The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim.
Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb's). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb's were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.
Chen
Chun-Rong
CR
Autoimmune Disease Unit, Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles, Los Angeles, California 90048, USA.
Pichurin
Pavel
P
Nagayama
Yuji
Y
Latrofa
Francesco
F
Rapoport
Basil
B
McLachlan
Sandra M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D006111:Graves Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D016296:Mutagenesis; D021122:Protein Subunits; D011989:Receptors, Thyrotropin / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D013961:Thyroid Gland / Q000473:pathology
D019138:Antibodies, Blocking; D001323:Autoantibodies; D001324:Autoantigens; D021122:Protein Subunits; D011989:Receptors, Thyrotropin