Could the Epstein-Barr Virus - Autoimmunity Hypothesis Help Explain Chronic Fatigue Syndrome?
( Find a 'quick' summary at the bottom of the blog)
The Epstein-Barr Virus Question in ME/CFS
We recently saw evidence suggesting that increased viral loads of EBV (in whole blood) may be common in Chronic Fatigue Syndrome.We also saw that ME/CFS patients antibody responses to some proteins produced by EBV may be are impaired as well.Those findings made sense given anecdotal evidence from doctors and study evidence from Dr. Lerner and Dr. Montoya indicating that antivirals can be very helpful in some patients. Dr. Montoya's recent review of anti-herpesvirus antivirals indicated he believes they play a role but these results conflict with the Lipkin/Chronic Fatigue Initiative study which found almost no active herpesvirus infections in either Dr. Montoya's or in the CFI's study groups.
How to reconcile these findings ? Kristin Loomis of the HHV-6 Foundation and Dr. Chia have stated that while the method Dr. Lipkin used to detect herpesviruses (in plasma) works very well in people with highly active herpesvirus infections, they do not believe it would pick up the type of smoldering, lower-level infection suspected in ME/CFS.The existence of that 'smoldering infection' is, of course, controversial. It's possible, even probable, that most researchers outside this field including Dr. Lipkin do not believe that such a small infection could have such serious consequences.Indeed, the 'increased viral loads' in the German study did not indicate a highly active infection was present, but they were still significantly higher in the ME/CFS patients than in the controls. Dr. Lerner, Kristin Loomis and others believes that's significant and that's the result they believe Dr. Lipkin would have received if he had used a different technique.After XMRV it's no surprise to see controversy in the pathogen field. The bottom line is that EBV is still a possible culprit in ME/CFS. Given that and the Rituximab findings suggesting that an autoimmune component may be present in ME/CFS, let's look at a fascinating hypothesis that ties EBV infections and autoimmunity together and could have implications for ME/CFS.
Epstein-Barr Virus and Autoimmunity
CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Pender MP. Autoimmune Dis. 2012;2012:189096. doi: 10.1155/2012/189096. Epub 2012 Jan 24.If this hypothesis is right, Epstein Barr Virus - still the virus most closely associated with ME/CFS - has a very, very close connection to autoimmune disorders.
About a decade ago Michael Prender proposed being exposed to EBV is a prerequisite for having autoimmune disorder. In doing so he tossed aside the usual EBV mimicry hypothesis; that proteins found in EBV confused the immune system into attacking the body and put forth a much encompassing idea. He proposed that EBV's residence in B-cells - which are ground zero for an autoimmune response - was responsible for most types of autoimmunity. His hypothesis, a decade later, remains alive and well.B-cells produce antibodies and autoantibodies. As we learned in the Rose autoimmune talk, the production of autoantibodies primed to attack the body is a natural outcome of an immune system that must defend the body against microbes containing proteins that are very similar to those found in humans. The immune system has ways to deal with these autoantibodies and in most cases it succeeds. When it doesn't you have an autoimmune problem.
An Admiring Look at a Virus
In some ways you've really got to give it up to Epstein-Barr Virus (EBV). EBV just happens to be the only virus known to survive in B-cells. In fact, EBV doesn't just survive in B-cells they are its home. Somehow B-cells have managed to thrive survive in the very cells that are designed to attack them. That takes a special kind of viral hutzpah..Every time EBV infects a B-cell it tells it to reproduce and when the cells does, EBV inserts itself into the B-cell's 'germinal center' where it will reside, largely untouched, for the rest of the B-cells life. Every time the B-cell replicates EBV hijacks its reproductive machinery to produce more EBV virions.
Because B-cells aren't long-lived and because EBV can't replicate in them when they're pumping out antibodies, EBV has found ways to keep B-cells alive and in a state of latency for longer and longer periods of time.EBV has found ways in induce B-cells to undergo what's called 'clonal' expansion in which B-cells produces EBV infected clones of themselves. One way EBV does this is by tricking the immune system to believe an pathogen is present, thereby causing it to ramp up B-cell production.Keeping the immune system on high alert, though, can cause problems. Think of our missile defense system. If it's on high alert the risk of a catastrophic mistake increases greatly, and here is where Pender and his hypothesis comes in.
