PERSISTENT ACTIVATION OF THE TUMOR-NECROSIS-FACTOR SYSTEM IN A SUBGROUP OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY-POSSIBLE IMMUNOLOGICAL AND CLINICAL CONSEQUENCES

In patients with common variable immunodeficiency (CVI), we have previ ously defined a subgroup of patients (CVIHyper) characterized by decre ased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, an d persistent immune activation in vivo, particularly of monocytes/macr ophages. To further characterize this hyperactivity, parameters of act ivation of the tumor necrosis factor (TNF) system (TNF alpha and solub le TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 2 0 healthy controls. Patients with CVI had significantly higher serum l evels of TNF alpha and both types of sTNFRs, with the highest levels i n the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purifled monocytes from CVIHyper patients spontaneously rel eased significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75- TNFR than cells from both other CVI patients and healthy controls. CVI Hyper patients also had significantly higher TNF alpha:sTNFRs ratios i n both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, p articularly in the CVIHyper subgroup. This activation may contribute t o the pathogenesis of both clinical and immunologic manifestations in CVI. (C) 1996 by The American Society of Hematology.