Endocrinology, Vol 125, 1211-1218, Copyright © 1989 by Endocrine Society

ARTICLES

Relationship between immunological structure and biochemical properties of human thyroid peroxidase

J Ruf, ME Toubert, B Czarnocka, JM Durand-Gorde, M Ferrand and P Carayon
U 38 INSERM-URA 178 CNRS, Faculte de Medecine, Marseille, France.

Although the primary structure of human thyroid peroxidase (hTPO) has been recently deciphered, little is known about its spatial conformation. Such information is of crucial importance in any attempt to relate the structure with the function of hTPO. To probe the antigenic surface of hTPO and to correlate its immunological structure to its biochemical properties, we used 13 monoclonal antibodies (mAb) displaying various affinity for hTPO. Criss-cross experiments showed 7 clusters of reactivity which were interpreted as reflecting 7 epitopes on the surface of the hTPO molecule. Extending our analysis to partial and nonsymmetrical cross-reactivities, these epitopes were shown to be localized in 4 antigenic domains of the hTPO. We further investigated the nature of these 7 hTPO epitopes by testing mAb binding to peroxidases from various origins and chemically modified hTPO; 3 epitopes were shown to be evolutionary conserved, and 5 resistant to reduction and denaturation. We also analyzed the role of the hTPO epitopes in the enzymatic activity and autoimmune targeting of the molecule. Nine epitopes were shown to be localized at the vicinity of both catalytic sites as the binding of their respective mAb modulated the enzyme activity. Autoantibodies from patients presenting with autoimmune thyroid disorders were essentially directed to epitopes similar or adjacent to those recognized by 8 of the 13 mAb and present on only 2 antigenic domains of hTPO. Taken together these data allowed us to propose a tentative map of the surface of the hTPO molecule which associates its epitopic structure with its biochemical functions.

This article has been cited by other articles:

				A. Giraud, P.-J. Lejeune, J. Barbaria, and B. Mallet A Plasminogen-Like Protease in Thyroid Rough Microsomes Degrades Thyroperoxidase and Thyroglobulin Endocrinology, June 1, 2007; 148(6): 2886 - 2893. [Abstract] [Full Text] [PDF]

				M. Dubska, J. P. Banga, D. Plochocka, G. Hoser, E. H. Kemp, B. J. Sutton, A. Gardas, and M. Gora Structural Insights into Autoreactive Determinants in Thyroid Peroxidase Composed of Discontinuous and Multiple Key Contact Amino Acid Residues Contributing to Epitopes Recognized by Patients' Autoantibodies Endocrinology, December 1, 2006; 147(12): 5995 - 6003. [Abstract] [Full Text] [PDF]

				S. A. Rebuffat, D. Bresson, B. Nguyen, and S. Peraldi-Roux The key residues in the immunodominant region 353-363 of human thyroid peroxidase were identified Int. Immunol., July 1, 2006; 18(7): 1091 - 1099. [Abstract] [Full Text] [PDF]

				H. P. Ng and A. W. C. Kung Induction of Autoimmune Thyroiditis and Hypothyroidism by Immunization of Immunoactive T Cell Epitope of Thyroid Peroxidase Endocrinology, June 1, 2006; 147(6): 3085 - 3092. [Abstract] [Full Text] [PDF]

				J. Guo, S. M. McLachlan, P. N. Pichurin, C.-R. Chen, N. Pham, H. A. Aliesky, C. S. David, and B. Rapoport Relationship between Thyroid Peroxidase T Cell Epitope Restriction and Antibody Recognition of the Autoantibody Immunodominant Region in Human Leukocyte Antigen DR3 Transgenic Mice Endocrinology, November 1, 2005; 146(11): 4961 - 4967. [Abstract] [Full Text] [PDF]

				S. M. McLachlan, Y. Nagayama, and B. Rapoport Insight into Graves' Hyperthyroidism from Animal Models Endocr. Rev., October 1, 2005; 26(6): 800 - 832. [Abstract] [Full Text] [PDF]

				D. Bresson, S. A. Rebuffat, B. Nguyen, J. P. Banga, A. Gardas, and S. Peraldi-Roux New Insights into the Conformational Dominant Epitopes on Thyroid Peroxidase Recognized by Human Autoantibodies Endocrinology, June 1, 2005; 146(6): 2834 - 2844. [Abstract] [Full Text] [PDF]

