Elevated Serum Levels of Interleukin-4 and Inteleukin-6 in Patients with Common Variable Immunodeficiency (CVI) Are Associated with Chronic Immune Activation and Low Numbers of CD4 + Lymphocytes

Abstract

Serum immunoreactive interleukin (IL-)1 α, IL-4, IL-6 and tumor necrosis factor (TNF) α were measured in 42 patients with primary hypogammaglobulinemia (25 common variable immunodeficiency (CVI), 10 congenital hypogammaglobulinemia (CH), 7 X-linked agammaglobulinemia (XLA), and in 21 healthy controls. The cytokine levels were correlated to other immunological parameters including serum levels of neopterin and soluble CD8 (sCD8) antigen. IL-6 was detectable in 48% and IL-4 in 36% of the CVI patients, but in none of the controls. Seventy-five percent of the CVI patients with elevated IL-4 levels had detectable IL-6. In contrast, no patients in the XLA group and only three CH patients had detectable IL-4 or IL-6 levels. TNF α and IL-1 α were detected in only a few serum samples with no significant differences between patients and controls. In the CVI group elevated IL-6 levels were significantly associated to reduced numbers of CD4 + and CD19 + lymphocytes, elevated levels of neopterin and sCD8 antigen, and occurrence of splenomegaly and bronchiectasis. The raised IL-6 levels were confirmed in longitudinal testing, probably reflecting a characteristic immunological dysregulation in these patients. Cytokine alterations may play a role in the pathogenesis of the immunodeficiency and for the clinical manifestations in CVI patients. Alternatively, elevated cytokine levels may be only a marker of chronic immune activation, particularly in monocytes, possibly delineating a distinct subgroup of patients within the heterogeneous CVI group.