“Our results indicate a markedly disturbed immune signature in the CSF of ME/CFS subjects that is consistent with immune activation in the CNS.”
Dr. Mady Hornig, Director of Translation Research, Columbia University
Columbia University just published groundbreaking results of the first spinal fluid study to compare ME/CFS with Multiple Sclerosis and healthy controls. For almost his entire career treating CFS patients, Dr. Daniel Peterson has been working toward this day.
Simmaron Research, founded by Dr. Peterson, was a key collaborator in this study, along with Konstance Knox Ph.D. of Coppe Healthcare. Drs. Peterson and Knox provided the spinal fluid samples, and Simmaron’s Research Manager Gunnar Gottschalk did clinical coordination. Drs. Mady Hornig (lead author) and Ian Lipkin (senior author), who run Columbia’s Center for Infection and Immunity, designed the study and led the sample and data analyses. Many thanks are due all the collaborators and especially the Chronic Fatigue Initiative and Evans Foundation for funding this novel work.
Molecular Psychiatry. 2015 Mar 31. doi: 10.1038/mp.2015.29. [Epub ahead of print]Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Hornig M1, Gottschalk G2, Peterson DL2, Knox KK3, Schultz AF4, Eddy ML4, Che X4, Lipkin WI5.
Cerebral spinal fluid is a colorless fluid that surrounds and cushions the brain and spine. Constantly being produced and absorbed it is fully replaced about four times a day. It provides immunological protection and removes metabolic wastes from the brain.
Lumbar punctures such as those used in this study are primarily used to diagnose neurological disorders.
In several ways, this study distinguished itself from other spinal fluid studies in chronic fatigue syndrome. It examined a more comprehensive cytokine panel (n=51), did more sophisticated statistical analyses (logistic regression/network analysis) and included a multiple sclerosis group as a control. With ninety-one subjects, it was a large sample size for a spinal fluid study (32 ME/CFS patients, 40 MS patients, 19 controls) and it was suitably complex.
Highly Significant Results
Major differences were found. With all the central nervous system problems present in MS, we expect MS would be different from healthy controls. The levels of over half of the cytokines tested (26/51) in the MS group vs the controls were significantly different. An almost equal degree of difference, however, also occurred in the ME/CFS group. Almost half the immune factors tested (23/51) were significantly different in the ME/CFS patients relative to the healthy controls.
Highly significant differences in immune factor levels (p<.0003 or less) were found in 13 cytokines in MS group vs healthy controls, in 4 cytokines in ME/CFS vs healthy controls, and in 8 cytokines comparing ME/CFS to MS.
The immune system is a complex place. Cytokines have a role in both producing and controlling inflammation. Some evidence points to ME/CFS being an inflammatory disorder, and there’s no doubt that multiple sclerosis is an inflammatory disorder. Interestingly, the cytokine levels in the MS patients spinal fluid were even lower than those in the ME/CFS patients.
In general both MS patients and ME/CFS trended in the same direction – mostly reduced cytokine levels relative to the controls – but the immune dysregulation was very different. With twenty-three immune factors differing between the ME/CFS and MS patients, a case could be made that the ME/CFS and MS groups differed the most immunologically. The researchers stated ME/CFS patients demonstrated a “markedly greater degree of CNS immune activation” than the MS group.
People in the current study had had chronic fatigue syndrome for about seven years. The relatively low cytokine levels found parallel those found in the longer duration patients in the large blood cytokine study the Columbia researchers recently completed.
“I think what we’re seeing is an immune system exhaustion over time,” Dr. Hornig speculated in HealthDay.
Chemokines, Infections and CNS Damage
Scientists at Columbia … identified a unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that provides insights into the basis for cognitive dysfunction—frequently described by patients as “brain fog”
Chemokines are of special interest in neuroinflammation because these very small proteins regulate immune cell entry into the brain. When an infection occurs, they draw immune cells into the brain by increasing the permeability of the brain blood barrier. The microglia and astrocytes are the primary chemokine producers in the brain.
Two chemokines (CCL11 and CXCL10) were increased in both the MS and ME/CFS groups with much higher levels of both found in the MS group.
CXCL10 clears the way for the entry of natural killer cells and T lymphocytes into the brain. It is often prominently expressed in the CNS in response to viral infection.
As always the immune system walks a fine line. Too little chemokine expression and a deadly infection can take root. Too much chemokine expression and brain damage and seizures can result. While CXCL10 plays an important role in combating viral infections, excessive CXCL10 levels can cause neuron die off and trigger a immune-mediated demyelinating disease.
