Hodgkin twins: double good, double trouble

In this issue of Blood, Cozen and colleagues report on cytokine levels and the presence of a genetic polymorphism in the twins of patients with young-adult Hodgkin lymphoma. The analysis focuses on interleukin-12 in monozygotic twins, dizygotic twins, and control donors. The results suggest an interesting hypothesis that builds on the “polio” and “hygiene” hypotheses that have previously been offered to explain the epidemiology of young-adult Hodgkin lymphoma.

The higher incidence of young-adult Hodgkin lymphoma in more affluent populations with smaller family sizes has long attracted the interest of epidemiologists. In the prevaccine era, poliomyelitis, the devastating consequence of poliovirus infection, was much more common in those who were infected in adolescence or early adulthood rather than in those infected in early childhood, during which the major manifestation of poliovirus infection was a diarrheal illness. It was proposed that the age-incidence curve of Hodgkin lymphoma in Western countries, with a young-adult peak, might also reflect the consequence of a common infection that was delayed until adolescence or early adulthood.^1,2  When Epstein-Barr virus DNA was found to be present in the tumor cells of a subset of Hodgkin lymphoma patients, it appeared that this ubiquitous viral infection might explain the epidemiology of young-adult Hodgkin lymphoma. However, although there is a clear link between symptomatic infectious mononucleosis and Hodgkin lymphoma, the link is only between infectious mononucleosis and EBV⁺ Hodgkin lymphoma. EBV⁻ Hodgkin lymphoma appears not to be increased in people with a history of infectious mononucleosis.³  And since most young-adult Hodgkin lymphoma is EBV⁻, further explanations were needed.⁴ 

Enter the “hygiene” hypothesis. Originally invoked to explain an increased susceptibility to allergic diseases, this hypothesis holds that lack of early childhood exposure to a variety of infectious agents perturbs immune development in a sometimes deleterious way. Could immune dysfunction related to exposure to childhood pathogens be important in the development of Hodgkin disease? Cozen and colleagues had previously used a remarkable twin registry to demonstrate a genetic susceptibility to Hodgkin lymphoma.⁵  In the present report, Cozen et al return to their twin registries, now reporting that low levels of IL-12 may be a risk factor for Hodgkin lymphoma and that IL-12 levels may be determined by exposure to a variety of childhood infections and host genetics. So far, double good.

There is, however, double trouble. Although the authors studied cytokine production and genetic polymorphism in the same subjects, they are unable to link the 2 sets of data. The consent form used to collect blood specimens did not mention genetic analyses, and in order to study genetics, it was necessary to break linkages. Although cytokine production analysis and genetic analysis would seem to support the general hypothesis offered, there remains the possibility that, if the data were linked, the IL-12 levels might not be associated with the genetic polymorphism, or that the association might be the inverse of what the investigators anticipated. Thus the investigators have offered an interesting hypothesis to explain aspects of the epidemiology of young-adult Hodgkin lymphoma. However, the case is not yet closed, and Hodgkin investigators will have to redouble their efforts in the future.