PMID- 7726800 OWN - NLM STAT- MEDLINE DCOM- 19950519 LR - 20191031 IS - 0950-351X (Print) IS - 0950-351X (Linking) VI - 9 IP - 1 DP - 1995 Jan TI - The thyrotropin receptor as a model to illustrate receptor and receptor antibody diseases. PG - 95-113 AB - The thyrotropin receptor (TSHR) has been used as an example to illustrate how disease may be the consequence of: 1. Modifications or inappropriate production of the natural ligand. 2. Production of abnormal agonists or antagonists such as autoantibodies. 3. Modifications in receptor structure resulting in constitutive activation or the absence of activation following ligand binding. 4. Changes in the cellular machinery which transduces the signal from the receptor to the cytoplasmic or nuclear endpoint target. This chapter concentrates on mechanisms (2) and (3). Since the cloning of the TSHR it has been shown that approximately 50% of cases of toxic adenoma can be explained by somatic point mutations in the nucleotide sequence of the receptor gene which causes single amino acid substitutions. The resulting modified TSHR structure constitutively activates adenylate cyclase (via Gs), intracellular cAMP levels are increased and, since cAMP controls both growth and function of the human thyrocyte clonal expansion of the mutated cell ensues. Similarly, activating mutations of the TSH receptor gene in the germline are responsible for hereditary hyperthyroidism with goitre, which is transmitted in the autosomal dominant mode. Changes in receptor primary structure, i.e. a modified autoantigen, do not seem to be responsible for the escape from tolerance which must precede production of thyroid stimulating antibodies (TSAB) which cause hyperthyroid Graves' disease and thyroid blocking antibodies (TBAB) which are responsible for some cases of hypothyroid idiopathic myxoedema. The eukaryotic expression of wild-type, experimentally mutated and chimeric TSHR has enabled some progress in delineating the residues involved in binding TSH, TSAB and TBAB. All three ligands bind numerous discontinuous residues in the extracellular domain of the receptor. The difference between the bioactivity of TSAB and TBAB cannot be explained completely by different binding sites on the receptor. Subtle differences in, for example, glycosylation and sialation of the immunoglobulins may be implicated, since bioactivity of TSH itself seems to depend on these. Attempts to define T cell epitopes have not identified a major immunogenic region. Indeed heterogeneity seems to be a hallmark of TSHR autoantibodies (TRAB). The possibility that thyroid-associated ophthalmopathy and pretibial myxoedema may be receptor antibody diseases is discussed. Further progress awaits large-scale production of TSHR able to bind TSH to facilitate X-ray crystallographic studies, the development of specific T cell clones and the cloning of TSAB autoantibodies. FAU - Ludgate, M E AU - Ludgate ME AD - IRIBHN-University of Brussels, Erasme Hospital, Belgium. FAU - Vassart, G AU - Vassart G LA - eng PT - Journal Article PT - Review PL - England TA - Baillieres Clin Endocrinol Metab JT - Bailliere's clinical endocrinology and metabolism JID - 8704785 RN - 0 (Immunoglobulins, Thyroid-Stimulating) RN - 0 (Receptors, Thyrotropin) RN - 9002-71-5 (Thyrotropin) SB - IM MH - Amino Acid Sequence MH - Animals MH - Drug Resistance MH - Humans MH - Immunoglobulins, Thyroid-Stimulating/immunology MH - Molecular Sequence Data MH - Protein Conformation MH - Receptors, Thyrotropin/chemistry/*immunology/physiology MH - Thyroid Diseases/*immunology/physiopathology MH - Thyroid Gland/physiopathology MH - Thyrotropin/pharmacology RF - 95 EDAT- 1995/01/01 00:00 MHDA- 1995/01/01 00:01 CRDT- 1995/01/01 00:00 PHST- 1995/01/01 00:00 [pubmed] PHST- 1995/01/01 00:01 [medline] PHST- 1995/01/01 00:00 [entrez] AID - 10.1016/s0950-351x(95)80851-5 [doi] PST - ppublish SO - Baillieres Clin Endocrinol Metab. 1995 Jan;9(1):95-113. doi: 10.1016/s0950-351x(95)80851-5.