Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3: role of interleukin-1

Abstract

Lymphocytes from normal individuals with the histocompatibility antigens HLA-B8 and DR3 have impaired proliferative responses when stimulated with suboptimal concentrations of mitogens. We have previously shown that an important factor in the impaired response is a failure to produce normal quantities of interleukin-2 (IL-2). To examine the mechanism of decreased responsiveness further, we measured interleukin-1 (IL-1) production of low responder subjects compared with controls. The peripheral blood mononuelear cells of five low responder individuals with HLA-B8/ DR3 stimulated with 0.05 μg/ml of phytohaemagglutinin (PHA) accumulated only 0.036 U/ml of IL-I compared with 0.32 U/ml for normal respondcrs. There was a highly significant correlation between the PHA-stimulated IL-1 concentration at 12 h and the subsequent IL-2 concentration at 48 h (r=0.89, P<0.000l) suggesting a role of decreased IL-1 production in the impaired response. A study of unfractionated or column-fractionated culture supernatants revealed no evidence that the decreased IL-1 activity in the supernatants of low responder subjects was related to increased IL-1 inhibitor concentrations. These results suggest that impaired IL-2 production and lymphocyte proliferation in healthy subjects with HLA-B8/DR3 may be mediated at least in part by decreased IL-1 production, and implicates a defect of a very early event in lymphocyte activation.