All posts by Cort Johnson

Symposium Calls For Use of Immunotherapy To Treat Chronic Pain

October 2, 2014

“Despite the availability of different drugs, most patients with chronic nociceptive pain do not receive satisfactory pain relief…”

We all know the medical profession is poor at providing pain relief in general, but its record with regards to neuropathic or nerve pain is something else indeed. Despite the fairly large array of drugs physicians use (few of which were developed to reduce nerve pain), no more than 30-40% of  nerve pain patients receive as much as 50% relief from the medications doctors  provide.

pain

The medical profession is poor at treating pain. The experience of these doctors and researchers suggests it may be missing some options.

Despite research that has uncovered important factors in the production of pain, much clearly remains to be learned.  The production of pathological pain has been shown to be a very complex process. Researchers know, for instance, that damage to the ion channels on nerves, increased levels of excitatory neurotransmitters and reduced activity in the pain inhibition pathways in the brain all play a role.

These authors suggest, though, that a critical component of the pain production pathway – the immune system – has been, if not ignored, then not fully investigated.  Studies show that a variety of immune components, from mast cells to macrophages and cytokines to the microglia play a role in pain production.

Recent studies suggest that autoantibodies to the potassium channels – the dorsal root ganglia – key pain processing sites located just outside the spinal cord -are opening up new windows on how pathological pain may be produced.

Other than corticosteroids and anti-inflammatories, however, few immune affecting drugs are used to fight pain.  Human immunoglobulin G (IgG) is an immune drug these authors believe may be useful in pain disorders where evidence of increased cytokine production can be found. IgG can be delivered intravenously (IVIg) or subcutaneously (SCIg) and may work by suppressing the immune system.

The fifteen members of this workshop came from Italy, Sweden, Switzerland, Japan, Canada, the U.K., and the U.S. to report on where and when IgG may be useful in treating chronic pain. Some studies were reported on and a good deal of the information derived from case studies.

Symposia Report Immunoglobulin G for the Treatment of ChronicPain: Report of an Expert Workshop, Stefano Tamburin, MD, PhD,* Kristian Borg, PhD,†Xavier J. Caro, MD,‡ Stefano Jann, MD,§Alexander J. Clark, MD,¶ Francesca Magrinelli, MD,* Gen Sobue, PhD,** Lars Werhagen, PhD,†Giampietro Zanette, MD,†† Haruki Koike, PhD,**Peter J. Späth, PhD,‡‡ Angela Vincent, FRCPath,§§ and Andreas Goebel, MD, PhD¶¶ Pain Medicine 2014; 15: 1072–1082

 Sjogrens Syndrome

Sjogrens Syndrome (SS) is an autoimmune disorder mostly affecting women.  Often misdiagnosed as other disorders, including ME/CFS and Fibromyalgia, SS can cause a wide variety of neuropathic (nerve) problems.

IVIG

IVIG is the focus of this review -but other immune drugs may apply.

Some evidence suggests that the neuropathic pain in SS, which can be quite severe, comes from neuron loss in the dorsal root ganglia perhaps caused by ‘cytotoxic autoimmunity” – a intriguing result given similar findings in some Chronic Regional Pain Syndrome patients.

Of five patients treated with IgG for SS with severe neuropathic pain, all showed ‘remarkable’ reductions in pain (73% reduction VAS scale) within two weeks which lasted from two to six months.  Long term follow-up indicated two had relapsed, but resumption of treatment was successful.

Fibromyalgia

Several findings including increased cytokine levels in the skin and blood suggest the immune system plays a role in Fibromyalgia.  An inverse correlation between Il-2 receptor levels and reduced nerve density in the skin (small nerve fiber neuropathy) suggested immune mediated nerve destruction had occurred.

myelinated nerves

Caro finds immune therapies to be the most effective for his Fibromyalgia patients

Studies reporting large nerve fiber demyelination in the periphery and reduced nerve fiber density in the skin suggest FM may in part be a neuropathic disorder.  Pain symptoms in FM are similar to those reported by people with neuropathic pain.

Caro found that from fifty to seventy percent of 45 FM patients responded positively (<50% reduction in pain) to IVIG ((0.4 g/kg/day for 5 days followed by 1.2 g/kg every 3 weeks, given as 0.4 g/kg/day). The pain reduction usually started five days after the end of the first course of IVIG and then peaked at 3-6 months.  Relapse may occur after that.

Caro, who has been treating and studying Fibromyalgia for decades, stated that he’s had more success using immune modulating treatments than using traditional approaches using  FDA approved drugs.

Post Poliomyelitis Syndrome (PPS)

Pain associated with poliomyelitis relapse decades after apparent recovery presents an interesting case for immune mediated therapies. The pain, which usually occurs in combination with muscle weakness and atrophy, and can be severe, is localized to the muscles and joints.  Neuropathic pain usually occurs in combination with nerve compression or disc herniation.

Structural components do not tell the entire story, however. Increased cytokine levels in the cerebral spinal fluid, serum and peripheral blood suggest systemic inflammation is present and may be contributing to pain.

Four studies examining IVIG effectiveness in PPS found significant reductions in CSF cytokines, reduced TNF-a levels in the blood, significant clinical improvement, increased muscle power, quality of life and/or reduced pain. Decreased pain levels were still evident a year after treatment in one study.

One of the authors reported 35% of PPS patients experienced a greater than 50% reduction in pain

Complex Regional Pain Syndrome (CRPS)

CRPS is one of the most painful disorders known. We saw in a recent blog that autoimmune processes appear to play a significant role in some CRPS patients.

An open-label trial of low-dose IVIG (0.5g/kg) found that 3/11 CRPS patients received >70% pain relief – an astounding feat in CRPS – after repeated treatments. Six of eleven received no benefit.  The pain, unfortunately, returned to baseline levels within three months.

wow!

Long term use of IVIG completely eliminated CRPS in some patients

In a small follow up trial three patients who had received >30% relief continued on a weekly maintenance dose (0.5g/kg or 1g/kg). Not only did two of the three patients experience ‘profound and sustained pain reduction” during the 3-12 months they were on the drug, but both remained in remission 12 months after the termination of the treatment.

Given the successes the following “Liverpool” protocol was suggested in CRPS:

  1. Patients should first be treated with an intravenous loading dose of 0.5 g/kg; if >40% pain relief is achieved, patients should—commencing 2 weeks after the loading dose—be offered
  2. a trial of 6–12 months of low-dose maintenance treatment; either 0.5 g/kg/month divided into weekly portions (or even smaller portions if a “push technique” is used instead of a pump) for subcutaneous therapy, or 0.5 g/kg every 3 weeks intravenously
  3. after 3–6 months an attempt should be made to halve these doses,
  4. after 6–12 months an attempt should be made to stop treatment.

A multicenter trial examining the efficacy of long term IVIG use in CRPS is currently underway in the UK.

Diabetic Polyneuropathy

Diabetes mellitus is the commonest cause of peripheral neuropathy.  The most intense kind of peripheral neuropathy in diabetes is diabetic lumbosacral radiculoplexus neuropathy (DLRPN), an extremely painful and difficult to treat form of peripheral neuropathy.

Eighty percent of five patients with diabetic polyneuropathy responded well to IVIG with pain intensity dropping from 77/100 on the Visual Analogue Scale (VAS) to 33.  Pain reduction peaked at one to two months and one patient relapsed at seven months.

diabetic-neuropathy

Some diabetic neuropathy patients that didn’t respond to steroids – did respond to IVIG

The fact that general inflammatory markers (erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies) are negative in DLRPN, yet anti-inflammatory treatments may be helpful suggests DLRPN consists of a local microvasculitis.  Indeed, the reduction in pain with IVIG makes sense if ischemic damage to the nerve roots and peripheral nerves has been caused by a microvasculitis.

Some patients that responded to IVIG do not respond to the immune suppressant effects of steroids.

Distal Symmetric Painful Polyneuropathy is another form of polyneuropathy found in diabetes. Twelve patients for whom standard treatments were ineffective received either IVIg (0.4 g/kg/day for 5 days) or continued with their standard treatments.

In the five diabetic patients treated with IVIg, mean pain intensity significantly dropped and 80% of patients were responders (i.e., pain reduced by >50%).  The study was very small, but this was a far higher percentage of relief than achieved by traditional pain medications.

Autoantibody Caused Pain 

Autoantibody attack of neurons and glial cells has been definitively linked to central nervous system problems. In acquired neuromyotonia antibodies to the VGKC complex causes peripheral nerve hyperexcitability and pain symptoms similar to those found in FM (aching, cramping, shooting, lancing, or burning pains). (One study has found peripheral nerve excitability in Fibromyalgia.)

These same antibodies have been linked to pain in Morvan’s syndrome and people with idiopathic pain.  Immune therapies including IVIG and steroids have effectively reduced pain levels in some of these patients.