Demyelination is a major problem in MS but is only a possibility at this point in ME/CFS. A small recent Stanford study suggested myelin abnormalities along with white matter atrophy may be present in ME/CFS. .
Not surprisingly, CXLC10 clearly has an impact on symptoms. Neutralizing CXCL10 even during a persistent infection can greatly reduce symptom severity.
Allergic Response, Eotaxin and Brain Fog
“These immune findings may contribute to symptoms in both the peripheral parts of the body and the brain, from muscle weakness to brain fog.” Dr. Mady Hornig
IL1ra is supposed to tamp down an allergic response as well. The network analysis in this study suggests that it’s not working so well in ME/CFS patients. The inverse relationship between IL1ra and CSF2 (GMCSF) levels in the ME/CFS patients, indeed, suggested an allergic response was underway. Reduced CSF2 levels were found in a prior ME/CFS spinal fluid study as well.
Then there is eotaxin (CCLII). Eotaxin recruits white blood cells called eosinophils that are involved in producing an allergic response in the brain. The logistic regression suggested increased levels of eotaxin (and decreased levels of IL1b) are highly associated with “ME/CFS caseness”.
Eotaxin is not a chemokine one particularly wants to have around. Increased eotaxin levels have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age. Introducing eotaxin into the CNS of young mice reduces neuron production. (At the last IACFS/ME Conference, the CDC reported reduced telomere length – another possible sign of increased aging – was present in ME/CFS.)
“…we now identify systemic immune-related factors (eotaxin) as potentially critical contributors to the susceptibility of the aging brain to cognitive impairments”. Villeda et. al. 2011 – From a mouse study published in Nature
One doesn’t think of allergy in terms of the central nervous system, but the authors reported that allergic processes could be indicative of a central nervous system infection. The chemokines upregulated in the ME/CFS patient’s spinal fluid have been associated with microglial activation and central nervous system infections.As the publication notes, “Persistent secretion of cytokines by activated microglia, brain immune cells of macrophage-monocyte lineage, may contribute to this pattern.”
“The inverse relationship we found between IL1ra and CSF2 in the CSF of cases using a network analysis approach suggests that neuroimmune responses may be shifted toward allergic or Th2 (autoimmune) patterns in the CNS of individuals with ME/CFS.”
The Hornig/Lipkin team also found evidence of disturbed “networking” in ME/CFS; i.e. immune cells communicating strangely. IL-1ra is an interleukin that prevents cells with IL-1 receptors from producing the powerful pro-inflammatory cytokines IL-1A or IL-1B. It stops that part of the immune response in its tracks, but the network analysis suggested it wasn’t doing that in ME/CFS.
- The fact that the alterations in the immune factors in the ME/CFS were almost as extreme as in multiple sclerosis – a disorder characterized by severe central nervous system dysfunction – suggests a major pathology is present in the central nervous systems of ME/CFS patients.
- The low cytokine levels suggest that some sort of immune exhaustion – caused by an infection or by immune upregulation – is present in ME/CFS. These findings parallel those of the recent Hornig/Lipkin study suggesting that immune up regulation early in the disorder may lead to immune burnout later on.
- Several of the immune factors in the ME/CFS patients spinal fluid suggest an allergic type of reaction may be occurring in their CNS. A similar finding is also found in some central nervous system infections; i.e. an infection could be driving this process.
- The immune factor most identified with the ME/CFS patients has been associated with cognitive declines, aging and reduced neuron production.
“Diagnosis of ME/CFS is now based on clinical criteria. Our findings offer the hope of objective diagnostic tests for disease as well as the potential for therapies that correct the imbalance in cytokine levels seen in people with ME/CFS at different stages of their disease,” adds W. Ian Lipkin, MD, John Snow Professor of Epidemiology and director of the Center for Infection and Immunity.
Early on, MS didn’t have biomarkers or diagnostic tests, and it had skeptics like CFS does. Later it was diagnosed by specific proteins in spinal fluid. Now there are FDA-approved treatments.
ME/CFS patients often have central nervous system symptoms, like cognitive dysfunction, balance problems, and nerve and pain issues. Those symptoms convinced Dr. Peterson many years ago that spinal fluid may hold the key to understanding the disease. His perseverance helped make this study possible.
Columbia University’s press release stated:
“There is precedent for use of human monoclonal antibodies that regulate the immune response in a wide range of disorders from rheumatoid arthritis to multiple sclerosis. However, the researchers note, additional work will be needed to assess the safety and efficacy of this approach.”
We need more research to translate these unprecedented findings into diagnostics and treatments.