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I've posted some key sections below.
Basically, the study suggests the severe symptoms in mono result not from an "abnormal" immune response, but rather from the high proportion of latently infected B cells at that time that are going into their lytic cycle (active replication) and subsequently dying.
The idea is that in the early stages of mono symptoms, a huge number of B cells are doing this. Then fewer, then fewer still, till eventually the number is sufficiently low that you're asymptomatic.
This is really different from the conventional account, which is that people with severe mono essentially "overreact" to the infection, mobilising too many T cells and expanding their numbers too fast.
Now, imagine if some of these people manage to contain the initial lytic replciation, but still have a high viral load (lots of latently infected B cells). They might be fine till another infection comes along, which might provide a trigger towards more lytic replication. Then the cycle starts again, and again and so on... it starts to look like ME.
Its relevant to ME because:
* Early antiviral studies suggested that in some cases of ME, there might be a higher-than-normal proportion of B cells latently infected with EBV. But later researchers came to doubt this, because almost everyone carries EBV latently infected B cells, and they're not sick. So came the idea that its not the infection itself, but rather our abnormal immune response to it that causes the problem. This article suggests that the two might be linked after all.
* It could be extended to any virus that has latent and lytic phases. Like enteroviruses? But the triggering factors could be different.
I like it because:
*Its never made sense to me what sustains our "abnormal immune response". I understand that an abnormal immune event might lead to others further down the line, but eventually, the effects would diminish, if only because T cells are being constantly replaced. A latent virus provides a mechanism for sustaining the process indefinitely.
* There's a big danger that if the abnormal immune response account is wrong, then we might end up treating the reaction, not the problem. That could end up making things worse. So if there is a virus at the bottom of all this, we need to know.
What I don't so much like about it:
*Where is the evidence of lytic replication in ME? I suppose we might be largely succesfull at aborting the full relicaiton cycle (abortive replication, as Glaser and Lerner believe). But as @Butydoc points out, shouldn't we be able to detect some of the waste products of this kind of major event?
*At best, it could surely only account for some cases.
* The account they offer of multiple sclerosis seems dodgy - why would the byproducts of this war between the virus and the immune system predispose to autoimmunity? It seems more likely to me that the latently infected B cells have a more direct role here.
Hadinoto, V., Shapiro, M., Greenough, T. C., Sullivan, J. L., Luzuriaga, K., & Thorley-Lawson, D. A. (2008). On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood, 111(3), 1420-1427.
Our data show conclusively that by the time the clinical symptoms of AIM (actue infectious mononucleosis) arise, the level of mBLats (Memory B cells latently infected with Epstein-Barr virus) is always rapidly decreasing. Therefore, the emergence of clinical symptoms coincides with the massive cell death associated with the exponential decay of mBLats, not with infection per se. In this study, we have proposed that this death is associated with homeostatic culling by apoptosis, which in turn triggers entry into viral replication. It is conceivable therefore that the difference between asymptomatic primary EBV infection and AIM in adults is the extent to which the dying mBLats initiate viral replication. These ideas cast doubt on the findings of Silins et al28 who claimed that the main difference between symptomatic and asymptomatic primary EBV infection lies not in the levels of infected cells but in the extent to which T cells are mobilized and expanded. However, they measured viral loads at the peak of infection for asymptomatic patients (ie, the appearance of antiviral antibodies) but past the peak for AIM patients (ie, the time when clinical symptoms arise). Had they measured viral loads at the peak for AIM patients they would have found consistently higher viral loads than in the asymptomatic carriers.
….
EBV infection and AIM in particular are risk factors for several important diseases, including Hodgkin disease8 and multiple sclerosis.5 It has also been suggested that AIM permanently impacts the immune system.4 We have proposed that AIM symptoms are coincidental with the rapid destruction by CTLIEs of mBLats as they enter into viral replication. Since up to 50% of mBLats are latently infected at the peak of infection and their half-life is approximately 7 days, this implies that 50% of mBLats, constituting 25% of the entire memory B-cell compartment, may be destroyed in 1 week at the height of the infection. This constitutes a massive, continuous deposition of cellular and viral antigens into the system. This action could be what is responsible for the long-term damage inflicted on the immune system and the predisposing factor for the AIM-associated diseases.
We conclude that by the time AIM patients arrive at the clinic the immune response has already minimized the cycles of reactivation and infection of new B cells, leaving the high levels of mBLats in the blood to simply decay through reactivation of viral lytic replication until a low-level equilibrium is attained. This culling process may be initiated by the same processes that regulate the normal half-life of memory B cells.