These findings suggest that pain in autoimmune disorders such as multiple sclerosis and neuromyelitis optica may be amenable to IVIG. The authors called the arena of autoantibody induced pain via neuronal  attack  “ripe  for investigation”.

Conclusions

“Polyvalent IgG represents a promising treatment in a number of chronic pain (neuropathic, nociceptive, and complex) conditions”

The Workshop participants propose that, in contrast to prevailing thought, that nerve or neuropathic pain may at times be immune mediated and respond well to immune therapies, in particular, antibody therapy. They note IgG is generally well tolerated with mild side effects, if any, but that costs are high (up to $8500 per protocol  in the U.S.), and insurance reimbursement for pain can  be problematic.

step-by-step

The authors hope to spark rigorous study to assess the effectiveness of IVIG and other immune therapies in treating chronic pain.

Most of the evidence for IgG use in pain comes from case studies and rigorously controlled trials are needed.  Much work remains to be done to validate these findings and at least study is underway. A successful outcome to the British IVIG study of CRPS – one of the most intractable and painful of all pain disorders – would surely open eyes.

IVIG administration appears to be successful in a subset of patients with these pain disorders.   Long term IVIG treatment has been rarely tried but has lead to complete remission in a few cases.  Future immune analyses should be able to identify those patients in pain who would benefit from immunotherapies such as IgG.

Given the poor track record of treating chronic pain, immunotherapy will hopefully be given the funding and study it needs.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Treatment Resistant Depression or Chronic Fatigue Syndrome? Child Psychiatrist Finds Success With Antivirals

September 23, 2014

A Different Kind of Psychiatrist

“I have now treated dozens of adults and adolescents who came to me with the diagnosis of “treatment-resistant depression” and instead they had Chronic Fatigue Syndrome. With proper treatment, this viral illness can be successfully controlled.”

ted-henderson

Dr. Henderson is one of the rare psychiatrists to acknowledge the role the immune system and viruses can play in producing symptoms many associate with psychiatric disorders like fatigue

Chronic Fatigue Syndrome in all its forms is difficult to treat, but one doctor in Centennial, Colorado is apparently having some success with antivirals. Dr. Theodore Henderson is not a virologist or even an infectious disease specialist. He’s a child psychiatrist – perhaps the last profession one might expect to be open to viral theories of ME/CFS or childhood depression.  (I remember Environmental Medicine specialist Dr. William Rea telling me that he could count on the fingers of one hand the number of psychiatrists who didn’t believe environmental illness was mental.)

On his website Dr. Henderson descries the DSM approach that attempts to pigeonhole patients and put them in one category or the other. Instead he tries to approach the neurobiological problems of each patient uniquely.

I approach psychiatry from a brain-based biological perspective.. Most people cannot be pigeon-holed into a single category and most psychiatric conditions are actually a range of disturbed neurobiological processes. As a result, I approach each patient, child or adult, as an individual with a unique brain.

While Dr. Henderson uses traditional approaches to treat mental  disorders, he also recognizes the role the immune system and  viruses can play in producing some psychiatric symptoms.

“More importantly, growing evidence suggests that not all psychiatric symptoms, such as anxiety, fatigue, listlessness, low mood, or poor concentration, result from intrinsic flaws in the patient’s brain. Extrinsic causes, such as infections and toxins, can cause these psychiatric symptoms. The resulting cluster of symptoms might mimic anxiety, depression and other psychiatric disorders, leading to misdiagnosis and ineffective treatment.

Certain rare autoimmune disorders can lead to the formation of antibodies against specific neurotransmitter receptors. Much more widespread autoimmune disorders, such as systemic lupus erythematosus, can lead to cognitive changes, anxiety, seizures, and mood disorders”

Dr. Henderson reported he has been effectively treating both adolescent and adult Chronic Fatigue Syndrome patients with antivirals for several years. He recently published a paper describing his results with adolescents.

The Paper

Henderson TA.  Adv Mind Body Med. 2014 Winter;28(1):4-14. Valacyclovir treatment of chronic fatigue in adolescents.
pathogens

Dr. Henderson cites Dr. Lerner’s work with antivirals and ME/CFS on his website

In the paper, Dr. Henderson first cites the low diagnostic rates for Chronic Fatigue Syndrome (20%).  Then he argues that studies suggest reactivated herpesvirus infections, particularly HHV-6, are common in ME/CFS.  Arguing – as did Dr. Brewer at the Simmaron Research Foundation’s Immunology Workshop in San Francisco – that IgM antibodies are not diagnostic in this disease, Dr. Henderson asserted that primary cell cultures in combination with antibody or PCR tests indicate HHV-6 infection rates are very high in ME/CFS.

The Antiviral Subset?

In Dr. Henderson’s experience (approximately 65 patients treated) ME/CFS patients whose illness began with flu-like onset and who have:

  • have elevated IgG levels against a herpesvirus
  • low natural killer cell activity
  • high ribonuclease activity
  • high levels of angiotensin converting  enzyme (>35)
  • high TNF-a levels
  • elevated total IgM or IgG levels

responded well to antivirals.  He undertook a retrospective chart review of 15 adolescents he had treated with valacyclovir (Valtrex) between 2007 and 2013.

Valtrex is used to treat herpes zoster and herpes simplex and, in Chronic Fatigue Syndrome, Epstein-Barr Virus reactivation. Two studies by Lerner suggest Valtrex can be effective in ME/CFS.

young-man

Many of the adolescents who responded to antivirals had been referred to Dr. Henderson for treatment resistant depression

Dr. Henderson evaluated these patients like any good child psychiatrist would: He looked for mood disorders, a history of childhood abuse, assessed their sleep quality, and reviewed their school performance. He looked for any other significant symptoms and did laboratory work.  He noted that most of them had been referred to him for having ‘treatment-resistant depression’. All experienced fatigue, low motivation, academic problems, and unrefreshing sleep. Most had tried antidepressants or other mood altering drugs without effect. They did not, however, meet the CDI self-report test for depression.

Upon further evaluation six were given a diagnosis of Chronic Fatigue Syndrome, four were given an ME/CFS diagnosis plus anxiety, and three were given a diagnosis of ME/CFS diagnosis plus mood disorders.

Eleven were receiving failing grades in at least one class, and almost half had dropped out of school.  A third were sleeping more than 12 hours a day.

Ten could remember an infectious event they didn’t recover from.  Interestingly, a third of the group reported that they had always experienced significant fatigue.

fatigued-young-woman

The fatigue levels of his young patients were incredibly high

Their self-reported fatigue levels were almost off the charts.  While ‘significant fatigue’ is indicated by a score of 39 on the Fatigue Symptom Index (FSI), their mean score was 95. Similarly, they topped out on the Fatigue Severity Scale with almost two-thirds of the participants scoring near maximum fatigue levels (56 out of a possible 63).

The doctor provided them with the option of going on Valacyclovir, noting that the published evidence that it would work was small and confined to adults, not adolescents.  They began on an oral dose 500 mg BID and worked their way up to 1000 mg BID over a couple of weeks.

Results

“The medical understanding of CFS has been impeded to a degree by the resistance to the concept  of chronic viral infections of the central nervous system.”

Almost all of the adolescents responded quickly to the antivirals. Within three months 12 out of 15 reported greater than an 80% improvement in symptoms. After 8 months 14 out of 15 adolescents reported increased energy, improved sleep, increased motivation, and “return to normal functioning”. Ten of the 14 reported a “complete resolution of fatigue” and their depressive symptoms disappeared. Five of the seven who had dropped out of school returned to school and ultimately enrolled in college.

upwards graph

Fatigue scores generally dropped dramatically in response to antiviral therapies

The changes in the fatigue self-report scores were astonishing. Mean Fatigue Symptom Index (FSI) scores for nine of the fifteen dropped from the whole group FSI score of 56 to and FSI score of 12.  Fatigue Severity Scale scores dropped from 95 to 19. All ME/CFS symptoms measured by the MFSI dropped significantly.

The impressive results bring to mind Dr. Montoya’s initial Stanford valganciclovir trial in adults (9/12 recover) and the reminder that the results of his more rigorous double blinded, placebo-controlled trial, while positive, were much less successful.  Still, Dr. Henderson has clearly experienced real success with his adolescent ME/CFS patients, none of whom had responded to other approaches.

Noting that his adolescent patients were more likely to have acute infectious onset than adults and less likely to experience depression, Dr. Henderson suggested adolescents might have more success with antivirals.

While he didn’t mention it, one wonders if late exposure to Epstein-Barr Virus is playing a major role in adolescent onset ME/CFS.  Adolescence is becoming a more and more likely time of first exposure to Epstein-Barr virus (EBV).  Early exposure to EBV (during childhood) often doesn’t cause symptoms, but as cytotoxic T-cells decline after early childhood, later exposure causes a much more virulent illness. Some researchers believe delayed exposure to EBV is behind the increased levels of autoimmune disorders seen.

