Immunoregulatory abnormalities in patients with Epstein-Barr virus-associated B cell lymphoproliferative disorders

EBVirus-associated B cell lymphoproliferative disorder (BLPD) is a recognized complication of primary immunodeficiency and organ as well as bone marrow transplantation. Although the nature of the immune defects that predispose to the development of BLPD are unknown, it is postulated that aberrant T cell responses are involved. It is our hypothesis that unbalanced lymphokine production is a major contributory factor to abnormal B cell growth in response to EBV, resulting in BLPD. Since IFN-alpha and IL-4 are important regulators of B cell proliferation and also regulate the synthesis of IgE, we determined serum levels of IFN-alpha, IL-4, and IgE in 8 patients with newly diagnosed BLPD. Comparison was made to healthy recipients of organ transplants on immunosuppressive therapy without BLPD, and normal EBV seropositive controls. Levels of serum IL-4 were significantly elevated in both patients with BLPD as well as in healthy immunosuppressed organ transplant recipients as compared with normal healthy individuals. Patients with BLPD exhibited a combination of significantly lower levels of serum IFN-alpha, and significantly higher levels of serum IgE than either healthy EBV seropositive individuals or healthy recipients of organ transplants on immunosuppressive therapy. These results suggest that imbalance in the proportions of circulating cytokines favoring B cell proliferation may be contributing to the development of EBV-associated BLPD. The potential significance of the finding of low IFN-alpha in patients who develop BLPD is exemplified by our recent success in the treatment of BLPD with IFN-alpha and intravenous IgG.