Basically, the study suggests the severe symptoms in mono result not from an "abnormal" immune response, but rather from the high proportion of latently infected B cells at that time that are going into their lytic cycle (active replication) and subsequently dying.
The idea is that in the early stages of mono symptoms, a huge number of B cells are doing this. Then fewer, then fewer still, till eventually the number is sufficiently low that you're asymptomatic.
This is really different from the conventional account, which is that people with severe mono essentially "overreact" to the infection, mobilising too many T cells and expanding their numbers too fast.
Now, imagine if some of these people manage to contain the initial lytic replciation, but still have a high viral load (lots of latently infected B cells). They might be fine till another infection comes along, which might provide a trigger towards more lytic replication. Then the cycle starts again, and again and so on... it starts to look like ME.
Its relevant to ME because:
* Early antiviral studies suggested that in some cases of ME, there might be a higher-than-normal proportion of B cells latently infected with EBV. But later researchers came to doubt this, because almost everyone carries EBV latently infected B cells, and they're not sick. So came the idea that its not the infection itself, but rather our abnormal immune response to it that causes the problem. This article suggests that the two might be linked after all.
* It could be extended to any virus that has latent and lytic phases. Like enteroviruses? But the triggering factors could be different.
I like it because:
*Its never made sense to me what sustains our "abnormal immune response". I understand that an abnormal immune event might lead to others further down the line, but eventually, the effects would diminish, if only because T cells are being constantly replaced. A latent virus provides a mechanism for sustaining the process indefinitely.
* There's a big danger that if the abnormal immune response account is wrong, then we might end up treating the reaction, not the problem. That could end up making things worse. So if there is a virus at the bottom of all this, we need to know.
What I don't so much like about it:
*Where is the evidence of lytic replication in ME? I suppose we might be largely succesfull at aborting the full relicaiton cycle (abortive replication, as Glaser and Lerner believe). But as @Butydoc points out, shouldn't we be able to detect some of the waste products of this kind of major event?
*At best, it could surely only account for some cases.
* The account they offer of multiple sclerosis seems dodgy - why would the byproducts of this war between the virus and the immune system predispose to autoimmunity? It seems more likely to me that the latently infected B cells have a more direct role here.
Hadinoto, V., Shapiro, M., Greenough, T. C., Sullivan, J. L., Luzuriaga, K., & Thorley-Lawson, D. A. (2008). On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood, 111(3), 1420-1427.
Our data show conclusively that by the time the clinical symptoms of AIM (actue infectious mononucleosis) arise, the level of mBLats (Memory B cells latently infected with Epstein-Barr virus) is always rapidly decreasing. Therefore, the emergence of clinical symptoms coincides with the massive cell death associated with the exponential decay of mBLats, not with infection per se. In this study, we have proposed that this death is associated with homeostatic culling by apoptosis, which in turn triggers entry into viral replication. It is conceivable therefore that the difference between asymptomatic primary EBV infection and AIM in adults is the extent to which the dying mBLats initiate viral replication. These ideas cast doubt on the findings of Silins et al28 who claimed that the main difference between symptomatic and asymptomatic primary EBV infection lies not in the levels of infected cells but in the extent to which T cells are mobilized and expanded. However, they measured viral loads at the peak of infection for asymptomatic patients (ie, the appearance of antiviral antibodies) but past the peak for AIM patients (ie, the time when clinical symptoms arise). Had they measured viral loads at the peak for AIM patients they would have found consistently higher viral loads than in the asymptomatic carriers.
….
EBV infection and AIM in particular are risk factors for several important diseases, including Hodgkin disease8 and multiple sclerosis.5 It has also been suggested that AIM permanently impacts the immune system.4 We have proposed that AIM symptoms are coincidental with the rapid destruction by CTLIEs of mBLats as they enter into viral replication. Since up to 50% of mBLats are latently infected at the peak of infection and their half-life is approximately 7 days, this implies that 50% of mBLats, constituting 25% of the entire memory B-cell compartment, may be destroyed in 1 week at the height of the infection. This constitutes a massive, continuous deposition of cellular and viral antigens into the system. This action could be what is responsible for the long-term damage inflicted on the immune system and the predisposing factor for the AIM-associated diseases.
We conclude that by the time AIM patients arrive at the clinic the immune response has already minimized the cycles of reactivation and infection of new B cells, leaving the high levels of mBLats in the blood to simply decay through reactivation of viral lytic replication until a low-level equilibrium is attained. This culling process may be initiated by the same processes that regulate the normal half-life of memory B cells.