Cytotoxic T-cells and A Numbers Game
"CD8+ T-cell deficiency would appear to be a general feature of human chronic autoimmune diseases. " Pender et.al.
EBV infections in the body are usually tightly controlled by killer or cytotoxic T-cells (CD8+ T-cells). These CD8+ T-cells kill EBV infected B-cells when they proliferate.
Pender and other researchers believe an inherited defect in cytotoxic T-cells that prevents them from controlling EBV may be behind a lot of autoimmunity. (A Simmaron Research Foundation project involves looking for inherited problems in T-cells, B-cells and NK cells killing capacity.) It turns out that a long list of autoimmune disorders are, in fact, characterized by low cytotoxic T-cell levels.In what is essentially a numbers game, Pender believes that poorly functioning cytotoxic T-cells allow more EBV infected B-cells to proliferate. Because EBV induces these B-cells to proliferate at a higher than normal rate the outcome of a less controlled EBV infection is simply more and more B-cells. That means more autoantibodies (remember they're a natural feature) for the immune system to filter out, and more possibility of a catastrophic mistake being made; i.e. a full-blown autoimmune or autoinflammatory disorder.
Cytotoxic T-cells and Chronic Fatigue Syndrome
CD8+ T-cells have not received a lot of attention in ME/CFS, but early evidence suggests they're not working too well. A recent German study found a reduced frequencies of an EBV specific T-cells in people with Chronic Fatigue Syndrome and an Australian group found reduced cytotoxic T-cell (and NK cell) killing capacity in ME/CFS.
In fact, given the similarity in the killing systems in cytotoxic T-cells and NK cells, it wouldn't be surprising to find the same dysfunction in both NK cells and CD8+ T-cells. (If your NK cells aren't doing so hot, it's possible your cytotoxic T-cells aren’t doing so well either.)If that's true, your cytotoxic T-cells may not be taking out as many EBV infected B-cells as normal. That fits Pender's hypothesis to a T.
Another Numbers Game
Timing could be everything in EBV, ME/CFS and autoimmunity. An EBV infection in young children usually doesn't cause symptoms. It turns out that infants have very high levels of cytotoxic T-cells that allow them to stop the virus in its tracks.By age sixteen, however, those cytotoxic T-cell levels are a third of what they were at age two. That means that an infection which most infants wouldn't even notice often causes infectious mononucleosis (glandular fever) and a greatly increased risk for ME/CFS and multiple sclerosis in adolescents.
It appears that the Western fanaticism with cleanliness is pushing the date most children are exposed to EBV further and further forward. In the developing world most children are exposed to EBV by age three, and almost 100% are exposed by age ten, but some studies suggest about half the children in the developed world have not been exposed to EBV by the time they're ten.As many as 50% of these children may come down with a symptomatic, infectious mononucleosis-like illness and during that illness as many as half of B-cells in their blood may become infected with EBV - producing a huge reservoir of highly active EBV infected B-cells.The Jason Northwestern ME/CFS study estimates as many as 10% of college students will come down with infectious mononucleosis. The increased IgM antibody rates in the ME/CFS patients in the German study suggested they may have been suffering from a primary (first-time) infection as well.Data is lacking on date of first time EBV infection in ME/CFS, but the German study with its high IgM levels suggests a substantial number of ME/CFS patients may have encountered EBV later in life when their immune systems are less prepared to deal with it. Could ME/CFS in some people simply be the consequence of encountering EBV later in life?Pender ties in other autoimmune factors, many of which are found in Chronic Fatigue Syndrome as well.
Heritability
Autoimmune disorders are have a higher degree of heritability than most disorders - an intriguing factor given that cytotoxic T-cell functioning is largely governed by heredity. The heritability factor in ME/CFS and Fibromyalgia has not been the subject of many studies, but one study suggests that heritability may be even higher in these disorders than in autoimmune disorders.
