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Hashimoto's thyroiditis has been shown to be associated with the HLA-specificities DR4 and DR5. Since former association studies yielded variable results, we used novel molecular typing methods to assess predisposing immunogenetic factors. Gene analysis of the HLA-DR-DQ and tumor necrosis factor region was performed in a group of Hashimoto's thyroiditis patients and randomly chosen controls using standards and nomenclature of the 10th International Histocompatibility Workshop. Genomic DNA of patients and controls was analyzed using a cDNA probe of the DQB1 gene. The resulting restriction fragment patterns allowed the determination of newly defined DQw-types 1-9. We find the strongest relative risk conferred by DQw7 (RR = 4.7), that is observed in 36 of 64 patients (56%) and only 21 of 98 controls (21%) (P corr less than 0.002). Comparison of DNA sequence variation in the DQB1 gene, that is found predominantly in Hashimoto's thyroiditis patients, indicates that codons 45 and 57 are critical features in DQw7 which distinguish it from other DQw specificities. The adjacent DQA1 genes also display a significant association with Hashimoto's thyroiditis (DQA1*0201/*0301 heterozygotes were found in 37% of patients and 15% controls, P less than 0.03). No significant association could be found with polymorphisms of the tumor necrosis factor gene. These results provide a new basis for the concept of genetic susceptibility in Hashimoto's thyroiditis and will help to elucidate the underlying autoimmune mechanisms that lead to disease at the functional level.

Old male rats of 22\p=n-\24 months and young ones of 3\ p=n-\ 5 months were studied to find the effects of ageing, of orchidectomy and of orchidectomy and treatment with testosterone propionate (TP) on the basal serum concentrations of thyrotrophin (TSH) and on the total and free concentrations of tri-iodothyronine (T3) and thyroxine (T4) in the serum. The changes in TSH after treatment with thyrotrophin releasing hormone (TRH) were also observed. Intact old rats had significantly (P < 0\m=.\001) lower basal T4 and T3 as well as lower (P < 0\m=.\05) testosterone concentrations than were present in young rats. They also had higher basal TSH and per cent free T4 but lower absolute free T3 concentrations than had young rats. Two weeks after orchidectomy, basal TSH concentrations were slightly but significantly (P < 0\m=.\05) decreased in both young and old rats while T4 decreased significantly (P < 0\ m=. \ 05) only in the young. The responses of TSH to TRH were also reduced by orchidectomy in both age groups with the old rats being less responsive than the young. Orchidectomy and treatment with pharmacological doses of TP produced similar effects on the pi tui tary\x=req-\ thyrotrophic response for both old and young rats but a greater effect occurred in the basal T4 response in young rats. In all groups basal TSH was influenced by orchidectomy or by treatment with TP but was always higher in the aged rat. Tri-iodothyronine concentration was always lower in the older rat and was not altered by orchidectomy or by treatment with TP in either young or old rats.These results indicate that (1) in the male rat these age-specific effects on the thyroid\p=n-\ pituitary system are probably due, not only to a reduction in thyroid gland function and plasma T4 protein-binding, but also to a concomitant hyporesponsiveness of the aged male rat pituitary thyrotroph to TRH stimulation and (2) there is probably a significant influence of testicular function on the pituitary\p=n-\thyroidsystem of the male rat.