-antibodies, is the common denominator of human Thyroid autoimmunity, encompassing patients with overt hyper-or hypoThyroidism as well as euThyroid individuals with subclinical disease. The identification and cloning of TPO (the “Thyroid microsomal antigen”) provided the critical tool for analyzing B and T cell reactivity to this major Thyroid autoantigen. In particular, the availability of immunoreactive TPO permitted the isolation of essentially the entire repertoire of human monoclonal antibodies, a feat unparalled in an organ-specific autoimmune disease. These recombinant autoantibodies (expressed as Fab) provide insight into the genes encoding their H and L chains as well as the conformational epitopes on TPO with which serum autoantibodies interact. Analyses of TPO autoantibody epitopic “fingerprints” indicate a lack of epitope spreading as well as a genetic basis for their inheritance. Limited data are available for t...
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the molecular biology of Thyroid Peroxidase cloning expression and role as autoantigen in autoimmune Thyroid disease
Endocrine Reviews, 1992Co-Authors: Sandra M Mclachlan, Basil RapoportAbstract:I. Introduction Thyroid Peroxidase (TPO) is the primary enzyme involved in Thyroid hormone synthesis, catalyzing iodide oxidation, iodination of tyrosine residues, and coupling of iodotyrosines to generate the iodothyronines T3 and T4 (1). It is a membrane-bound glycoprotein with a heme prosthetic group. In addition to the pivotal physiological role of TPO, there was strong immunological evidence, even before its molecular cloning, that this enzyme was the elusive “Thyroid microsomal antigen” in autoimmune Thyroid disease (discussed below). The molecular cloning of the complementary DNA for a protein provides powerful new opportunities for studying protein structure and function at an unprecedented level of detail. In t h e past decade, three of the four major Thyroid-specific proteins have been cloned, namely thyroglobulin (TG) (2–4), TPO (see below), and the TSH receptor (5–8). Molecular cloning of the Thyroid iodide transporter may occur soon (9). As might be expected, these advances have been followed...
Hennie Bikker - One of the best experts on this subject based on the ideXlab platform.
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molecular analysis of mutated Thyroid Peroxidase detected in patients with total iodide organification defects
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Hennie Bikker, Frank Baas, Jan J M De VijlderAbstract:Wild-type and mutant Thyroid Peroxidase (TPO) was expressed in a Semliki Forest Virus (SFV)-based transient expression system in Chinese hamster ovary-K1 cells. Twenty four hours after transfection proteins immunoreactive with TPO antibodies could be detected on a Western blot. Peroxidase activity was assayed using both the guaiacol and the I3- assay. Addition of hematin was necessary to obtain enzymatic active TPO. Thyroid Peroxidase complementary DNA constructs containing mutations originally found in patients with hereditary congenital hypoThyroidism caused by total iodide organification defects were analyzed using these techniques. In all cases TPO was expressed as shown by Western blotting and immunostaining. Enzymatic activity (measured by guaiacol and iodide oxidation assay) was below the detection level in four out of five mutants. The only mutant yielding TPO with enzymatic activity was G 1858 A (Gly 590 Ser). However, the mutation could affect splicing of TPO messenger RNA, leading to inactive TPO, because it is located at the exon 10/intron 10 border.
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congenital hypoThyroidism caused by a premature termination signal in exon 10 of the human Thyroid Peroxidase gene
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Hennie Bikker, J J J Waelkens, B Bravenboer, Jan J M De VijlderAbstract:The molecular basis of a total iodide organification defect causing severe congenital hypoThyroidism has been elucidated. The defect occurred in a family in which two of five siblings were affected. Thyroid tissue from one patient was available for investigation. The total Thyroid Peroxidase (TPO) messenger ribonucleic acid level was reduced and consisted mainly of the alternatively spliced form of TPO missing exon 10 (TPO-2). No TPO-1 (wild-type) protein was detected by Western blotting. The TPO-2 translation product of a slightly smaller mol wt was present in Thyroid tissue of this patient. TPO activity was absent and thyroglobulin was not iodinated, showing that iodination in vivo did not occur. Denaturing gradient gel electrophoresis and subsequent sequencing revealed in both alleles of the patients a C-->T transition of nucleotide 1708 of the TPO gene, involving a CpG dinucleotide. The mutation introduces a premature termination signal in exon 10 of the TPO gene, preventing the synthesis of enzymatic...