Location and the Vitamin D3 Connection
Living further from the equator also increases the risk of autoimmune disorders such as multiple sclerosis and rheumatoid arthritis. Reduced sunlight and vitamin D3 could aggravate cytotoxic T-cell problems thus imperiling control of EBV. It turns out that cytotoxic T cells contain more vitamin D3 receptors than any other immune cell.Dr. Bateman was astonished at how low the Vitamin D3 levels were in her ME/CFS and FM patients but people with ME/CFS and FM probably get less exposure to sunlight than do healthy people. People who are bedridden, of course, get very little exposure to sunlight.
Gender
Cytotoxic T-cells are believed to be hormonally regulated (with increasing estrogen reducing Tc levels) and women tend to have fewer cytotoxic T-cells than men. The gender imbalance found in FM and ME/CFS as another.Reduced cytotoxic T-cell functioning, high heritability, reduced vitamin D3 levels, and female predominance all appear to be present in ME/CFS and all fit Pender's paradigm for an EBV induced autoimmune disorder.
Treatment
Pender's treatment recommendations for EBV triggered autoimmune disorders are enticing given what we know about Chronic Fatigue Syndrome. They start with none other than Rituximab.
"Improvement of an autoimmune disease with rituximab therapy would be consistent with an essential role of EBV in the development of the disease"
Pender asserts an EBV triggered autoimmune disorder could be treated in two ways.(1) Depleting B-cells with monoclonal antibodies such as Rituximab would reduce total B-cell levels which would reduce the levels of EBV infected B-cells and autoantibody production. ( Since Rituximab would also reduce the levels of non-EBV autoreactive B-cells a successful course of Rituximab does not constitute proof.)(2) Boosting immunity to EBV - Getting EBV under control is another option.
- the gp350 vaccine - vaccinating young adults with recombinant gp350 has been shown to stop the development of infectious mononucleosis after EBV infection. If Pender is right, gp350 vaccination could be one way of cutting down ME/CFS rates in adolescents. This would simply require determining which adolescents have not been exposed to EBV and vaccinating them. Given that Jason expects perhaps as many as 10 percent of college freshman to come down with some form of infectious mononucleosis this would seem to be a really good idea.
- using monoclonal antibodies against gp350.
- Intravenous infusion of autologous EBV-specific cytotoxic CD8+ T cells after expansion in vitro
- interleukin-7, which expands the population of functional virus-specific CD8+ T cells in chronic viral infection
Summary
- Michael Pender, has proposedthat exposure to Epstein-Barr virus, a virus that takes up residence in the B-cells, is required for autoimmunity.
- All B-cells produce autoantibodies that would, if the immune system didn't filter them out, attack the body.
- EBV prompts B-cells to produce EBV infected B-cells which live longer and produce more B-cells than usual. Their longer lifespan and higher productivity means EBV infected B-cells also produce more autoantibodies than normal B-cells.
- Pender believes high numbers of autoantibodies produced by these B-cells overwhelm the immune system causing an autoimmune disorder.
- The key problem in autoimmunity Pender believes, then, is large numbers of EBV-infected B-cells.
- Since cytotoxic T-cells kill EBV-infected B-cells, a poor cytotoxic T-cell response may be the key, and indeed reduced cytotoxic T-cell responses appear to be common in autoimmune disorders. (Two studies suggest reduced cytotoxic T-cell responses are present in ME/CFS as well.)
- Because cytotoxic T-cell responses decline over time, someone exposed to EBV as an adolescent typically has a much more difficult time fighting off EBV than a young child does. (Could late exposure to EBV be a common feature in Chronic Fatigue Syndrome?)
- ME/CFS shares factors like low Vit D3 levels, a high degree of heritability and gender predominance with autoimmune disorders. All these plus the increased EBV viral loads, the reduced antibody response to the latent stage of EBV and the possibly reduced cytotoxic T-cell functioning suggests ME/CFS could very well fit Pender's hypothesis of an EBV triggered disorder.
Conclusions
The role Epstein Barr virus or autoimmunity plays in Chronic Fatigue Syndrome is unclear, but Pender's hypothesis suggesting that poorly controlled EBV infections cause many autoimmune disorders is intriguing given recent study evidence of increased EBV viral loads in ME/CFS. Time will tell but the reduced cytotoxic T-cell functioning, gender imbalance, the low Vit. D3 levels, the high heritability factors, and the positive response to Rituximab reported all suggest Pender's EBV/autoimmune hypothesis is something we should keep an eye on.