Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency - Possible immunologic and clinical consequences

Abstract

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVI(Hyper)) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNFα and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNFα and both types of sTNFRs, with the highest levels in the CVI(Hyper) subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVI(Hyper) patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNFα and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVI(Hyper) patients also had significantly higher TNFα:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVI(Hyper) subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.