Mature APCs play a key role in the induction of Ag-specific immunity. This work examines whether genomic DNA released by dying cells provides a stimulus for APC maturation. Double-stranded but not single-stranded genomic DNA triggered APC to up-regulate expression of MHC class I/II and various costimulatory molecules. Functionally, dsDNA enhanced APC function in vitro and improved primary cellular and humoral immune responses in vivo. These effects were dependent on the length and concentration of the dsDNA but were independent of nucleotide sequence. The maturation of APC induced by dsDNA may promote host survival by improving immune surveillance at sites of tissue injury/infection.

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

Transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of epithelial cell proliferation. Signal transduction by TGF-beta1 involves direct binding to the TGF-beta Type-II receptor and then the formation of a heterodimeric complex of TGF-beta Type-I and Type-II receptor. To explore the role of TGF-beta1 in thyroid carcinoma, we examined the expression of TGF-beta1 and TGF-beta Type-II receptor mRNA by northern blotting analysis in both 14 papillary thyroid carcinomas and surrounding normal thyroid tissues. Relative mRNA level was determined by scanning densitometry of the autoradiogram and corrected for loading differences using a human beta-actin cDNA probe. The relative mRNA levels of TGF-beta1 in 12 out of 14 papillary thyroid carcinomas were higher than those in surrounding normal thyroid tissues. In contrast, the relative mRNA levels of TGF-beta Type-II receptor were reduced to 60.1+/-18.3% of those of normal thyroid tissues in 10 papillary thyroid carcinomas. There were no clear relationships between the relative mRNA levels for TGF-beta1 and TGF-beta Type-II receptor and the histological characteristics of papillary thyroid carcinomas. The relative mRNA levels for TGF-beta1 and TGF-beta Type-II receptor did not show significant differences in thyroid carcinomas with or without lymph node metastases. There was a negative correlation between the TGF-beta Type-II receptor mRNA level and tumor size, while no significant correlation was observed between the TGF-beta1 mRNA level and tumor size. In conclusion, most papillary thyroid carcinomas overexpress TGF-beta1 mRNA but exhibit a reduction in TGF-beta Type-II receptor mRNA. The reduction of TGF-beta Type-II receptor mRNA may play a role in the pathogenesis of papillary thyroid carcinoma.

A 66-year-old man was admitted with destructive arthropathy, and calcium pyrophosphate dihydrate was demonstrated in the synovial fluid specimen. He was found to have a hyponatremia. The serum sodium concentration was 121 mmol//, plasma arginine vasopressin (AVP) 6.6 pmol//, and serum interleukin (IL)-6 96 pg//. The clinical findings suggest the diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, destructive arthropathy with increased values of C-reactive protein and IL-6 is the only background of SIADHin this patient. We suggest the possibility that IL-6 produced at inflammatory lesions may have stimulated an excessive release of AVPresulting in the hyponatremia and hypochloremia of SIADH. (Internal Medicine 37: 792-795, 1998)