As do some others in the field, Dr. Henderson, took issue with the medical community’s unwillingness to more fully investigate the impact central nervous system viruses have on a range of disorders including ME/CFS, multiple sclerosis, schizophrenia, Alzheimer’s, and Autism.

Follow-up

The average duration on the drug was over two years.  Four patients discontinued treatment after about 18 months and remained well at the time of this report. Five patients who discontinued treatment in a similar time frame, however, immediately relapsed and had to go back on the drug.

Treatment Resistant Depression = Chronic Fatigue Syndrome?

“The authors secondary hypothesis is that treatment-resistant depression may often, in fact, be CFS that has been misdiagnosed.”

Dr. Henderson proposed that a significant number of adolescents diagnosed with treatment-resistant depression actually have a form of chronic fatigue syndrome that may respond to antivirals.

question-mark

Remarkably, most of the adolescent referred to Henderson for treatment resistant depression….did not meet the criteria for it

The medical profession’s eagerness to diagnose adolescents experiencing severe fatigue with depression was evident. Despite the fact that most of his adolescent patients did not met the DSM criteria for depression nor did they have CDI scores consistent with depression, many of them were still diagnosed with depression.  Other findings, such as low cortisol and cerebral hypoperfusion, were at odds with a depression diagnosis, yet over half the adolescents had been treated for depression and had not responded.

One is reminded of the saying that if your only tool is a hammer, everything begins to look like a nail.  But Dr. Henderson’s specialty is psychiatry.  He recognizes true depression when he sees it.

In fact, adults with inflammation-associated depression who make up perhaps a third of all cases of depression – do not respond to antidepressants either. Interestingly, a subset of depressed patients without inflammation-associated depression get worse when given anti-inflammatories. (For them some inflammation is good!)

The doctor provided a case report involving an adolescent experiencing fatigue, brain fog, and depression diagnosed with ‘treatment resistant depression’ who had failed to respond to either SSRIs or SNRIds.  Tests showed she had reduced NK cell counts and high IgG titers to EBV and HHV-6. Three months after going on 1000 mg a day of Valacyclovir she had experienced a complete resolution of all her symptoms. Three months later, after forgetting her meds on a trip to Disneyland, her symptoms quickly returned and she spent most of the vacation in bed at her hotel. One week after resuming the medication her symptoms completely disappeared again.

Dr. Henderson proposed a placebo-controlled trial be done involving seropositive (antibody positive) and seronegative ME/CFS patients. The trial should not, he emphasized, employ acyclovir, an antiviral he asserted has low bioavailability and is rapidly eliminated by the body.

Conclusion

In a retrospective case analysis Dr. Henderson reported very high response rates to Valacyclovir (Valcyte) in a small group of adolescents with ME/CFS. Fatigue and other symptoms virtually disappeared for many in the study, a significant portion of whom had been diagnosed with treatment-resistant depression.

He proposed that that many adolescents diagnosed with treatment-resistant depression may have Chronic Fatigue Syndrome.  Dr. Henderson also suggested that the high incidence of infectious onset and low incidence of depression in adolescents with ME/CFS made them good targets for antiviral therapy.

Check out Dr. Henderson’s website and blog here.

 

 

 

 

 

 

 

 

Simmaron Scientist Awarded NIH Grant Probing Cause of Immune Holes in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

August 31, 2014

NIH Grant to Study Genetics of Immune Response in ME/CFS

Simmaron Research Foundation’s Scientific Director, Isabel Barao PhD, has been awarded the IDeA Clinical and Translational Research Pilot Grant (CTR-IN) from the National Institutes of Health (NIH) to examine ways ME/CFS patients’ genetic heritage may contribute to immune dysfunction and their inability to fight off viruses. Dr. Peterson will select the patients, collect their blood and provide their clinical information. The laboratory work will be performed at University of Nevada School of Medicine (UNSOM), Department of Microbiology and Immunology, where Dr. Barao is academically affiliated.

DNA

This study will probe genetic holes in natural killer cells

The $75,000 grant is small, but it is an important sign of Simmaron’s ability to advance new investigators involved in immunological research on ME/CFS at the NIH. The CTR-IN grant is supported by the National Institute of General Medical Sciences. The 1-year grant supports 20% of Dr. Barao’s pay and supplies for laboratory work.

Dr. Barao has also submitted an R21 grant proposal to the NIH in collaboration with the National Cancer Institute (NCI), Dr. Peterson and UNSOM.

ME/CFS is believed to be a multi-factorial disorder caused by a combination of one’s genetic makeup, an environmental trigger such as a pathogen, and other factors. It’s believed that 20-40% of the reason people came down with ME/CFS lies in their genes.

Take away that genetic component and maybe that infection that never went away passes on through like every other cold did. Maybe that bout of fatigue that stayed and got worse resolves with rest this time. It may take one factor to tip the system into the situation we call ME/CFS. That factor could lie in our genes.

First Line of Immune Defense Down

This grant will help determine if altered FcRs (e.g. CD16) on natural killer (NK) cells have made it more difficult for ME/CFS patients t0 fight off viruses.  NK cells are the cells our immune system uses to hold the invader at bay while cytotoxic T-cells and B-cells gear up to wipe out the invader.

We know that poorly functioning NK cells could be allowing pathogens to get entrenched more deeply into ME/CFS patients’ systems, perhaps even into immunologically privileged parts of our nervous system that the big guns of our immune system have trouble getting to.

Second Line of Immune Defense Down As Well?

pathogens

Could ME/CFS genetics be giving pathogens the upper hand in ME/CFS?

It turns out, though, that natural killer cells not only play a vital role in the first lines of our immune defense – they also play an important role in fighting off chronic infections. This study suggests NK cell problems in ME/CFS may also be allowing chronic viral infections to persist.

During an infection, B-cells start pumping out IgG antibodies that attach to and stop pathogens from infecting our cells. Once IgG antibodies have attached to a pathogen, NK cells are able to recognize, attack and kill cells infected with pathogens through FcRs, using a process called ‘antibody-dependent cell-mediated cytotoxicity’ (ADCC).

Studies have shown that individuals with genetic alterations (polymorphisms) of the genes associated with that ADCC response have an increased risk of cancer and autoimmune disorders. Genetic impairment of the ADCC response could also make it more difficult to clear herpes viral infections, which are of such interest in ME/CFS.

A Talk With Isabel Barao Ph.D

Dr. Barao is Adjunct Assistant Professor at UNR’s Department of Microbiology and Immunology and Scientific Director of Simmaron Research.

How did you get involved in ME/CFS research?

In 2009, the Whittemore Peterson Institute (WPI) invited me to be their scientific consultant and to find out why NK cells are dysfunctional in CFS. I conducted immunological studies at the WPI until September of 2010.

What has your research into ME/CFS told you about this disease thus far?

Isabel Barao Ph.D

Isabel Barao Ph.D

I believe that variations in particular genes that affect the functioning of the immune system increase the risk of CFS.

You recently presented a paper at the 1st Annual Mountain West CTR-IN meeting suggesting that ME/CFS patients may have higher than normal levels of “hybrid” immune cells. Can you tell us what those immune cells are and what effects they might have?

The ‘hybrid’ lymphocytes are NKT-like cells that are increased in the blood of some of Dr. Peterson’s CFS patients and that may have unique properties in CFS patients.

We are characterizing these immune cells further.

You’re also engaged in a Simmaron Research Foundation study examining genetic changes in a range of immune cells in ME/CFS. Most ME/CFS research has focused on natural killer cells but you’re also really interested in other immune cells. Why?

Because NK cells communicate with B cells, T cells, macrophages, etc. and if the communication between them is defective, immune deregulations involving all these cells can occur and lead to disease. 

What comes next and what are the treatment implications if the study is positive?

Our expectations are that FcRs polymorphisms define CFS and its severity and predict those patients who may benefit from ADCC-based therapies.

Read more about Isabel’s work at Simmaron Research Foundation Study Targeting Roots of Immune System Breakdown in Chronic Fatigue Syndrome (ME/CFS)

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

Simmaron Foundation’s Immunology Workshop: the Forefront of Diagnosing and Treating ME/CFS

Simmaron’s Immunology Workshop on ME/CFS, Part I

survey

Immunologists came to the Simmaron Foundation’s Immunology Workshop to decide if immune tests should be standard practice in ME/CFS diagnosis and treatment

Immunologists came to the Simmaron Foundation’s Immunology Workshop to decide if immune tests should be standard practice in ME/CFS diagnosis and treatment.

