Antibody-induced modulation of TSH receptor post-translational processing.
The post-translational processing of the TSH receptor (TSHR) includes intra-molecular cleavage with the loss of a 50 amino acid ectodomain region and the formation of two subunits (alpha and beta), followed by likely alpha subunit shedding. TSHR antibodies (TSHR-Abs), which are directed at the ectodomain, may influence thyroid function by stimulating or inhibiting TSHR signaling or may bind without any such influence (the neutral group of antibodies). When we examined the characteristics of a series of monoclonal TSHR-Abs, we found that many were able to inhibit receptor cleavage and enhance TSHR expression. This was especially apparent with the neutral type of TSHR-Abs directed to the cleaved region of the ectodomain (aa 316-366). Indeed, such inhibition appeared to be epitope dependent with TSHR-Abs directed to regions after residues 335-354 showing no such activity. We propose that this aberrant process, whereby TSHR-Abs influence antigen processing, is a novel mechanism for the maintenance and exacerbation of autoimmune thyroid disease.
Ando
Takao
T
Thyroid Research Unit, Mount Sinai School of Medicine, The James J Peters VA Medical Center, Box 1055, 1 Gustave L Levy Place, New York, New York 10029, USA.
Latif
Rauf
R
Davies
Terry F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000937:Antigen-Antibody Reactions; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D011499:Protein Processing, Post-Translational; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013961:Thyroid Gland / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D000939:Epitopes; D011989:Receptors, Thyrotropin