Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in mice

[Christopher]

2012 February 17

B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313622/

 

[Christopher]

In infected individuals, EBV acquires a “dormant” state in a minute fraction of B cells and persists for life. Under conditions of immunosuppression, the virus can spread from these few cells, resulting in explosive expansion of infected B cells and their malignant transformation, as seen in pathologies such as post-transplant lymphoproliferative disorder (PTLD) and AIDS-associated B cell lymphoma (Kutok and Wang, 2006).

 

[Christopher]

Ian Lipkin:

Now, with respect to polyclonal B cell reactivity, as I mentioned in the very beginning, in work that we published in the 1990’s that is Birgitte Evengård, and I published together, we found evidence of polyclonal B cell reactivity and at that point, we described in the final paragraph of the paper we wrote, and we describe specifically as to whether borna virus could be implicated in Chronic Fatigue Syndrome, we said, in fact, that we were unable to find any evidence of that, genetic or antibody based; but at that point, as many of you will recall, there was a very strong sentiment in some portions of the scientific and clinical communities, not all of it, but in some portions of the community, that this is a psychological illness. And what I said was that, based on our findings, we had very strong evidence that people with Chronic Fatigue Syndrome were ill. It was a real, physical illness, and they deserved a deep dive to find out why they were ill. This was back… you know, we wrote this paper in 1997, a long time ago, and I am now pleased to see that people are paying much more attention to this disorder and what we can do about it.


That said, our evidence suggests, based on the cytokines that I’ve described to you, that there is, in fact, ongoing stimulus to the immune system which results in activation and may well account for many of the symptoms associated with the disease.


The challenge, as I’ve said, is that we have no resources to go after identifying what it is that is stimulating these responses. So, again, I think it is critical that you apply pressure on your congressmen and your senators to generate more research funding for Chronic Fatigue Syndrome research, and if you have the means yourself to do something about this, that you become invested in it because we are partners in this thing. We cannot do this work without your support. We do not have the resources to do what is required. I remember in the very early days of HIV/AIDS when I was still a trainee at the CSF in fact, it was very early days. And in those days there was very little support for HIV/AIDS. It really took advocacy to force that.


Now you’ve got a number of people who are very receptive to this. Tom Frieden is receptive to it. Tony Fauci is receptive to it. But their hands are tied right now because of sequestration. So it is important to that you do something to propose additional resources be allocated to the National Institutes of Health, the Centers for Disease Control, so that this work can proceed, and so that we can get the answer that we need.

http://www.mecfsforums.com/wiki/Lipkin_presentation,_CDC_Conference_Call_9/10/2013

 

[anciendaze]

Please note that those lymphoproliferative disorders are much more severe than ME/CFS. In our case we are probably looking at a pathological process which has not yet breached the last firewall. What I've said elsewhere is that a process which is able to exploit clonal expansion may evade both immune response and standard measures of viral load.

General measures of immune function may not show anything, but it is possible for specific immune response to a particular pathogen to become crippled. The only way around this is detailed examination of precisely what is taking place in immune response to specific challenges. These tests have been avoided almost completely. The idea has been to find some marker which would distinguish patients from controls without any serious thinking. This is unlikely to be available.

The immune system is about the best example I can think of a system with complex dynamics. It is complex both in having many components, and in having complicated behavior. There is unlikely to be anything which will allow you to wait six months after a major immune challenge and easily differentiate patients from controls. This is about the point where immune tolerance sets in. In effect the immune system gives up, and throttles back in order to avoid doing more damage itself. In those disorders called autoimmune, this tolerance is inadequate.

There is evidence of higher levels of common infectious agents in patients with autoimmune disorders at the same time autoantibodies are present. It is not so much too much or too little as misdirected response. This has suggested to me that we should be looking for defective specific immune response to common pathogens which are acting to protect themselves.

You don't have to believe these are conscious decisions. (Indeed, the pathogens may not be alive, as viruses are not.) What happens is that they randomly try every strategy possible, and those which get lucky survive. Only a tiny percentage of virions get lucky.

The problem with virtually all previous investigation of immune dysfunction in ME/CFS is that it takes a static view of a very dynamic system. There are abundant reports that patients fail to "bounce back" from things as simple as a few minutes of exercise, or a common cold. (I can report feeling "wiped out" for three days after a glucose tolerance test, and staying awake for 48 hours after a shot of prednisone.) There are plenty of reports here of people fighting to maintain synchronization with day and night. These things are commonly ascribed to endocrine function, but the line between endocrine and immune system response is especially fuzzy. All these reports seem to either fall on deaf ears, or end up in the bit bucket.

Research on immune function in ME/CFS will not go anywhere in particular until we start doing more than looking at group averages at a single point in time. If you are investigating dynamics you absolutely must consider rates of change. Analysis of response to perturbations is also an old way of testing dynamics. (There are some fairly amusing stories about testing the dynamics of airplanes by kicking rudder pedals at different speeds. There was a time when engineers went along for the flight, and parachutes were de rigueur.) This is not special pleading for a single disease, it is the product of wide experience with systems where dynamics are important.

While I will defer to doctor Lipkin on research politics, I am less impressed than he with people being "receptive" to ideas. (Perhaps it comes from painful personal experience with venture capitalists.)

I'm afraid those individuals in question were around and even powerful when psychological explanations were wildly proliferating at NIH and CDC. They seem most receptive to ideas which will allow them to use expendable auxiliary troops to break budget deadlocks without risking any current funding. There are military parallels going back at least to Hannibal.

The problem is that the best predictor of future research funding is simply the number of researchers who have benefited from past funding. These naturally form self-perpetuating lobbies. I might suggest cutting any number of really dubious investigations which have had a decade or more to demonstrate some potential for changing medicine, and failed. These will all have stakeholders. Funding is important, but changing medicine is absolutely certain to upset any number of people. Any lasting institution ultimately concentrates on maintaining funding while avoiding change.

I don't expect "working within the system" to accomplish great things.

 

[lansbergen]

You don't have to believe these are conscious decisions. (Indeed, the pathogens may not be alive, as viruses are not.) What happens is that they randomly try every strategy possible, and those which get lucky survive.

Thats nature. Trial and error.

 

[SOC]

Thats nature. Trial and error.

And ultimately, evolution.

 

[lansbergen]

And ultimately, evolution.

Yep