				V. Le Fourn, M. Ferrand, and J.-L. Franc Endoproteolytic Cleavage of Human Thyroperoxidase: ROLE OF THE PROPEPTIDE IN THE PROTEIN FOLDING PROCESS J. Biol. Chem., February 11, 2005; 280(6): 4568 - 4577. [Abstract] [Full Text] [PDF]

				S. Quaratino, J. Ruf, M. Osman, J. Guo, S. McLachlan, B. Rapoport, and M. Londei Human Autoantibodies Modulate the T Cell Epitope Repertoire but Fail to Unmask a Pathogenic Cryptic Epitope J. Immunol., January 1, 2005; 174(1): 557 - 563. [Abstract] [Full Text] [PDF]

				V. Estienne, N. Brisbarre, S. Blanchin, J.-M. Durand-Gorde, P. Carayon, and J. Ruf An in vitro model based on cell monolayers grown on the underside of large- pore filters in bicameral chambers for studying thyrocyte-lymphocyte interactions Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1763 - C1768. [Abstract] [Full Text] [PDF]

				D. Bresson, M. Pugniere, F. Roquet, S. A. Rebuffat, B. N-Guyen, M. Cerutti, J. Guo, S. M. McLachlan, B. Rapoport, V. Estienne, et al. Directed Mutagenesis in Region 713-720 of Human Thyroperoxidase Assigns 713KFPED717 Residues as Being Involved in the B Domain of the Discontinuous Immunodominant Region Recognized by Human Autoantibodies J. Biol. Chem., September 10, 2004; 279(37): 39058 - 39067. [Abstract] [Full Text] [PDF]

				H. P. Ng, J. Paul Banga, and A. W. C. Kung Development of a Murine Model of Autoimmune Thyroiditis Induced with Homologous Mouse Thyroid Peroxidase Endocrinology, February 1, 2004; 145(2): 809 - 816. [Abstract] [Full Text] [PDF]

				S. Blanchin, V. Estienne, J.-M. Durand-Gorde, P. Carayon, and J. Ruf Complement Activation by Direct C4 Binding to Thyroperoxidase in Hashimoto's Thyroiditis Endocrinology, December 1, 2003; 144(12): 5422 - 5429. [Abstract] [Full Text] [PDF]

				D. Bresson, M. Cerutti, G. Devauchelle, M. Pugniere, F. Roquet, C. Bes, C. Bossard, T. Chardes, and S. Peraldi-Roux Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases J. Biol. Chem., March 7, 2003; 278(11): 9560 - 9569. [Abstract] [Full Text] [PDF]

				M. Ferrand, V. Le Fourn, and J.-L. Franc Increasing Diversity of Human Thyroperoxidase Generated by Alternative Splicing. CHARACTERIZATION BY MOLECULAR CLONING OF NEW TRANSCRIPTS WITH SINGLE- AND MULTISPLICED mRNAs J. Biol. Chem., January 31, 2003; 278(6): 3793 - 3800. [Abstract] [Full Text] [PDF]

				J. Guo, S. M. McLachlan, and B. Rapoport Localization of the Thyroid Peroxidase Autoantibody Immunodominant Region to a Junctional Region Containing Portions of the Domains Homologous to Complement Control Protein and Myeloperoxidase J. Biol. Chem., October 18, 2002; 277(43): 40189 - 40195. [Abstract] [Full Text] [PDF]

				V. Estienne, C. Duthoit, S. Blanchin, R. Montserret, J.-M. Durand-Gorde, M. Chartier, D. Baty, P. Carayon, and J. Ruf Analysis of a conformational B cell epitope of human thyroid peroxidase: identification of a tyrosine residue at a strategic location for immunodominance Int. Immunol., April 1, 2002; 14(4): 359 - 366. [Abstract] [Full Text] [PDF]

				J. Guo, X.-M. Yan, S. M. McLachlan, and B. Rapoport Search for the Autoantibody Immunodominant Region on Thyroid Peroxidase: Epitopic Footprinting with a Human Monoclonal Autoantibody Locates a Facet on the Native Antigen Containing a Highly Conformational Epitope J. Immunol., January 15, 2001; 166(2): 1327 - 1333. [Abstract] [Full Text] [PDF]

