Are we beginning to understand how PML develops in MSers on natalizumab? #MSBlog #MSResearch
“The following paper may prove to be important and needs to be repeated. Bone marrow stem cells, which are responsible for making blood cells, are kept in their niche, or factory, by adhesion molecules (biological velcro). Natalizumab makes this velcro malfunction and some of these stem cells are released into the peripheral blood. They are detected in the blood as they express on their surface a marker, or label, called CD34. These stem cells can migrate to other areas of the body, including the brain. Why is this important? This study shows that when you collect stem cells from MSers on natalizumab 31% had JC virus inside them compared to only 6% of healthy controls. Similarly, 24% of MSers had JCV in their B cells (CD19-positive cells) compared to 0% of healthy controls. Could natalizumab be mobilizing cells infected with JCV from the bone marrow and turning them into trojan horses? Once these cells enter the brain they may release their deadly cargo and set-up infection with JCV that leads to PML.”
|Trojan horse theory of PML
“This is a nice theory, but it is very speculative, and unproven. For JCV to cause PML it needs to undergo several mutations in its surface proteins that allow it to infect glial cells within the brain. In addition, it also acquires mutations in genes that regulate itself virus. These mutations suggest that the virus is being selected by some evolutionary selection process that allows it to infect glials cells and cause PML. In which compartment is this evolutionary selection occurring? I suspect it may be in the brain compartment, but I have no evidence to prove it. Why do I think this? I think this because the glials cells (oligodendrocytes and astrocytes) that the virus infects are in the brain and the virus may need them for this evolutionary selection; i.e. the cells are used as fertilizer to give the mutants a survival advantage. If a new mutant is able to bind to a glial cell it is more likely to survive, or hide, from the immune system if it cannot bind to these cells. After several rounds of mutation and alteration in its regulation we have a killer virus that can cause PML. If I am correct then PML, or pre-PML, may start many months or years before PML actually presents. This is why we need to be very cautious about what drugs we use after natalizumab in MSers at high-risk of PML. We don’t want to use drugs that are potent immunosuppressive agents and can’t be reversed. Why? If you develop carry-over PML from being on natalizumab you need a fully functioning immune system to recover from PML. If the new drug you are taking prevents your immune system from responding to the virus the outcome is likely to be fatal. This is why I am reluctant to recommend switching from natalizumab to alemtuzumab without a washout period that is long enough to make sure there is no carry-over PML. How long should this period be? I have no idea, but until we find out I would suggest a 6-12 month period on a non-induction therapy drug, e.g. fingolimod or DMF.”
“You will notice that one MSer in this study had virus detected in their body and was JCV seronegative; i..e they had the virus and no antibodies. Importantly in this study the antibodies were checked using a 1-step and 2-step assay. This suggests that either the detection of the virus was a false-positive result, or the detection of antibodies was a false-negative result, or it means you can be infected with the virus and have no antibodies. An explanation needs to found as this has implications for MSers on natalizumab who are JCV seronegative. Fortunately, this scenario is rare and should not affect our counselling at this stage.”
“A very interesting study!”
Epub: Frohman et al. JC Virus in CD34+ and CD19+ Cells in Patients With Multiple Sclerosis Treated With Natalizumab. JAMA Neurol. 2014 Mar 24. doi: 10.1001/jamaneurol.2014.63.
IMPORTANCE: Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in MSers who are treated with natalizumab.
OBJECTIVE: To determine whether mononuclear cells in circulation from MSers treated with natalizumab harbor JCV DNA.
RESULTS: Thirteen of the 26 MSers (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MSers (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers had virus in CD34+ cells and none in CD19+ cells. Nine MSers and 1 healthy volunteer had virus (viremic) but had seronegative test results for JCV antibodies.
CONCLUSIONS AND RELEVANCE: JC virus DNA was detectable within cell compartments of natalizumab-treated MSers after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.