Defective DNA synthesis by T cells in acquired 'common-variable' hypogammaglobulinaemia on stimulation with mitogens

Abstract

We have studied T cell defects in acquired 'common-variable' hypogammaglobulinaemia (CVH) by measuring the synthesis of DNA, RNA and protein in vitro in response to mitogens and to interleukin 2 (IL-2). We have confirmed that some patients have defective DNA synthesis in response to PHA and shown that this extends to responses to cell-derived B cell growth factor (c-BCGF) which is also mitogenic to T cells. DNA synthesis induced by IL-2 was not defective in these patients suggesting IL2-receptor induction is normal. The mitogen-related defect in DNA synthesis was not accompanied by any reduction in synthesis of RNA or of protein. Levels of the rate limiting enzyme (thymidylate synthetase EC 2.1.1.45) responsible for de novo DNA synthesis in the absence of endogenous thymidine were measured following PHA stimulation and found to be in the normal range. In the CVH patients (but not in normal individuals) the relationship between the levels of thymidylate synthetase and DNA synthesis in response to PHA approached significance, suggesting that this pathway becomes more important in CVH patients than in normal individuals perhaps because of defects in the thymidine 'salvage' pathway.