Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28. CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association of Graves’ disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity. In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared from GD (n = 45), Hashimoto’s thyroiditis (HT) (n = 18), and NC (n = 43). There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% in NC), and significantly fewer patients with the A/A allele (17.8% vs 34.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose-dependent manner. Augmentation induced by CTLA-4 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC). Although PBMC from individuals with the G/G alleles showed 132% augmentation, those with the A/A alleles showed 193% augmentation (p = 0.019). CTLA-4 polymorphism affects the inhibitory function of CTLA-4. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.

Episode frequency is a highly familial trait in bipolar affective disorder, associated with several indicators of severity, and may be useful in defining clinical subtypes of bipolar affective disorder with greater genetic liability. DSM-IV rapid cycling was not supported by these data as the best predictor of familiality or severity.

The translated products of v-erbA-related cDNAs have been demonstrated to be thyroid hormone receptors, and three different forms of receptor (alpha 1, alpha 2, and beta) have been found in human tissues. We synthesized five peptides corresponding to different portions of these three receptors and raised site-specific polyclonal-antipeptide sera in rabbits. Each antibody displayed high titer and specificity for its respective antigen when tested in an enzyme-linked immunosorbent assay. Each immunoprecipitated the corresponding in vitro translated products of human c-erbA alpha 1, alpha 2, or beta. Two of the antisera were specific for beta, one for alpha 2, and one detected a sequence common to alpha 1 and alpha 2. The fifth was directed toward the DNA-binding area of the proteins and interacted with each receptor. The four antibodies against alpha 1 and beta immunoprecipitated the native thyroid hormone receptor from rat liver and caused a partial shift in the elution profile of the native receptor labeled with [125I]T3 on Sephacryl S-300 column chromatography. The antibody against alpha 2 protein did not interact with native thyroid hormone receptor from rat liver. Using the indirect immunofluorescence technique with the five antibodies, we detected immunoreactivity primarily in the nucleus of cells in several tissues. In general, there was coordinate expression of both alpha and beta receptors in each organ examined, in agreement with previous data on tissue distribution of mRNAs for human thyroid hormone receptors. These studies prove the identity of v-erbA-related gene products with native thyroid hormone receptors and the expression of both alpha and beta receptors in nuclei of human and rat tissues.

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