				P. Hobby, A. Gardas, R. Radomski, A. M. McGregor, J. P. Banga, and B. J. Sutton Identification of an Immunodominant Region Recognized by Human Autoantibodies in a Three-Dimensional Model of Thyroid Peroxidase Endocrinology, June 1, 2000; 141(6): 2018 - 2026. [Abstract] [Full Text] [PDF]

				, , , , , , , , , and Human Anti-Thyroid Peroxidase Single-Chain Fragment Variable of Ig Isolated from a Combinatorial Library Assembled In-Cell: Insights into the In Vivo J. Immunol., April 15, 2000; 164(8): 4162 - 4169. [Abstract] [Full Text] [PDF]

				L. Fayadat, S. Siffroi-Fernandez, J. Lanet, and J.-L. Franc Calnexin and Calreticulin Binding to Human Thyroperoxidase Is Required for Its First Folding Step(s) But Is Not Sufficient to Promote Efficient Cell Surface Expression Endocrinology, March 1, 2000; 141(3): 959 - 966. [Abstract] [Full Text] [PDF]

				V. Estienne, C. Blanchet, P. Niccoli-Sire, C. Duthoit, J.-M. Durand-Gorde, C. Geourjon, D. Baty, P. Carayon, and J. Ruf Molecular Model, Calcium Sensitivity, and Disease Specificity of a Conformational Thyroperoxidase B-cell Epitope J. Biol. Chem., December 10, 1999; 274(50): 35313 - 35317. [Abstract] [Full Text] [PDF]

				J. C. Jaume, J. Guo, Y. Wang, B. Rapoport, and S. M. McLachlan Cellular Thyroid Peroxidase (TPO), Unlike Purified TPO and Adjuvant, Induces Antibodies in Mice That Resemble Autoantibodies in Human Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1651 - 1657. [Abstract] [Full Text]

				L. Fayadat, P. Niccoli-Sire, J. Lanet, and J. L. Franc Human Thyroperoxidase Is Largely Retained and Rapidly Degraded in the Endoplasmic Reticulum. Its N-Glycans Are Required for Folding and Intracellular Trafficking Endocrinology, October 1, 1998; 139(10): 4277 - 4285. [Abstract] [Full Text] [PDF]

				P. Niccoli, L. Fayadat, V. Panneels, J. Lanet, and J.-L. Franc Human Thyroperoxidase in Its Alternatively Spliced Form (TPO2) Is Enzymatically Inactive and Exhibits Changes in Intracellular Processing and Trafficking J. Biol. Chem., November 21, 1997; 272(47): 29487 - 29492. [Abstract] [Full Text] [PDF]

				R. S. McIntosh, M. S. Asghar, E. H. Kemp, P. F. Watson, A. Gardas, J. P. Banga, and A. P. Weetman Analysis of Immunoglobulin G{kappa} Antithyroid Peroxidase Antibodies from Different Tissues in Hashimoto's Thyroiditis J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3818 - 3825. [Abstract] [Full Text] [PDF]

				B. Czarnocka, M. Janota-Bzowski, R. S. McIntosh, M. S. Asghar, P. F. Watson, E. H. Kemp, P. Carayon, and A. P. Weetman Immunoglobulin G{kappa} Antithyroid Peroxidase Antibodies in Hashimoto's Thyroiditis: Epitope-Mapping Analysis J. Clin. Endocrinol. Metab., August 1, 1997; 82(8): 2639 - 2644. [Abstract] [Full Text] [PDF]

				V. Kaczur, Gy. Vereb, I. Molnar, G. Krajczar, E. Kiss, N. R. Farid, and Cs. Balazs Effect of anti-thyroid peroxidase (TPO) antibodies on TPO activity measured by chemiluminescence assay Clin. Chem., August 1, 1997; 43(8): 1392 - 1396. [Abstract] [Full Text] [PDF]

				R.-T. Tsai, T.-C. Chang, C.-R. Wang, S.-L. Lee, C.-J. Wang, and G.J. Tsay Thyroid peroxidase autoantibodies and their effects on enzyme activity in patients with systemic lupus erythematosus Lupus, August 1, 1995; 4(4): 280 - 285. [Abstract] [PDF]

				L. Fayadat, S. Siffroi-Fernandez, J. Lanet, and J.-L. Franc Degradation of Human Thyroperoxidase in the Endoplasmic Reticulum Involves Two Different Pathways Depending on the Folding State of the Protein J. Biol. Chem., May 19, 2000; 275(21): 15948 - 15954. [Abstract] [Full Text] [PDF]