B cell proliferation is impaired in patients with chronic renal failure, but the mechanisms underlying this defect are not known. Lymphocytes have receptors for parathyroid hormone, and it is possible that the state of secondary hyperparathyroidism of renal failure is responsible for the B cell defect. Our studies were designed to (a) examine T cell-independent B cell proliferation ((H-3)thymidine incorporation) induced by Staphylococcus aureus Cowan 1 after 5 days of culture, (b) evaluate the effect of parathyroid hormone on S. aureus Cowan I-induced B cell proliferation, and (c) investigate the mechanisms through which parathyroid hormone may exert its effect on B cell proliferation. Lymphocytes were obtained from 37 normal subjects and 21 dialysis patients. S. aureus Cowan I induced significant stimulation (P < 0.01) of the proliferation of B cells from both groups, but the effect was smaller on B cells from dialysis patients (10.0 x 10(3) +/- 1.4 x 10(3) cpm) than on those from normal subjects (21.8 x 10(3) +/- 2.0 x 10(3) cpm). Both the intact molecule of parathyroid hormone (1-84 PTH) and its amino-terminal fragment (1-34 PTH) caused significant inhibition of proliferation of B cells from normal subjects in a dose-dependent manner, with the effect being significantly greater (P < 0.01) with an equimolar concentration of 1-84 PTH than that of 1-34 PTH. Inactivation of 1-84 PTH by oxidation abolished most of its inhibitory effect on B cell proliferation. The effect of 1-84 PTH was significantly greater (P < 0.05) on proliferation of B cells from normal subjects (-58.4 +/- 2.5%) than on B cells from dialysis patients (-47.4 +/- 3.9%). There was a significant (P < 0.01) inverse relationship between the blood levels of parathyroid hormone in the patients and the magnitude of the in vitro inhibition of B cell proliferation by parathyroid hormone. 1-84 PTH produced significant stimulation (P < 0.01) of cAMP production by B cells from normal subjects. Both forskolin and cholera toxin, agents that elevate levels of cAMP, also produced significant inhibition (P < 0.01) of S. aureus Cowan I-induced B cell proliferation. In contrast to the different effects of parathyroid hormone on the proliferation of B cells from normal subjects and dialysis patients, the actions of forskolin and cholera toxin on proliferation of B cells from these two groups were not different. The results indicate that (a) B cells are a target for parathyroid hormone action, and these cells may have receptors for the hormone (b) the inhibitory effect of parathyroid hormone on B cell proliferation is most likely mediated by the stimulation of cAMP production; and (c) the lesser effect of parathyroid hormone on the proliferation of B cells from dialysis patients could be due to desensitization and/or downregulation of parathyroid hormone receptors on B cells. The results are consistent with the notion that the impaired proliferation of B cells in patients with chronic renal failure is, at least in part, due to the state of secondary hyperparathyroidism in these patients. Our data assign a new role for excess parathyroid hormone in the genesis of the uremic syndrome.
