Epitopes for > 95% stimulating
thyrotropin receptor autoantibodies (TSHRAbs) causally implicated in
Graves' disease (
Basedow's disease or
primary hyperthyroidism) have been identified on on the N-terminal portion of the TSHR extracellular domain, residues 8-165. If the stimulating TSHRAb activity is solely dependent on this region, it is termed homogeneous; if its activity is only largely related to this region, it is termed heterogeneous. The presence of a heterogeneous stimulating TSHRAb in a patient is associated with rapid responses to
propylthiouracil or
methimazole and may be predictive of long term remission with these oral immunosuppressives.
Epitopes for two different Graves'
autoantibodies that inhibit TSH binding, TSH binding inhibition
immunoglobulins or TBIIs, have also been identified on this region of the TSHR. They do not increase cAMP levels, although one may activate the
inositol phosphate, Ca++, arachidonate release signal system. The
epitope of blocking TSHRAbs with the ability to inhibit TSH binding (TBII activity), TSH activity, and stimulating TSHRAb activity, and that are causally implicated in the
primary hypothyroidism of patients with idiopathic
myxedema or some patients with
Hashimoto's disease have, in contrast, been largely identified largely on the C-terminal portion of the TSHR extracellular domain, residues 270-395. They have been implicated as important in pregnancy where they attenuate the signs and symptoms of Graves'
hyperthyroidism. The appearance of these blocking TSHRAbs during pregnancy in Graves' patients might cause overt or occult
hypothyroidism, with resultant effects on fetal development and postnatal intelligence levels. The different TSHRAbs can exist in the same patient at any moment in time, potentially making disease expression a sum of their activities. Assays taking advantage of the
epitope mapping findings enable us to detect individual TSHRAbs within a single patient and to better understand their clinical significance.