Simmaron Research Foundation is focused on redefining ME/CFS scientifically. They produced the Immunology Workshop at the 2014 IACFS/ME Conference in order to get a consensus from immunologists and practitioners on whether immune testing should help guide diagnosis and treatment in Chronic Fatigue Syndrome (ME/CFS). Immunologists were invited to give presentations and then queried regarding whether immune tests should be incorporated into diagnostic protocols for this disorder.  Dr. Unger, the head of the CDC’s CFS program, was invited to attend.

Overviews of  some of the presentations make up Pt I of the Immunology Workshop Overview.

(I used my notes from the Workshop to build the foundation for this blog and then expanded on many of the subjects presented; i.e. the blog reflects my interpretation of the presentations and what they mean; it may not in places reflect the presenters viewpoints.)

Troy Querec, Ph.D, CDC – Natural Killer Cell Testing 

The CDC ignored natural killer (NK) cell functioning in ME/CFS for many years, but they appear to be convinced now that it’s a key problem.

Natural killer cells are called ‘natural killers’ because they don’t need to be activated to kill cells that don’t have the right MHC markers on them. They are also the only immune cells that can recognize infected cells without antibodies and MHC markers being present.

medical tests

The NK cell function test that reveals how effective NK cells are at killing invaders is laborious, expensive and, according to an NSU presentation at the IACFS/ME conference, not suited to most labs.  (This isn’t the first immune test relevant to ME/CFS that has not been readily available. Most of the tests associated with the RNase L enzyme are still available only at one lab in country.)

Recognizing the need for your average doctor to have access to a less expensive test of NK cell functionality, the CDC is working on one. (They’re not the first. The Klimas/Fletcher group in Miami was reportedly working on one several years ago.)

They’re focusing on measuring how effective the receptors found on the surface of NK cells are at turning the cells on. Receptor deficiency could play a role in the poor NK cell functioning found in ME/CFS. To that end they’re developing CD 107 antibodies that attach to the receptors.

Because shipping has also been shown to reduce NK cell viability, they’re also proposing ways to optimize NK cell viability during the shipping process. This involves keeping cells in their natural habitat – the whole blood – and isolating PMBC’s first. They propose a pilot study to determine ways to optimize viability of NK cells during shipping.

Finding an easier and more effective way to measure NK cell functionality would go a long way to establishing NK cell dysfunction as a biomarker for ME/CFS.

Dr. Constance Knox – B-cells and Chronic  Fatigue Syndrome

“Lots of vacuums in this field” 

After noting how little we know about the role B-cells play in ME/CFS, Dr. Knox echoed Mady Hornig’s statements that there are “lots of vacuums in this field” and then went onto a short overview.

A cornerstone of our immune defense, B-cells directly ‘attack’ pathogens and trigger other parts of the immune system to respond.

B_cell_activation

B-cells could be a major contributor to ME/CFS but the role they play is largely a mystery

First, they are activated by antigens (proteins associated with pathogens) brought to them by macrophages and dendritic cells – two innate immune cells. B-cells then produce hordes of pathogen specific antibodies that search for the pathogen outside the cell and attach to it in order to prevent it from attacking our cells. They also take that antigen and present it to killer T-cell’s which then mount a pathogen specific defense which gets at pathogens located inside the cell.

Two recent findings have overturned medical dogma concerning B-cells.

Naturally Occurring Antibodies: At one time it was thought B-cells only produced antibodies that were directed at specific invaders, but it’s now clear that naturally occurring antibodies – which are not directed at specific pathogens – are present as well. These antibodies are derived from unusual sugar residues synthesized in the gut – an interesting finding given the emphasis both Dr. Hornig and Dr. Lipkin place on the gut in ME/CFS.

Regulatory B-Cells – Cells regulating the powerful T-cell response (T-regulatory cells) received most of the attention until regulatory B-cells were discovered. Regulatory B-cells make up only 0.5% of total B-cells but are powerful regulators of immune activation and inflammation. They induce two important anti-inflammatory cytokines (IL-10, TGF-beta), which dampen the inflammation produced by the innate immune system.

b-cell signaling

Problems with B-cell signaling would pose problems for other parts of the immune system.

IL-10 restores Th1/Th2 balance (a problem in ME/CFS) and inhibits inflammatory cascades while TGF-B wipes out some types of T-cells, dampens the activity of cytotoxic T-cells, and takes other actions to reduce inflammation. These cells often get upregulated in states of chronic inflammation and elevated levels of both have been found in ME/CFS.  (They suggest the immune systems of ME/CFS patients are attempting to reign in inflammation.)

Research  is need to determine if either cell plays a role in ME/CFS, but several ongoing studies may give us clues regarding the role B-cells play. Rituxian (Rituximab) – an monoclonal antibody directed against mature or activated B-cells – reduces B-cell numbers. (A successful result in Rituximab trial could indicate B-cells in ME/CFS are triggering an autoimmune response or could implicate EBV infection.)

A 2011 study documenting increased rates of lymphoma in ME/CFS patients suggests more problems with B-cell regulation may  be present in a subset of  patients.

David Baewer, M.D., Ph.D – Serology and HHV-6 Infections

Most humans carry latent herpesviruses in their cells that do little harm. Once activated, though, in people with poorly functioning immune systems such as transplant patients, these seemingly innocuous viruses can cause enormous damage. With their immune systems intentionally knee-capped in order to avoid an immune attack on their transplanted organ, they are ripe for herpesvirus activation. Several antivirals under development that could assist some people with ME/CFS come from research devoted to preventing herpesvirus activation in transplant patients.

herpesvirus

Some researchers believe herpesvirus activation is common in ME/CFS -but that the typical virus tests are not up to the job.

Dr. Baewer proposed that the same  general processes causing herpesvirus reactivation in transplant victims is occurring in ME/CFS. Standard testing for herpesviruses, however, is unable to distinguish the kind of active herpesvirus infections he believes are present in ME/CFS.

He noted that primary active infections – which occur when the body is first introduced to a pathogen – are often diagnosed via a high IgM response.

The kind of herpesvirus infection suspected in ME/CFS, however, (and the kind that mostly occurs in adults) involves reactivation from a latent infection. Because these kinds of infections rarely generate a robust IgM response, Dr. Baewer asserted IgM readings in adults have little clinical value.

Viral DNA with PCR isn’t effective either because it only tells us if the virus is present and it is present in 95-100% of population.

Viral mRNA using reverse transcriptase PCR, on the other hand, shows whether the virus replicating or not.  This type of testing tells which genes in herpesvirus genome are present in the blood – and identifying which genes show up is the key to determining whether the virus is actively replicating or not.

Herpesviruses need to be able to attack and establish themselves in B-cells, ward off the immune system’s efforts to find them and then replicate when the time is right. They are complex viruses with big genomes that have genes associated with maintaining latency, with altering the immune response and with building new viruses. Viral mRNA using reverse transcriptase PCR can identify which stage the virus is  in.

gene

Tests can reveal which stage of its lifecycle EBV is in. Unfortunately, those tests are rarely done in ME/CFS patients

If there is evidence of genes associated with latency, but nothing is present, the virus is simply maintaining latent state. If genes produced later in its life cycle are found, the virus is active but not replicating. If genes devoted to building the outer membrane of the herpesvirus are present – you have an active, replicating virus on your hands.

(The fact that Epstein-Barr virus can hijack the nuclear machinery in B-cells and go through its early, medium and late cycles without ever replicating suggests it can cause much mischief simply sitting in B-cells.  We know that in order to maintain latency, EBV affects how B-cells, a critical part of the immune machinery, function.  We know EBV increases the lifespan of B-cells and that it prompts them to replicate. Some researchers believe EBV’s effects on B-cells underlie all autoimmune processes in the body. )

The smoldering herpesvirus infection hypothesis in ME/CFS produced by Dr. Lerner and researchers at Ohio State University proposes EBV is perturbing immune cells and causing immune cell dysfunction without causing cell death, while producing only very low levels of viral transcription.

Because herpesvirus serology tests will not pick up this type of infection, however, it will never be picked up by standard serology tests.

