Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1994-11-08
1999-12-07
Housel, James C.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 74, 435 792, 435192, 435975, 436506, 436518, 436536, 436811, 530326, 530854, 930240, G01N 33564, G01N 33573, A61K 3843
Patent
active
059981539
DESCRIPTION:
BRIEF SUMMARY
GENBANK INFORMATION
Thyroid peroxidase sequence has been previously accorded GenBank Accession No. J02969.
FIELD OF THE INVENTION
The present invention relates generally to thyroid peroxidase and, more specifically, to autoantibody epitopic regions of thyroid peroxidase and diagnostic and therapeutic applications thereof.
BACKGROUND OF THE INVENTION
Thyroid peroxidase (TPO) is the major thyroid-specific membrane autoantigen implicated in Hashimoto's thyroiditis, an autoimmune disease characterized by intense lymphocytic thyroiditis resulting in the destruction of the thyroid. Weetman, A. P. et al, Endocrinol. Rev. 5:309-355 (1984). TPO's role in autoimmune disease and the precise localization of autoantibody binding has, however, been a subject of much debate. For example, there has been controversy as to whether autoantibodies inhibit thyroid peroxidase activity, thereby contributing to thyroid dysfunction in autoimmune thyroid disease. See Yokoyama, N. et al., J. Clin. Endocrinol. Metab. 68:766-773 (1989); Saller, B. et al., J. Clin. Endocrinol. Metab. 72:188-195 (1991). Reports on variations in the structure of TPO have suggested alternative mRNA splicing as a source of antigenicity. Kimura, S. et al., PNAS (USA) 84:5555-5559 (1987); Nagayama, Y. et al., J. Clin. Endocrinol. Metab. 71:384-390 (1990); Zanelli, E. et al., Biochem. Biophys. Res. Commun. 170:735-741 (1990). The appearance of these alternative transcripts in normal thyroid glands has, however, brought the relationship of alternative splicing and autoimmunity into question. Elisei, R. et al., J. Clin. Endocrinol. Metab., 72:700-702 (1991). It also now appears that carbohydrate structures are not involved in TPO antigenicity. Foti, D. et al., Endocrinol. 126:2983-2988 (1990).
Recent reports on the number and type of autoantibody epitopes found in human TPO have been conflicting. One group has suggested that TPO autoantibodies bind only to conformation epitopes and that no localized epitopes exist. Finke, R. et al., J. Clin. Endocrinol. Metab. 71:53-59 (1990). Given that this group demonstrated binding to recombinant TPO produced in CHO cells, but was unable to show binding to whole recombinant TPO in the bacterial expression system employed, the failure to identify localized epitopes could have resulted from a problem with the expression of intact TPO in bacteria. In contrast, another group has reported the identification of localized autoantibody of TPO epitopes using in vitro translated TPO cDNA clones. Libert, F. et al., EMBO J. 6:4193-4196 (1987); Ludgate, M. et al., J. Clin. Endocrinol. Metab. 68:1091-1096 (1989). Using sera from Hashimoto's disease patients, localized autoantibody binding was identified between amino acids 590 and 675 of the TPO coding sequence. Id. While initially identifying only a single antibody binding site in this region, more recent publications of this group indicated the presence of multiple antibody binding sites in the carboxyl half of the TPO molecule. Elisei, R. et al., Autoimmunity 8:65-70 (1990); Libert, F. et al., J. Clin. Endocrinol. Metab. 73:857-560 (1991). Several other studies using trypsin digests of purified native TPO have also suggested the presence of multiple autoantibody epitopes, including some which appear to be conformational and require disulfide bonds. Nakajima, Y. et al., Mol. Cell Endocrinol. 53:15-23 (1987); Yokoyama, N. et al., J. Clin. Endocrinol. Metab. 70:758-765 (1990). However, there has been no consensus on the exact number and type of epitopes present in TPO.
