Effect of T-cell deficiency on the formation of periapical lesions in mice: histological comparison between periapical lesion formation in BALB/c and BALB/c nu/nu mice.

The role of T-cells in the development of periapical lesions was investigated immunohistochemically using 16 normal (BALB/c) mice and 16 nude (BALB/c nu/nu) mice (congenitally T-cell-deficient mice). The pulp chambers of maxillar first molars of all mice were opened, and the infiltrated immunocytes (anti-Thy1.2, -Lyt-1, -Lyt-2, -L3T4, -I-Ad, -IgG, and -IgM positive cells) were determined immunohistochemically at 2, 4, 6, and 8 wk after operation. Periapical lesions appeared at 2 wk in both mouse groups. Numerous anti-I-Ad positive-stained cells appeared at 2 wk, anti-I-Ad, -Thy1.2 (-Lyt-1, -L3T4), -IgG positive-stained cells appeared between 4 and 8 wk, and periapical lesions with bone resorption rapidly increased until 4 wk in normal mice. On the other hand in nude mice, only anti-I-Ad and -IgG positive cells were present from 4 to 6 wk, and the progress of periapical lesions with inflammatory cells stopped at 6 wk. Furthermore, numerous fibroblasts were found instead of inflammatory cells at 8 wk. These findings suggest that the progression of periapical lesions with bone resorption required helper T-cells and numerous immunoglobulin-producing cells.

Abnormality of oral ursodeoxycholic acid tolerance test in the Dubin-Johnson syndrome.

Serial measurement of serum bile acid levels before and after oral administration of ursodeoxycholic acid (UDCA) was performed in 10 patients with Dubin-Johnson acid levels were significantly elevated in the patients compared with the controls (p less than 0.05). Oral UDCA tolerance studies revealed impaired bile acid clearance from serum in the patients and showed markedly increased serum bile acid levels 120 min after administration (p less than 0.01). These results indicate that some DJS patients have abnormal bile clearance which may be attributable to defects in hepatic uptake and biliary excretion of bile acids.

Metabolic fate of exogenous delta-aminolevulinic acid in Dubin-Johnson syndrome.

The underlying mechanism of abnormal urinary distribution of CP isomers in DJS is unknown. We administered ALA to DJS patients and carriers as well as to normal controls, and urinary and biliary porphyrins and plasma bilirubin were studied. In sharp contrast to the remarkable increase in urinary CP-III excretion in normal controls (2234 nmol/gm creatinine during the first 2 hr) after ALA, very small increase was observed in DJS patients (19 nmol). In DJS carriers the increase took intermediate values (1122 nmol). The increments in urinary CP-I were smallest in DJS patients, and the peak of its increase was delayed. These data are compatible with the hypothesis that a carrier-mediated mechanism in transporting CP-gen isomers I and III from the liver cells to the plasma may be anomalous in DJS hepatocytes and that the increased urinary CP-I characteristic of DJS may be the result of a disturbance in the uptake process of CP-gen I, derived mainly from the erythropoietic tissues, by DJS liver cells. Although the biliary percent of CP-I in controls decreased after ALA, it remained unchanged in DJS, suggesting the existence of a bile canalicular barrier against CP-gen-III in DJS. The elevated biliary porphyrins and plasma bilirubin after ALA in DJS patients favor an idea that there may be no major enzymatic derangements in the metabolic sequences from ALA to bilirubin. The increased excretion of PP in DJS bile after ALA remained to be explained.

Unconjugated bilirubin kinetics in Dubin-Johnson syndrome.

Plasma unconjugated bilirubin kinetics were studied by a two-compartment analysis in 10 patients with Dubin-Johnson syndrome (DJS) and 7 normal controls. The clearance of unconjugated bilirubin from plasma was significantly reduced in the patients with DJS as compared to the controls (p less than 0.01). Kinetic analysis of plasma disappearance data showed an increase in reflux and decrease in conjugation. These results indicate that defects in both conjugated and unconjugated bilirubin metabolism exist in DJS.

Uroporphyrinogen III cosynthetase in liver and blood in the Dubin-Johnson syndrome.

The activities of uroporphyrinogen III cosynthetase in blood lysates from five patients with the Dubin-Johnson syndrome (DJS) and four control subjects and in liver homogenates from four patients and four control subjects were determined. No significant difference was found in enzyme activity between the two groups in either blood lysate or liver homogenate. These results indicate that low urinary coproporphyrin III output in the DJS is not due to deficiency of uroporphyrinogen III cosynthetase in the liver and the erythropoietic system.

Coproporphyrin isomers in Dubin-Johnson syndrome.

To shed light on the nature of abnormal porphyrin metabolism in Dubin-Johnson syndrome (DJS), coproporphyrin isomer distribution in urine and bile was investigated in carriers and patients with DJS selected from among the families in the cluster area of the syndrome in Japan. Urinary total coproporphyrin content in patients with DJS exceeded that of normal controls (P less than 0.01). However, the increase in urinary excretion of total coproporphyrin was of a much lesser degree compared to a remarkable increase in urinary total coproporphyrin reported for erythropoietic porphyria in which a deficiency of uroporphyrinogen III cosynthetase had been demonstrated. Urinary total coproporphyrin content in carriers was significantly smaller than that of normal controls (P less than 0.05). This paradoxical decrease of urinary total coproporphyrin concentration in DJS carriers was observed in consequence of a decrease in coproporphyrin III excretion without concomitant increase in type I isomer. Administration of griseofulvin, in the dose which had been shown to precipitate attacks of acute porphyria in susceptible subjects, to carriers and patients with DJS did not elicit clinical signs suggestive of porphyria, and urinary total coproporphyrin concentration and the percentage of coproporphyrin I remained unchanged. These results were interpreted to demonstrate an aspect of DJS that was not consistent with the hypothesis that a partial defect in uroporphyrinogen III cosynthetase of the liver might be the cause of DJS. Coproporphyrin in the bile of DJS patients was preponderantly type I.