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The Thyrotropin (TSH)-Releasing Hormone Receptor: Interaction with TSH and Autoantibodies¹

Autoimmune Disease Unit, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, and the University of California, Los Angeles, California 90048

I. Introduction

II. TSHR Ectodomain Structure

A. Primary amino acid structure

B. Subunit structure

C. Disulfide bonds in the TSHR ectodomain

D. Carbohydrate moieties in the TSHR ectodomain

E. TSHR dimerization

III. Recombinant TSHR Expression

A. Approaches to TSHR expression

B. TSHR expression in prokaryotes

C. TSHR expression as cell-free translates or as synthetic peptides

D. TSHR expression in eukaryotic insect cells

E. TSHR expression in mammalian cells

IV. TSH and Autoantibody Binding to the TSHR Ectodomain

A. Holoreceptor vs. ectodomain

B. Conformational nature of binding sites

C. TSHR carbohydrate: part of the binding site?

D. TSHR amino acid residues in TSH-binding site

E. Autoantibody epitopes

V. TSHR Autoantibody Assays

A. Historical background

B. In vivo and in vitro bioassays

C. Indirect TBI assays

D. Direct assays for TSHR autoantibodies

E. Confusion on the terminology and types of TSHR autoantibodies

VI. Monoclonal Autoantibodies to the TSHR Ectodomain

A. Introduction

B. Mouse TSHR mAb

C. Human monoclonal TSHR autoantibodies

D. Interpretation of the data on human TSHR-specific mAbs

E. Why is the subject of TSHR mAbs controversial?

F. Source of B cells used to obtain human TSHR monoclonal antibodies

VII. T Cell Epitopes

A. Background

B. Approaches to studying T cell responses

C. TSHR synthetic peptides

D. Endogenous antigen processing

E. TSHR-specific T cell receptor genes and cytokine production

F. Summary

VIII. Molecular Mimicry

IX. Animal Models of Graves’ Disease

A. Immunization with soluble TSHR antigen and adjuvant

B. Genetic immunization

C. Severe combined immunodeficiency (SCID) mouse model of Graves’ disease

D. Immunization with live syngeneic fibroblasts expressing the TSHR and class II molecules

X. Ectodomain Mutations and Polymorphisms

A. Spontaneous ectodomain mutations leading to enhanced TSHR function

B. Spontaneous ectodomain mutations leading to decreased TSHR function

C. Nonfunctional polymorphisms in the TSHR ectodomain

D. TSHR ectodomain splice variants

XI. Extrathyroidal Manifestations of Graves’ Disease