The kiss that scars

Comment on Sauce et al, page 11

In their article in this issue, Sauce and colleagues report that the syndrome of acute infectious mononucleosis leaves an immune scar that endures for years.

The syndrome of acute infectious mononucleosis (pharyngitis, fever, activated lymphocytosis) and its mode of transmission (kissing) were recognized long before the etiologic agent, Epstein-Barr virus (EBV), was first identified. Although the syndrome is common, the virus is much more common and asymptomatic infection is the rule. People with a history of acute infectious mononucleosis lack T cells expressing IL-15Rα. Other infections are associated with temporary depletion of IL-15Rα and IL-7Rα, but over time there is recovery. Only EBV-associated infectious mononucleosis—and not asymptomatic primary infection and not a similar symptomatic primary infection associated with cytomegalovirus—leads to this particular scar. Other investigators have failed to identify immunologic parameters that distinguish people with history of asymptomatic versus symptomatic primary infection.¹ 

EBV has been linked with a multitude of disorders including lymphoma, carcinoma, and a variety of autoimmune disorders that occur months or years after the acute phase of the infection. Hodgkin disease is of special interest here because it has been linked to the virus (viral DNA, RNA, and proteins are readily detected in at least a third of cases in tumor cells), and the syndrome per se is linked to the tumor. Thus, laboratory-confirmed symptomatic infectious mononucleosis is associated with an increased risk of developing EBV-associated Hodgkin disease.² 

But we know very little of the determinants of symptomatic infection. Are age of the host, the size of the viral innoculum, the strain or strains of infecting virus, or host genetics important determinants? Can symptomatic infection and its consequences be altered? These questions are very much at the forefront in research and clinical care. A vaccine designed to modify the natural history of primary infection in seronegative university students is presently in trials in Belgium.³  In patients with a special susceptibility to fatal primary EBV infection (X-linked lymphoproliferative syndrome), the use of rituximab at the first sign of infection may have blunted the course of the illness.⁴  A multitude of other approaches to treating EBV-associated Hodgkin disease, including the use adoptive T-cell therapy and therapeutic vaccines designed to target cells expressing particular viral antigens, are being explored.

The present report offers the possibility of an immunologic handle on the consequences of symptomatic infection versus asymptomatic infection. Questions brought to mind include the following: Do patients with a variety of diseases show the scar described in the present paper (EBV-Hodgkin, other EBV-associated tumors, multiple sclerosis, lupus, etc)? Do interventions such as vaccines, chemotherapies, anti-inflammatories, or adoptive cellular therapies change the long-term manifestations in terms of IL-15Rα-bearing T cells? Will such changes alter disease associations? ▪