Molecular Basis for the Autoreactivity Against Thyroid Stimulating Hormone Receptor

Abstract

The present report identifies an important immunogenic region of the TSH receptor and determinants on the TSH receptor for the two types of autoantibodies seen in hyperthyroid Graves' disease and hypothyroid idiopathic myxedema, TSAbs and TSBAbs, respectively. The immunogenic domain with no important functional determinants, is contained within residues 303-382 and involves residues 352-366 in particular. There are determinants flanking the immunogenic domain on the C-terminal portion of the receptor which are the TSBAb and high affinity TSH binding sites: residues 295-306, 387-395, and tyrosine 385. Determinants on the N-terminal portion of the external domain, centered on residues 38-45, are TSAb interactions linked to low affinity TSH binding important for signal generation: threonine 40 and residues 30-33, 34-37, 42-45, 52-56, and 58-61. These determinants are conserved in human and rat receptors, are not present in gonadotropin receptors, and are each related to separate actions of TSH: binding vs. signal generation. They can, therefore, account for organ specific autoimmunity and the different disease expression effected by TSBAbs vs TSAbs, i.e. hypo- vs. hyperthyroidism, respectively. It is proposed that, in the thyroid, hormonal (TSH, insulin, hydrocortisone, IGF-I) suppression of class I genes might be one means of preserving self-tolerance in the face of the hormone action to increase the expression of tissue specific genes such as thyroglobulin and thyroid peroxidase. Inappropriately high class I expression in the thyroid, i.e. if induced by interferon, viruses, or some as yet unknown agent, would contribute to the generation of autoimmune disease. Thus, it would result in increased antigen presentation to the immune system, particularly those autoantigens increased by TSH and its cAMP signal such as thyroglobulin or thyroid peroxidase, or whose turnover is increased by TSH and its cAMP signal, such as the TSH receptor. In the case of the latter, peptide 352-366, known to be near a protease sensitive site on the receptor [41,49], would now act as a potent self-antigen and induce the formation of receptor autoantibodies. It is further proposed that methimazole and high doses of iodide are therapeutically effective agents in thyroid autoimmune disease because they, in part, decrease MHC class I gene expression. Speculation is presented which suggests that elimination of negative regulation of MHC class I and the TSH receptor is an important factor in the development of autoimmune thyroid disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Prevalence of Autoantibodies in Patients with Hepatitis C Virus Infection in Oman

“…15,21,24,25,26 The mechanisms by which viruses in general, and HCV in particular, trigger or enhance autoimmunity can be explained in various ways. 27,28,29,30 According to one theory, viruses may non-specifically trigger immune regulatory cells, such as lymphocytes or macrophages, inducing them to react with self-antigens in multiple organs, and therefore cause tissue injury as well as extrahepatic diseases. Another theory suggests that viruses alter the antigenic profile of infected cells (such as hepatocytes) by changing, releasing or exposing selfantigens that are usually "hidden" and for which the immune system usually has no tolerance.…”

Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

“…A recent report by Sopedra et al (33), which showed the hyperinducibility of HLA class II expression in thyroid follicular cells from patients with GD, supports a possible role for class II molecules in the development of GD; our present data directly implicate aberrant class II expression as a potential causal factor in the development of stimulating TSHRAbs. Nevertheless, studies of 5'-flanking region cis regulatory elements of the class I and TSHR genes, together with their respective trans factors, suggest the importance of abnormal class I molecules in the expression of GD or other forms of autoimmunity (15)(16)(17)(18) and additionally indicate there are common elements in the class I and class II molecules (18). These findings (15)(16)(17)(18) indicate that both class I and class II molecules are important in the development of GD.…”

“…with overexpressed class I or aberrant II, alone or both together, may clarify their respective roles. Thus, greater levels of class II expression in the fibroblasts may increase the frequency of stimulating TSHRAbpositive mice, or increased MHC class I expression, by transfection or a-interferon treatment of the fibroblasts, might enhance the frequency of stimulating TSHRAb-positive mice, since the class I molecule has been shown to be involved in the development of autoimmune diseases (15)(16)(17)(18).…”

“…They did not take into account the possibility that the TSHR might be presented to the immune system as a result of abnormal major histocompatibility complex (MHC) class I or class II expression on thyrocytes, thereby allowing normal immune tolerance to be broken. Thus, several studies have implicated class I as an important component in the development of autoimmune thyroid disease and in the action of methimazole, a drug used to treat GD (14)(15)(16)(17)(18). In addition, aberrant class II expression, as well as abnormal expression of class I molecules, is evident on thyrocytes in autoimmune thyroid diseases (19)(20)(21), although the cause and role of aberrant class II in disease expression remains controversial (22).…”

Antithyrotropin Receptor Antibody: An Update

“…They have been extensively and intensively studied for several decades. Abundant clinical and basic studies about TSHR-Ab have been done and have clarified its characteristics, heterogeneity, and clinical significance, and several excellent reviews have been published (1)(2)(3)(4)(5)(6)(7). However, many problems and questions about TSHR-Ab remain unsolved and many new findings have been recently reported.…”