Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3 in clinically healthy individuals.

An important unanswered question in clinical immunology is why the histocompatibility antigens HLA-B8/DR3 should be associated with at least nine quite different immune-mediated diseases. The purpose of this study was to examine the mechanism of an immunologic abnormality, commonly found in healthy individuals with HLA-DR3, that may reflect an immune defect predisposing to autoimmunity. Fourteen healthy subjects with HLA-DR3 had a proliferative response to a suboptimal concentration of PHA nearly eight-fold lower than that observed in 10 individuals without this HLA antigen. Impaired responsiveness to PHA was more strongly associated with HLA-DR3 than with HLA-B8. The IL-2 concentration in mitogen-stimulated cultures was similarly decreased in subjects with HLA-DR3 and was highly predictive of the proliferative response 24 h later (r = 0.82, P less than 0.0001). Inhibition of IL-2 utilization by anti-IL-2 receptor antibody indicated that the reduced IL-2 concentration reflects impaired lymphokine production rather than increased utilization. Expression of IL-2 receptors is decreased in these subjects, although the magnitude of their proliferative response is appropriate for the available lymphokine. These results indicate that impaired lymphocyte activation associated with HLA-DR3 reflects impaired IL-2 production and an abnormality of activation events preceding the production of this lymphokine.