International Immunology, Vol. 14, No. 4, pp. 359-366,
April 2002
© 2002 Japanese Society for Immunology
Analysis of a conformational B cell epitope of human thyroid peroxidase: identification of a tyrosine residue at a strategic location for immunodominance
1 U555 INSERM/Laboratoire de Biochimie Endocrinienne et Métabolique, Faculté de Médecine, Université de la Méditerranée, 13385 Marseille Cedex 05, France 2 Pôle de BioInformatique Lyonnais, IBCP, UMR 5086 CNRS, 69367 Lyon Cedex 07, France 3 Laboratoire d’Ingénierie des Systèmes Macromoléculaires, IBSM, UPR 9027 CNRS, 13402 Marseille Cedex 20, France
Correspondence to: J. Ruf; E-mail: jean.ruf{at}medecine.univ-mrs.fr
Transmitting editor: E. Möller
Thyroid peroxidase (TPO) is involved in autoimmune thyroid diseases and high titers of TPO autoantibodies directed to various conformational B cell epitopes are frequently present in patients’ sera. Deciphering these epitopes is a difficult task, but can give insight into the structural basis of autoimmune recognition. TPO is a membrane-bound enzyme with the extracellular part organized in three protein domains, but of unknown three-dimensional structure. We previously localized a TPO B cell epitope within amino acid residues 742–848, a region encompassing the two C-terminal, extracellular domains of the protein. We found that at least one of the three tyrosine residues of the peptide 742–848 might be involved in autoantibody binding. In this study, we show by site-directed mutagenesis that the autoepitope contains tyrosine 772 located near the hinge area between the two protein domains, suggesting they are both involved in the epitope structure. The B cell epitopes of TPO are clustered in two overlapping immunodominant regions. To map the newly localized epitope with respect of these regions, competition experiments were performed using a reference panel of TPO mAb and a further mAb previously found to be specific for the TPO peptide 742–848 at variance with all the other ones. Here, we show that the tyrosine 772-bearing epitope in the peptide 742–848 maps in a region that partly overlaps the reported two immunodominant regions. These results are suggestive of a complex TPO folding that involves all the three TPO protein domains to form a highly conformational immunodominant region.
Keywords: autoimmunity, B cell epitope, circular dichroism, thyroid peroxidase, thyroperoxidase
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