Reprinted with the kind permission of Simmaron Research Foundation.
By Cort Johnson, July 13, 2014
Simmaron’s Immunology Workshop on ME/CFS, Part I
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.
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-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.
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.
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.
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.
Learn more about EBV’s fascinating possible connection with autoimmunity in
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.D, Medical 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