(to be continued…)___________________

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The Immunology Workshop – Redefining how ME/CFS is diagnosed and treated

Simmaron’s Immunology Workshop Participants

  • Daniel Peterson, M.D. Sierra Internal Medicine, Incline Village, NV
  • Nancy Klimas, M.D. Ph.D Nova South Eastern University, Miami, FL
  • Paula Waziry, Ph.D Nova South Eastern University, Miami, FL
  • Sonya Marshall, Ph.D Griffith University Gold Coast Australia
  • Sharni Hardcastle, Ph.D Griffith University Gold Coast Australia
  • Konstance Knox, Ph.D., Founder, CEO, Coppe Healthcare Solutions
  • David Baewer, M.D. Ph.DMedical Director, Coppe Healthcare Solutions
  • Isabel Barao, Ph.D., Research Assistant Professor, University of Nevada, Reno, Simmaron Research Scientific Director
  • Gunnar Gottschalk, B.S., Simmaron Research, Incline Village, NV
  • Troy Querec, Ph.D., Associate Service Fellow, Centers for Disease Control and Prevention, Atlanta, GA
  • Dennis Mangan, Ph.D., Former Chair, Trans-NIH ME/CFS Research Working Group, Office of Research on Women’s Health, U.S. National Institutes of Health
  • Mary Ann Fletcher, Ph.D., University of Miami Miller School of Medicine Professor of Medicine, Microbiology/Immunology and Psychology
  • Elizabeth Unger, M.D. Ph.D., Chief, Chronic Viral Disease Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases. Centers for Disease Control and Prevention, Atlanta, GA

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


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Simmaron Research Foundation Study Targeting Roots of Immune System Breakdown in Chronic Fatigue Syndrome (ME/CFS)

June 13, 2014

Simmaron Research’s  new immune study builds on exciting research that is changing how we think about ME/CFS.

Twenty years ago  the internationally known virus hunter, Dr. Ian Lipkin of Columbia University, didn’t find Borna Virus in people with ME/CFS, but he never forgot the immune dysfunction he found.  Twenty years later he found more immune dysfunction in another study.

Isabel Barao, PhD, Simmaron Research Scientific Director

Isabel Barao, PhD, the Simmaron Research Foundations Scientific Director believes a genetic predisposition to immune problems could underlie ME/CFS

He doesn’t know why it’s there but he does believe that all ME/CFS cases – no matter what pathogen or other factor has triggered them –  devolve to a ‘common pathway’. The fact that pathogens of all types – from Epstein-Barr Virus, to SARS, to Giardia – can trigger ME/CFS suggests a core immune deficiency lies at the heart of the illness.

Every genetic study suggests an inherited susceptibility to Chronic Fatigue Syndrome is present. Dr. Mady Hornig of the Center for Infection and Immunity at Columbia University believes that a genetic predisposition in combination with an environmental trigger (such as an infection) occurring at just the right (wrong) time is probably key to coming down with ME/CFS.

For thirty or forty years you might be able to easily slough off this bug or that pathogen, but at some point for some reason the stars aligned; you were depleted in just the right way, the pathogen hit and with your immune system genetically predisposed to crack under the pressure – it did – and your entire system faltered.

gene strand

Simmaron is looking for the genetic roots of an immune system breakdown

Simmaron Research’s next pilot study is looking for that immune crack in the dike – the genetic underpinnings of the system collapse that occurred. Led by Simmaron’s Scientific Director, Isabel Barao, PhD, in collaboration with researchers at the National Cancer Institute and University of Nevada Reno, it will determine if your NK and B-cells and macrophages are genetically predisposed to respond poorly to a virus, toxin, or cancer cell.

Dr. Barao is studying whether people with ME/CFS have polymorphisms – unusual gene formations – that make their key immune cells less likely to respond well to viruses and other threats. That immune ‘hole’ many people have talked about with regards to ME/CFS could start here. We all know about the rampant NK cell problems in ME/CFS, but this study could help explain the B-cell problems recently uncovered in a German research study – and perhaps even shed light on why Rituximab may be working in some patients.

It’s the initial part of a projected three-part study that could end with drugs for ME/CFS. Once genetic alterations have been found, they’ll be correlated with immune findings. If that holds up, it’ll  be time to look for drugs to fix the problem, two of which are currently in clinical trials.

We-Have-Ideas

Support the Simmaron Research Foundation as it redefines how ME/CFS is understood and treated

Think about it. The high heritability rates in ME/CFS indicate genetic problems exist somewhere. Where better to look than the immune system?

This study is a no-brainer to me. It’s relatively cheap – it has a quick six-month turnaround – and the data it produces will lay the foundation for an NIH grant on topics they’ve  shown they’re willing to fund.

Help us redefine ME/CFS.  Support breakthrough science on immune deficiencies at Simmaron.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

Brief Report From Dr. Prigden on the Fibromyalgia Antiviral Trial – and the Future Chronic Fatigue Syndrome One

It’s not too much to say that if successful, the Pridgen antiviral trials for Fibromyalgia would be a paradigm changer – turning FM from a poorly treated central nervous system disorder to a  disorder characterized by a (hopefully) treatable herpesvirus infection.

Is it a breakthrough? The results look good so far - stay tuned!

Is it a breakthrough? The results look good so far – stay tuned!

Pridgen’s approach is new in several ways. Not only has no one targeted herpesviruses in FM before, but the  herpesvirus Pridgen is targeting, herpes simplex virus, is one no one has connected with either FM or ME/CFS before.

Pridgen has also combined an antiviral with an anti-inflammatory (with antiviral properties).  Rumors have abounded regarding the identity or identities of the drugs, but we won’t know officially which they are until the report is made.

The fact that we haven’t had a press release by now regarding the Phase II trial has lead to some concern. (Phase two trials are typically larger trials (1-several hundred people) that further assess a treatment’s efficacy and safety. Pridgen’s Phase II trial was a large multi-center trial.)

I contacted Dr. Pridgen to see what he could say at this point. This is what he said.

  • They hope to present their research mid-Nov
  • A press release will predate that
  • The treatment was statistically significantly effective in improving nearly every primary and secondary endpoint
  • The treatment was significantly superior to placebo (p<.oo1) (not sure which  endpoints)
  • The treatment was better tolerated than placebo
  • The results in the FM trial are good enough that preliminary plans are being made for toxicology studies that will allow them to move forward on a similar Proof of Concept Phase 2 CFS (ME/CFS) trial; i.e. they’re beginning to work on a similar ME/CFS trial.
  • They will be looking for government/humanitarian funding for that.

The Earlier Video

Check out a confident Dr. Pridgen as he talks about the Fibromyalgia trial sometime around April at a local news station.

 

Conclusion

It’s going to take longer for the final results than many had hoped but the news otherwise is good.  The significant improvement in almost all the endpoints is promising (and I would say somewhat unusual).  The fact that they’re beginning preliminary planning for an ME/CFS trial suggests that the FM trial went well indeed.

Still, we won’t know how significant the significant improvements are until the press and study release probably in November.

That will be frustrating to those who want to get going on treatments now, but my understanding is that this period – prior to publication – is a delicate period in the development of any drug. If that’s true think how much more so it is for a startup company that’s going to need to raise significant funds for the  big Phase III trial.  Publicly releasing the full results and the drug combo they’ve identified this far in advance of publication would be a mistake.

For more on Pridgen’s antiviral trial check out

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.

smoldering fire

Some researchers think the tests used by Dr. Lipkin are not sensitive enough to pick up the kind of ‘smoldering’ infection they believe is found in ME/CFS

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.

EBV

Pender believes an EBV infection of B-cells sets the stage for autoimmunity in people with impaired T-cell responses

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.

EBV

EBV – A remarkable virus

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.

cytotoxic t-cell

Pender believes reduced cytotoxic T-cell functioning plays a key role in EBV triggered autoimmunity. Some evidence suggest cytotoxic T-cell functioning is reduced in ME/CFS.

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.

from youth to old age

Being exposed to EBV later in life greatly increases the difficulty the body has in fighting it off. How many people with ME/CFS were first exposed to EBV later in life?

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

Rituximab

Rituximab is high on Pender’s list of treatment options for people with EBV induced autoimmunity

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.

Report From San Francisco I: The “Father of Autoimmunity” Speaks

March 31, 2014

When the "Father of Autoimmunity' went to medical school 'autoimmunity' was not believed to exist

When the “Father of Autoimmunity’ went to medical school ‘autoimmunity’ was not believed to exist

Dr. Noel Rose M.D., PhD is  the Director of the Center for Autoimmune Disorders at Johns Hopkins University. Dr. Rose has been studying autoimmunity for over sixty years  but he was a pretty darn spry 80-something at the conference.

When I got close enough to  ask him a  quick question I would have sworn he was a well-preserved sixty something. The bow tie,though, still apparently in  fashion in some medical circles, gave it away as did his statement that the medical schools of his day scoffed, yes, scoffed at the idea that the body could attack itself.

In fact, in 1956 Dr. Rose was the first researcher to introduce autoimmunity as a cause of disease. In an interview he stated

“They were skeptical. People weren’t really prepared to believe it because it seemed so bizarre that you would develop an immune response to your own body. We had all been taught in medical school that the immune response is only directed to what’s foreign. But now we know that isn’t true.”

He’s one of the few people who could can say they wrote the book on it because he did. He wrote the first book on autoimmunity and it’s still being revised today. (Get the latest 1300 page edition for a cool $215)

Dr. Rose probably didn’t appear to know a lot about Chronic Fatigue Syndrome, but he does know  a lot about autoimmunity and with the Rituximab trials putting that subject on everyone’s mind it was good to get a primer on it.

