Quite a storm has been raised by a paper in Blood from Alan Rickinson's unit in Birmingham. I have known Alan for about 30 years. He runs the premier Herpes virus lab in the UK. Herpes viruses include Herpes Simplex, Zoster, CMV and Epstein-Barr virus. Epstein was Professor of Pathology in Bristol when I was a medical student and a junior doctor.
Herpes viruses have this in common: once you have them, you never lose them. CLL patients will know that they are prone to shingles attacks. Most people have chicken-pox as children - it's caused by the same virus. After recovery from chicken-pox the virus lodges in the spinal cord and at times of immunodeficiency (or other 'stress') it migrates down a peripheral nerve to infect the skin covered by that nerve. Likewise, as those who suffer from cold sores can testify, being 'run-down', getting a cold or exposure to sunlight can awaken the sleeping virus around the mouth.
I have been interested in EBV for many years and have written a few papers about it. In one of them I postulated that patients reacted to the infection in different ways, some made a rapid recovery, some a slow recovery and some kept getting recurrent symptoms. We were able to show a difference between T cell receptors in the different groups. Of course, in 1983 the methods were unbelievably crude compared with what can be done today, but I was interested to read the paper by Sauce et al in Blood . They studied the IL-7 and IL-15 receptors on CD8+ T cells in patients who had EBV infections.
Interleukin-7 and interleukin-15 are both pro-inflammatory cytokines, both having many targets and functions, but united in their ability to support and activate CD8+ cytotoxic T lymphocytes (CTL), the cells believed to be responsible for killing both tumor cells and virus infected cells. CD8+ T cells have receptors for both cytokines on their surface. These receptors are complicated affairs. In common with IL-2 and IL-12 they both use the common gamma chain as part of the receptor. This is what is missing in those 'boys in the bubble' who suffer from severe immunodeficiency syndrome (SIDS), and who have recently been treated by gene therapy (three of who have subsequently developed a T-cell leukemia). In the case of the IL-15 receptor it also shares the beta subunit with the IL-2 receptor, but also has a private alpha chain that is wholly its own. IL-7 on the other hand has only one other chain, an alpha chain that at least has a number, CD127.
Signaling through these receptors makes use of the JAK-STAT pathway. (Some may be familiar with this from all the publicity about JAK2 mutations in patients with polycythemia; in this case JAK1 or JAK3 are involved rather than JAK2). In mice both the IL-7 and IL-15 receptors are altered in response to a viral infection, IL-15R being upregulated and IL-7R being downregulated. The Birmingham study looked at these receptors in patients who had glandular fever.
Strictly speaking glandular fever and infections mononucleosis may not be quite the same thing, but the terms are used interchangeably. Glandular fever refers to the enlarged lymph nodes in the neck together with the fever; infectious mononucleosis refers to the presence in the blood of large numbers of mononuclear cells, which are now known to be CD8+ CTLs reacting to virally infected B cells. Although EBV is the commonest cause of this syndrome other viruses like CMV can produce a similar disease, as can the protozoan toxoplasma gondii.
They followed patients who developed glandular fever over a two year period. At first the T cells had no IL-7R alpha, but as time past this receptor appeared and after 2 years the level was back to normal. In contrast, the IL-15R alpha chain not only disappeared with the infection, but remained absent 2 years later. They were also able to study individuals in whom there was serological evidence of an EBV infection, but no history of any clinical disease - people who had had a silent infection. These individuals had normal levels of both IL-7R and IL-15R.
Thus the suggestion is that people who have glandular fever damage their CTLs for at least 2 years after the event, whereas those who have a subclinical infection with EBV recover normal CTLs. Is this defect permanent? It may be, though the evidence for this is not clear. One individual who had had glandular fever 14 years previously still had the IL-15R alpha defect, and there may be others in whom the effect was long lasting, but we are not given details in the paper. Is it specific for EBV? It would seem so because patients whose infectious mononucleosis was caused by CMV recover their IL-15R in a parallel way to the recovery of the IL-7R. Was there a defect in IL-15R in the first place that caused the patient to have a clinical rather than sub-clinical infection? That's a possibility because they were not able to study any of the patients' T cells from before their infection, but they did look at 30 individuals who had never been exposed to EBV and all of these had normal expression of IL-15R alpha. It would be very unlikely that there is a population of IL-15R alpha deficient individuals waiting to get a severe attack of glandular fever that would not be detected among 30 normal individuals.
Does the loss of the receptor matter? They did experiments to show that loss of receptor correlates with loss of function. Cells that lacked IL-15R alpha were 20 times less responsive to IL-15 than normal cells.
What does it all mean? It looks as though transient down regulation of IL-7 and IL-15 alpha receptors is a normal physiological response to viral infection and there for a purpose. The idea is that it regulates the response to that particular virus, so that the whole T cell repertoire isn't subverted by the immune response by non-specific cytokine stimulation, only those T cells designed to react with the particular virus. But in infectious mononucleosis the IL-15R alpha fails to recover even after many years. Does this matter? In mice this defect can be by-passed by monocytes capturing the IL-15 on their surface and presenting it to CD8+ T cells via the IL-15 beta and gamma receptor sub-units which are not affected by the virus infection. There is evidence that this does not happen in humans.
We do know, however, that post-IM patients maintain high levels of EBV-specific CD8+ T cells in their circulation and that these cells lack IL-15R alpha. Often patients continue to shed virus long after the attack and sometimes there are clinical recurrences. It seems that there is a precarious balance between virus and host after an attack.
We also know that in instances of immunosuppression EBV-related lymphomas may occur (after stem cell transplant or indeed any type of transplant, or after fludarabine or Campath). In Richter's syndrome EBV is often implicated. However, without such immunosuppression EBV-related lymphomas are not known to occur.
CLL Forum has wondered whether CLL might occur more frequently in people who have had a clinical rather than subclinical attack of EBV infection. They are conducting a survey. However, these sorts of data are very difficult to determine and interpret. Patients often believe that they have had glandular fever but never had a blood test to confirm it. Doctors sometimes tell patients that they have had glandular fever to fob them off. Patients with CLL need an explanation and their memories may deceive them. The comparator is difficult to assess. Normal individuals forget particular infections. I can't remember whether I have had mumps or not. Sore throats often go uninvestigated.
Although this story is stimulating and interesting, it is premature to draw conclusions just yet.