The identification of autoantibody thyroid-specific epitopes is important to the understanding and diagnosis of autoimmune thyroid disease and in developing effective immunotherapeutic strategies against thyroid disease and cancer. The identification of specific localized TPO epitopic regions would provide a powerful diagnostic tool for autoimmune diseases such as Hashimoto's to distinguish it from other thyroid conditions. The identification and ability to produce sequences encompassing specific TPO autoantibody ep
REFERENCES:
Weetman et al., "Autoimmune thyroid disease: Developments in our understanding" Endocrinol. Rev. (1984) 5:309-355.
Yokoyama et al., "Thyroid peroxidase and thyroid microsomal autoantibodies" J. Clin. Endocrinol. Metab. (1989) 68:766-773.
Saller et al., "Heterogeneity of autoantibodies against thyroid peroxidase in autoimmune thyroid disease: Evidence against antibodies directly inhibiting peroxidase activity as regulatory factors in thyroid hormone metabolism" J. Clin. Endocrinol. Metab. (1991) 72:188-195.
Kimura et al., "Human thyroid peroxidase: Complete cDNA and protein sequence, chromosome mapping, and identification of two alternately spliced mRNAs" Proc. Natl. Acad. Sci. USA (1987) 84:5555-5559.
Nagayama et al., "Characterization, by molecular cloning, of smaller forms of thyroid peroxidase messenger ribonucleic acid in human thyroid cells as alternatively spliced transcripts" J. Clin. Endocrinol. Metab. (1990) 71:384-390.
Zanelli et al., "Evidence for an alternate splicing in the thyroperoxidase messenger from patients with Graves' disease" Biochem. Biophys. Res. Comm. (1990) 170:735-741.
Elisei et al., "Demonstration of the existence of the alternatively spliced form of thyroid peroxidase in normal thyroid" J. Clin. Endocrinol. Metab. (1991) 72:700-702.
Foti et al., "Carbohydrate moieties in recombinant human thyroid peroxidase: Role in recognition by antithyroid peroxidase antibodies in Hashimoto's thyroiditis" Endocrinology (1990) 126:2983-2988.
Finke et al., "Evidence for the highly conformational nature of the epitope(s) on human thyroid peroxidase that are recognized by sera from patients with Hashimoto's thyroiditis" J. Clin. Endocrinol. Metab. (1990) 71:53-59.
Libert et al., "Thyroperoxidase, an auto-antigen with a mosaic structure made of nuclear and mitochondrial gene modules" EMBO J. (1987) 6:4193-4196.
Ludgate et al., "Antibodies to human thyroid peroxidase in autoimmune thyroid disease: Studies with a cloned recombinant complementary deoxyribonucleic acid epitope" J. Clin. Endocrinol. Metab. (1989) 68:1091-1096.
Elisei et al., "Studies with recombinant autoepitopes of thyroid peroxidase: Evidence suggesting an epitope shared between the thyroid and the gastric parietal cell" Autoimmunity (1990) 8:65-70.
Libert et al., "Thyroperoxidase, but not the thyrotropin receptor, contains sequential epitopes recognized by autoantibodies in recombinant peptides expressed in the pUEX vector" J. Clin. Endocrinol. Metab. (1991) 73:857-860.
Nakajima et al., "Structure-activity analysis of microsomal antigen/thyroid peroxidase" Mol. Cell. Endocrinol. (1987) 53:15-23.
Yokoyama et al., "Studies with purified human thyroid peroxidase and thyroid microsomal autoantibodies" J. Clin. Endocrin. Metab. (1990) 70:758-765.
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Banga et al., "Prediction of domain organisation and secondary structure of thyroid peroxidase, a human autoantigen involved in destructive thyroiditis" FEBS Letters (1990) 266:133-141.
Kimura et al., "Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family" Proteins (1988) 3:113-120.
Baker et al., "Development of a human monoclonal antibody from a Graves' disease patient that identifies a novel thyroid membrane antigen" J. Immunol. (1988) 140:2593-2599.
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Baker, Jr. James R.
Koenig Ronald J.
Grun James L.
Housel James C.
The Regents of the University of Michigan
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