Dr. Rose started off explaining the basics of the autoimmune response by stating that it’s a completely  natural response. We’re all doing autoimmune responses all  the time.  The reason for that is that ‘we all’; that is all the organisms on earth,  share proteins and enzymes and that means that the immune system is going to, in its fervor to rid the body of a pathogen, will inevitably accidentally attack the body instead at times. That means we  come loaded from the get-go with auto -antibodies and  self reactive T and B-cells and also that  we have a built-in way of suppressing those cells.

It’s when that suppression system goes down that you have trouble.

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out  more in seniors

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out more in seniors

An autoimmune response can affect essentially any organ disease in the body, and while  autoimmune disorders can show up very differently, they also share many features. They’re common – they’ve been diagnosed in about 20 million people in the U.S., but probably closer to 50 million Americans have one. They’re ‘chronic’  (usually life-long). They mainly affect women and they’re heavily hereditary.

There are no known cures, they’re expensive – costing the U.S. about a hundred billion (gulp) dollars yearly, and, in contrast to cancer and heart disease, they are on the rise.  About 80 autoimmune diseases have been identified and more are coming.

To the question why there are so many autoimmune  diseases, he stated

 “We think it’s the fact that the immune system is always looking for new pathogenic organisms and being very broad in its abilities to recognize organisms that it also responds to things within our own bodies that are of the same or a very similar substance.”

 

The Sex Bias

Hormones clearly play a major factor in the female predilection for autoimmune disorders.  Rates of autoimmune disorders in children  prior to puberty are equal  in males and females and pregnancy can have a huge effect on symptoms, with some women feeling much better.

They’re believed to  mostly result when  a genetic weakness plus an endocrine effect (female bias) bumps up against an environmental trigger such as an infection. Bad genes account for thirty percent of  the risk which means that 70% of it is probably some chance environmental factor you would have surely avoided if only you’d known.

Known environmental triggers include viruses (in particular EBV), bacteria (streptoccocus), drugs, foods (excess salt), pollutants such as mercury, hormones, stress (important but hard to quantitate). Because the exposure usually comes months or even years before you come down with an autoimmune disorder finding, the triggering factor is  often very  difficult.

gene

Genes account for 30% of the risk for getting an autoimmune disorder. Environmental triggers (infection, toxin, stress, drug) are far more important.

Celiac disease is one of the few autoimmune disorders in which the triggering factor is clear: gluten. Gluten-free diets may be important for more than Celiac patients, however. Dr. Rose believes they  can help people with other kinds of autoimmune disorders.

“Interestingly,” he added, “the gluten free diet may also be helpful for people who don’t have celiac disease but who have other forms of autoimmune disease. It’s just speculative, but as gluten free diets are more available, other people are trying them and often feel better.”

If you have a family member with an autoimmune disorder your risk of developing one jumps over 10-fold (from  .4% to 7%). If your twin has an autoimmune disorder you’ve got a 30% chance that you will come down with one  as well.

Once autoimmunity gets going it usually causes more damage and inflammation and generates more autoimmunity. One of the common signatures is  multiple autoantibodies to multiple antigens.

Treatment

Like ME/CFS and many other chronic illnesses, treatment is focused on symptom alleviation not curing the disorder. Progress is being made, however.

 “We still don’t have a cure, but new treatments have been introduced in the past 15, 20 years for autoimmune diseases like lupus and MS that are remarkable and very much improved. As we understand more about the autoimmune response we find more ways of developing drugs that will intervene, that will benefit the patient by at least alleviating the symptoms even if they won’t cure the disease.”

Autoimmune or Autoinflammatory?

Some disorders that have a strong inflammatory component and look like autoimmune disorders  are not auto-immune disorders; they’re auto-inflammatory disorders.  People with the autoinflammatory disorders carry  loads of auto-antibodies, but lack the self-reactive T and B cells found in true autoimmune disorders.  With regards to treatment  it’s often  a distinction without a difference because both involve the  innate immune system and they’re often  treated the same way.

innate immune diagram

Problems with the innate immune system (NK cell, neutrophils, complement, histamine, etc. ) are behind autoinflammatory disorders

The term  autoinflammatory only showed up in the scientific literature for the first time in 1990’s. Autoinflammatory disorders involve dysregulation of the innate immune system (NK cells, dendritic cells, macrophages,etc.) that result in high rates of inflammation.

Autoinflammatory disorders originally included ‘recurrent fever syndromes’, then branched out to include some genetic disorders, hard to understand disorders like Crohn’s disease, and now may include such common disorders as type II diabetes, gout and atherosclerosis. The  decreased adaptive immune response and increased innate immune response found in autoinflammatory disorders suggest aging could be included in this category. (In the Conference we’ll see some preliminary evidence of increased aging in ME/CFS)

We don’t know if some  individuals with ME/CFS have an autoimmune or an autoinflammatory disorder. Rose didn’t appear to know much about ME/CFS but after his  talk I asked Rose what I thought was THE question; the question that was not given to him  during the Q&A session even though I wrote it out twice,  the second time at least semi-legibly, and  that was:

“What does a positive response to Rituximab in a gender  specific disorder tell you about autoimmunity or  an auto-inflammatory response?” The MAN said it meant it could be either.

 ME/CFS Autoimmune Studies Underway

 “We hope this study will identify a pathogen as a likely causative agent of the disease in order to focus future study. Dr. Elledge

dorsal root ganglia

One CFIDS Association of America study will target autoantibodies to the dorsal root ganglia that the Light’s believe play a role in ME/CFS

Besides the two Rituximab trials two studies, both using the CFIDS Association of America’s Biobank, will shed light on the role autoimmunity plays in  ME/CFS. One promising study lead by Dr. Elledge of Harvard University will determine what the autoantibodies present in ME/CFS patients blood are targeting and what viruses the antibodies present are associated with.

“…autoantibodies to brain and dorsal root ganglia have been demonstrated in chronic post-Lyme disease syndrome, an entity essentially identical with chronic fatigue syndrome/fibromyalgia” Dr. Cooperstock

Another lead by Dr. Cooperstock will look for autoantibodies to nervous system targets including the dorsal root ganglia that feature in some theories of ME/CFS.

EBV I: A Deficient Immune Response, Increased Levels of Epstein-Barr Virus Opens Up EBV Question in Chronic Fatigue Syndrome Again

A Long History

Although altered EBV-specific antibody titers have been repeatedly demonstrated in CFS, no clear evidence for chronic EBV replication has been obtained so far. Authors

Perhaps the most common viral trigger for chronic fatigue syndrome (infectious mononucleosis, aka glandular fever) or Epstein Barr Virus (EBV) is a herpesvirus almost all adults have been exposed to and carry, usually in latent form in their cells.

conflicting signs

Conflicting results have made it difficult to determine the role EBV plays in ME/CFS. Will this German study signal a change?

EBV infection was proposed as the cause of chronic fatigue syndrome not long after the disorder became prominent in the 1980s, but inconsistent study results in the 1980s and 1990s followed by Straus’s 2000 paper (which suggested the search for herpesvirus infections in ME/CFS was over) put a damper on EBV research efforts.

From 2000 to the present only Dr. Lerner with his stream of positive studies (but sometimes challenging study designs) and Dr. Glaser published fairly consistently on EBV in ME/CFS. Recently Dr. Lipkin stated (unpublished) he found no evidence of active EBV infection using high throughput sequencing in the plasma of hundreds of ME/CFS patients.

Despite study inconsistencies, EBV has remained a pathogen of interest in ME/CFS. Both Lerner and Glaser have produced evidence suggesting that a defective form of the EBV virus may be causing the symptoms in some people with ME/CFS. Recent studies suggesting that EBV triggers autoimmune disorders are intriguing given the successful ME/CFS Rituximab treatment trials.

EBV’s ability to reactivate during stress and in hypoxic conditions may have implications for its possible role in ME/CFS as well. A recent laboratory study suggesting that high rates of oxidative stress can reactivate EBV and that antioxidants (including NAC, catalase, and L-glutathione) might be helpful in reducing EBV reactivation is intriguing given the high rates of oxidative stress found in ME/CFS.

Now, in a surprising turn, German researchers have not only put the spotlight back on EBV, but have dug deeper into EBV, ME/CFS, and the associated immune response than any group has before.

The Study

“Taken together, our study provides clear evidence that deficiency of EBV-specific immune response is present in CFS” The authors

The adaptive part of the immune system, the one that takes time to kick in, comes in the form of B-cell produced antibodies that lock onto proteins the virus produces and cytotoxic T-cells that attempt to the kill the virus. (B-cell’s attack the virus in the blood and cytotoxic T-cell attack virally infected cells.)

broken

Ohio State researchers believe a defective form of EBV that is spewing out proteins may be causing ME/CFS

Noting some unusual findings in their lab, these researchers looked at these antibodies and T-cells to see if people with chronic fatigue syndrome were mounting an effective immune response against EBV. They also looked for direct evidence of an active EBV infection.

