Complement activation by direct C4 binding to thyroperoxidase in Hashimoto's thyroiditis.
Biosynthesis of thyroid hormones is an oxidative process that generates reactive oxygen species (ROS) and involves thyroperoxidase (TPO) that is one of the main autoantigens involved in autoimmune thyroid diseases. The ectodomain of TPO consists of a large N-terminal myeloperoxidase-like module followed by a complement control protein (CCP)-like module and an epidermal growth factor-like module. The presence of these two additional gene modules suggests that they may play some crucial, hitherto unsuspected role associated with thyroid function. Because the CCP module is a constituent of the molecules involved in the activation of C4 complement component, we investigated the possibility that C4 may bind to TPO and activate the complement pathway in autoimmune conditions. We showed that TPO via its CCP module directly activated complement without any mediation by Ig. We suggested that this additional complement pathway requires the production of ROS and specially hydroxyl radicals that aggregate TPO and oxidize methionines of C4. Moreover, we found, in patients with Hashimoto's thyroiditis, that thyrocytes overexpress C4 and all the downstream components of the complement pathway. These results indicate that TPO has some as yet unknown function, which may contribute along with other mechanisms to the massive cell destruction observed in Hashimoto's thyroiditis. Investigating this complement pathway, therefore, would provide an excellent means of reaching a better understanding of the etiology of other degenerative diseases.
Blanchin
Stephanie
S
Institut National de la Santé et de la Recherche Médicale, Unité 555, Faculté de Médicine Timone, Université de la Méditerranée, Morseille, France.
Estienne
Valerie
V
Durand-Gorde
Josee-Martine
JM
Carayon
Pierre
P
Ruf
Jean
J
D000208:Acute Disease; D003167:Complement Activation / Q000502:physiology*; D003175:Complement C2 / Q000235:genetics; D003176:Complement C3 / Q000235:genetics; D003181:Complement C4 / Q000235:genetics / Q000378:metabolism*; D003182:Complement C5 / Q000235:genetics; D003183:Complement C6 / Q000235:genetics; D003184:Complement C7 / Q000235:genetics; D003185:Complement C8 / Q000235:genetics; D003186:Complement C9 / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007453:Iodide Peroxidase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D003175:Complement C2; D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D003183:Complement C6; D003184:Complement C7; D003185:Complement C8; D003186:Complement C9; D017382:Reactive Oxygen Species; D007453:Iodide Peroxidase