EBV replication occurs when the virus produces proteins in a sequence that allows it to build another virus. One theory, developed by Dr. Lerner and a group at The Ohio State University (that includes Drs. Ariza, Glaser, and Williams), proposes that EBV undergoes ‘abortive replication’ in some people with ME/CFS. In abortive replication, a defective form of EBV produces early proteins, but is unable to produce later ones. The Ohio State group believes continual production of these proteins is causing a chronic inflammatory state in some people with ME/CFS.

Results

First, the German researchers found evidence of primary EBV infection or reactivation (increased IgM antibodies to a late EBV protein in @15% of patients vs 3% of controls) in significantly more ME/CFS patients than controls. The fact that this could be a ‘primary infection’; i.e. it represents the first time these patients are exposed to the virus is intriguing. A primary infection of EBV early in life usually leads to nothing more than a cold; a primary infection later in life can have serious consequences including infectious mononucleosis.

Having found evidence that an active EBV infection was more common in people with ME/CFS than controls, they looked to see if a reduced immune response was responsible for that.

The first hint of a reduced immune response to EBV in ME/CFS came in the form of a lack of antibodies to EBV-produced proteins VCA and EBNA1.

But first, a short antibody primer:

antibody

Antibodies attack pathogens in the blood; cytotoxic T-cells attack them in the cell

Antibody Types

  • IgG antibodies are ‘memory antibodies’ that travel through our system looking for evidence that a pathogen is present. Once your B-cells have mounted an attack against a pathogen, they are always present in our system. Therefore, IgG antibodies are not evidence of an ongoing infection.
  • IgM antibodies are attack proteins associated with a pathogen. High IgM titers to a viral protein generally reflect a primary infection.

With two types of antibodies being manufactured against a range of viral proteins the situation becomes complicated, but a healthy immune system should produce an array of both IgG and IgM antibodies that can detect (IgG) and inhibit (IgM) pathogens (found outside cells) at different stages of their lifecycles.

As they dug deeper, the German researchers found holes in the immune response to EBV in ME/CFS patients.

Immune Holes to Epstein-Barr Virus Found

Immune Hole #1 – reduced antibody response

Evidence of a impaired B-cell response to EBV first came in the form of missing IgG antibodies to VCA and EBNA in 13% of ME/CFS patients compared to 4% of controls. This indicated that 13% of their ME/CFS study population did not have some of the memory B-cells needed to detect an EBV infection.

Increased IgM antibody responses in ME/CFS (17.5% in ME/CFS vs 4% in controls), on the other hand, suggested active and perhaps primary EBV infections were more commonly found in ME/CFS patients.

All told, 30% of the ME/CFS patients either had reduced IgG (EBNA-IgG) or increased IgM (VCA) responses to EBV.

That finding prompted a deeper look, and a much larger study that found no IgG response to a protein expressed during latency by EBV (called EBNA-1 protein) in 10% of IgG positive ME/CS patients. This indicated that the immune systems of approximately 10% of the ME/CFS group were unable to detect a very early stage of EBV latency.

EBV

The EBNA-1 protein featured in many of the tests helps EBV maintain its latency in B-cells

Latency – For EBV to maintain itself in the body over time, it needs to be able to maintain itself in B-cells in a process called latency. EBNA-1 is a protein that helps maintain EBV’s viral genome in the earliest stages of latency.

The authors noted that people with severe infectious mononucleosis and chronic active Epstein-Barr virus disease have similar findings (although it’s not clear why, given that EBNA-1 is not involved, so far as we know, in replication).

That brings up the question of how many people with ME/CFS would have fit into the category of severe mononucleosis at the time they got ill. The Dubbo studies found that more severe infections greatly increase the risk of coming down with ME/CFS.

Immune Hole #2 – reduced frequencies of two B-cell antibody producing cells

Intrigued by the findings, the German researchers dug deeper into the immune response to EBV. They took blood (PBMCs) from ME/CFS patients and then stimulated it with CpG, SAC, and PWM for seven days, and found reduced frequencies of B-cells producing antibodies against VCA and EBNA-1, and for the first time they found evidence of immune deficiencies in most people with ME/CFS.

No less than 59% of ME/CFS samples had a diminished response to a later stage EBV protein (VCA) produced during the late stage of lytic replication, and a whopping 76% of ME/CFS samples had a diminished response to the EBNA-1 protein. With the VCA finding we have evidence suggesting many people with ME/CFS may have trouble controlling EBV replication.

Calling the findings ‘remarkable’, the authors suggested that either the memory B-cells associated with these EBV antigens had been lost or had failed to develop into antibody-secreting cells.

Immune Hole #3 – Reduced T-cell response to EBNA-1

A similar deficiency in the T-cell response to EBNA-1 indicated that both arms of the adaptive immune response to Epstein-Barr Virus, the B-cells and the T-cells, had difficult recognizing and responding to this protein.

Citing other disorders such as HIV, they suggested that persistent EBV reactivation in ME/CFS had driven the T-cell response in ME/CFS into ‘exhaustion’. (A similar suggestion has been made with regard to natural killer cells that attack pathogens early in an infection, which use killing methods similar to those employed by T-cells.)

Further analysis suggested that T-cell suppressor cells which decrease B-cell responses were not responsible for the B-cell suppression found. Normal B-cell responses to herpes simplex and cytomegalovirus suggested that the deficient B-cell responses were associated with EBV and not other herpesviruses.

cytotoxic T-cell

Lower cytotoxic T-cell responses to EBNA-1 could be associated with an increased risk of autoimmune disorders

Immune Hole #4 – reduced T-cell response to EBNA-1, reduced T-cell responses to EBV

Next they explored T-cell induced cytokine production. The T-cells should produce an array of cytokines against EBV. About 20% fewer ME/CFS patients (70% of controls vs 50% of ME/CFS patients) were able to mount an IFN-y response against EBV.

Looking specifically at the latency associated EBNA-I protein, they found the startling result that no ME/CFS patients mounted an IFN-y response against it.

They also found that ME/CFS patients produced significantly lower amounts of the pro-inflammatory cytokine TNF-a in response to EBV. Finally, a lower percentage of patients produced IL-2 as well. The reduced cytokine production suggested cytotoxic T-cells, one of the big guns of the adaptive immune response, were not being strongly activated in response to EBV.

Immune Hole #5 – Reduced frequencies of EBNA-1 specific T-cells

The researchers dug deeper still. Next they stimulated the blood (PBMCs) of ME/CFS patients and healthy controls (n=40) with the EBNA-1 protein, expanded the cells in the presence of IL-2 and Il-7, and then checked the T-cell response to them. Specific types of T-cells should be produced to attack EBV, but reduced frequencies of EBV-specific T-cells occurred in about 50% of the ME/CFS samples. That again suggested the cytotoxic T-cell response to the EBNA-1 protein was substantially reduced in ME/CFS.

Direct Evidence of Active EBV Infection

“Remarkably, in line with this finding we could provide evidence of enhanced viral load of EBV by detection of EBV DNA in a significantly higher proportion of patients compared to healthy controls.” The authors

Using a real-time PCR test in the whole blood that looked for ‘low-copy’ numbers (<1,000-2930 copies/ml) they found evidence of increased EBV viral load in 7.2% of 290 ME/CFS patients. When they dug deeper and did the same test in PBMCs in a subset of patients, they found that a whopping 55% of patients (vs 13% of controls) tested positive for EBV.

The viral loads were far below those found in other EBV associated illnesses such as infectious mononucleosis or post-transplant EBV infections, and there was no evidence of lytic replication (i.e., full replication of the virus), but something the authors called ‘latency-associated replication’ was common in people with ME/CFS, yet not in healthy controls.

The Lipkin Study

Using PCR the German researchers found much higher rates of EBV infection in PBMCs vs whole blood and no evidence of EBV infection in plasma.

plasma-blood

Was looking for EBV in plasma somehow a mistake?

Neither the Lipkin CFI ME/CFS pathogen study nor the CFIDS Association of America BSR study found evidence of EBV infection in ME/CFS. According to Russell Fleming’s transcript of the Lipkin talk, the CFI study looked in the plasma of both the Montoya and the ME/CFS experts’ samples.

Whole blood contains plasma, red blood cells, white blood cells, and platelets. Plasma makes up 55% of blood volume and contains water (90%), proteins, nutrients, waste products, clotting factors, hormones and carbon dioxide. It does not contain red or white blood cells or thrombocytes.

EBV DNA has certainly been found successfully in plasma before and plasma has been used to track EBV activation. Serum/plasma EBV PCR kits are available for purchase. Researchers search and find EBV in plasma frequently.

Dr. Chia, however, reportedly stated he believes the use of plasma rather than blood was a serious mistake, and the Germans were able to find evidence of EBV activation in blood but not in plasma.

EBV (and CMV and HHV-6) are ‘cell-associated viruses. The only times their DNA escapes the cells is when the cell dies (and the DNA goes into the plasma) or when the virus is replicating. Otherwise the virus sits in a latent or semi-latent state in the cells
Medical dogma states if you can’t find EBV in the plasma, the infection is not active. EBV DNA can be found in the plasma when EBV replication rates are high, as sometimes occurs in transplant patients, but it’s not likely to be found in the smoldering infection believed present in ME/CFS. Many researchers do not accept the idea of a smoldering infection that pumps out proteins which trigger an inflammatory response.

The German researchers are deepening their study of EBV and ME/CFS and currently evaluating antibody responses against a broader variety of EBV peptides derived from 8 different proteins. They are also quantifying the levels of memory B-cells targeting EBNA-1 and VCA.

Conclusion

“We think the altered pattern of the specific immune response to EBV may be suitable as a diagnostic marker for CFS.” Authors

ball of string

The harder they looked, the more they found …

It was if these researchers kept pulling a string that got longer and longer. First their interest was piqued by some paradoxical antibody findings, then they found widespread deficiencies in some antibody responses and T-cell responses, and finally they saw evidence of an active EBV infection in the blood of 55% people with ME/CFS (vs 7% of controls).

Much is still unclear. The EBNA-1 protein that the immune systems of ME/CFS patients had trouble responding to is associated with ‘early latency’, not EBV replication. The authors’ reference to ‘latency associated replication’ is unclear given that latency is not usually associated with replication. When asked what importance their findings have for EBV reactivation or EBV survival or  more severe casesof infectious mononucleosis in ME/CFS, the authors stated they can’t answer those questions yet.

Some researchers believe, however, that reduced cytotoxic T-cell responses to EBV increase the risk for autoimmune disorders. (We’ll be covering that possibility in the next blog.) These findings also suggest that the proposal by Lerner and the OSU group of Drs. Ariza, Glazer, and Williams that an abortive lytic process (smoldering EBV infection) is present in many people with ME/CFS may be correct.

While it will take more work to determine what these findings mean for ME/CFS,  the broad range of dysfunction  found and the high rate of active EBV infection (in plasma) would appear to put this pathogen back into play in a meaningful way in ME/CFS.

Simmaron’s Immunology Workshop at IACFS/ME: Redefining How Chronic Fatigue Syndrome Is Diagnosed and Treated

Immunology Primer For Practitioners

I’ve been going to IACFS/ME conferences for eight years now and I’ve never seen a Workshop like this. This is a Workshop that could change how Chronic Fatigue Syndrome patients are tested and treated in the upcoming years. Called the “Immunology Primer for Practitioners“, it’s chaired by Dr. Daniel Peterson.

key

Standard immune tests for ME/CFS patients could change viewpoints and unlock new treatment opportunities for many.

It’s mission: to produce bulletproof recommendations for immune tests that will guide both the diagnosis and treatment of chronic fatigue syndrome. Doctors are interested, patients are surely interested, and Dr. Unger from the Centers for Disease Control (CDC) is interested, so Simmaron Research is seizing the moment.

Recognizing the opportunity and realizing that a consensus recommendation of experts would carry the most weight, Simmaron gathered 12  experts (sponsoring half of them), including nine immunologists, to produce ironclad recommendations.

Redefining ME/CFS Indeed

The Simmaron Research Foundation is committed to ‘Scientifically Redefining ME/CFS’ and  few things could change the landscape more rapidly for patients than the CDC including immune tests in its ME/CFS management guidelines.

We know common blood tests reveal little or nothing about ME/CFS, but  immune tests may not only be very revealing, but may open the door to a new conception of ME/CFS in the medical community, and to a whole swath of treatments most MD’s know little about.

Producing Real Change

vision

Simmaron is committed to funding work that alters how the medical profession sees and treats ME/CFS

In order to produce real change you need to get at the ‘levers of power’ and, like it or not, the CDC is one of those levers. The CDC is trusted by gatekeepers in the medical field. It’s recommendations matter. As we know, for better (in this case) or for worse (in the past), they get spread around.

Dr. Unger’s interest in immune test recommendations from ME/CFS experts is just the latest in a series of transformative moves at the CDC.  Instead of holding ME/CFS experts at arm’s length, Dr. Unger has embraced them. She has visited many of the experts’ centers, and her multi-year, multi-site clinical assessment study is bringing the insights of ME/CFS experts to the fore at the CDC and other agencies for the first time.

The Latest in Immune ME/CFS Research

Besides the recommendations, the Workshop will provide education for clinicians on the immune system in ME/CFS, overviews of immune findings, and insights into cutting-edge ME/CFS immunological research. We will hear highlights from the Australian NCNED teams intense focus on natural killer cells, learn what the  CDC is currently researching, uncover what very severely ill ME/CFS patients’ immune system looks like, understand how herpesvirus infections might be linked to autoimmunity and more.

The immune system features prominently in this years IACFS/ME Conference

The immune system features prominently in this years IACFS/ME Conference

Underscoring the strong immunological focus in this IACFS/ME Conference, Dr. Peterson’s session follows an opening presentation by Dr. Ian Lipkin.  Dr. Lipkin described evidence of “ongoing stimulus to the immune system” and a different immune profile  patients ill less than 3 years have compared to long term patients last fall on a conference call hosted by Dr. Unger.

Dr. Klimas’ panel the next day will go deep on “The Latest Research in Immunology”, including results from Dr. Lipkin’s collaborative research, the CDC’s genomic study, and Dr. Marshall’s natural killer cell research. Her panel follows the Plenary Session with Dr. Noel Rose, Director of the Center for Autoimmune Research at Johns Hopkins.

It is a pivotal time in ME/CFS, and immunity and autoimmunity are coming into focus. Simmaron seeks to take these groundbreaking sessions into clinical practice with consensus.

Simmaron Research Foundation Moving Forward

Yes

Redefining ME/CFS step by step

This is just one of the Simmaron Foundation’s efforts to redefine Chronic Fatigue Syndrome by taking advantage of the expertise and experience of Dr. Peterson and his fellow practitioners.

That effort began with Dr. Peterson’s retrospective analysis of treatment success using Vistide in selected patients and will continue with further analyses of the effects of other immune-based treatments, like IVIG and Ampligen.  Dr. Peterson will also be participating in the B-12/MFTHR trial this spring.

In order to address a critical need for more expert  ME/CFS clinicians the Simmaron Foundation has also funded a practitioner to learn from Dr. Peterson. Bringing expertise and research to patient care is Simmaron’s mission.

Support the Simmaron Research Foundation’s Work to Scientifically Redefine ME/CFS

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“Immunology Primer for Practitioners” Panelists

  • Daniel Peterson, M.D., Owner, Sierra Internal Medicine, Incline Village, NV, Simmaron Research Scientific Advisor
  • Sonya Marshall – Gradisnik, BSc (Hons), Ph.D. , Professor of Immunology, Director, National Centre for Neuroimmunology & Emerging Diseases, Griffith University, Australia
  • Sharni Hardcastle, Ph.D., Research Assistant and Practical Demonstrator , Bond University, Gold Coast, Australia
  • Nancy Klimas, M.D. Ph.D., Professor of Medicine and Director, NSU COM Institute for Neuro-Immune Medicine Director, Miami VAMC Gulf War Illness and ME/CFS Research Program
  • Paula Waziry, Ph.D, Assistant Professor, Neuro Immune Medicine, COM, Nova Southeastern University, Miami, Fl
  • Konstance Knox, Ph.D., Founder, CEO, Coppe Healthcare Solutions
  • David Baewer, M.D. Ph.DMedical Director, Coppe Healthcare Solutions
  • Isabel Barao, Ph.D., Research Assistant Professor, University of Nevada, Reno, Simmaron Research Scientific
  • Gunnar Gottschalk, B.S., Simmaron Research, Incline Village, NV
  • Troy Querec, Ph.D., Associate Service Fellow, Centers for Disease Control and Prevention, Atlanta, GA
  • Dennis Mangan, Ph.D., Former Chair, Trans-NIH ME/CFS Research Working Group, Office of Research on Women’s Health, U.S. National Institutes of Health
  • Mary Ann Fletcher, Ph.D., University of Miami Miller School of Medicine Professor of Medicine, Microbiology/Immunology and Psychology
  • Elizabeth Unger, M.D. Ph.D., Chief, Chronic Viral Disease Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases. Centers for Disease Control and Prevention, Atlanta, GA