When we think of immune problems we often think of the immune system going berserk and attacking healthy cells but another kind of immune issue called can be present. Recent studies suggest immune exhaustion may be more of a problem for many chronic fatigue syndrome (ME/CFS) and/or fibromyalgia patients than an immune system run amok.

CHRONIC FATIGUE SYNDROME (ME/CFS)

“I think what we’re seeing is an immune system exhaustion over time” Dr. Mady Hornig

Chronic fatigue syndrome (ME/CFS) has generally been thought of as an immune activation disorder. Although much of the interest in the Lipkin/Hornig 2015 study focused on the immune activation found early in the disease, the study found 13 downregulated immune factors in the plasma of longer duration patients relative to the healthy controls. Remarkably the same cytokines that were upregulated early in the disease were downregulated later in the disease.

That pattern smacked of something called “immune exhaustion”. Immune exhaustion is a well-known pattern of immune depletion seen in people with chronic infections or autoinflammatory diseases. Immune exhaustion may be the main reason why some people just can’t knock an infection.

The patterns seen in the big 2015 Lipkin/Hornig Chronic Fatigue Initiative immune blood study were intriguing but not conclusive. Studies published since then, though, suggest that immune exhaustion – not immune activation – could be the main culprit in people with longer duration chronic fatigue syndrome (ME/CFS) and fibromyalgia.

It should be noted, again, how important it was to differentiate shorter from longer duration patients. No immune abnormalities when the two subsets were mixed; only when they were differentiated by disease duration did the immune issues pop up.

The Simmaron Research/Lipkin/Hornig Spinal Fluid Study

Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI.Mol Psychiatry. 2016 Feb;21(2):261-9. doi: 10.1038/mp.2015.29. Epub 2015 Mar 31.PMID: 25824300

Next came the Lipkin/Hornig/Simmaron Research Foundation study examining immune factors in the spinal fluid of ME/CFS and multiple sclerosis patients and healthy controls. Not only was a broad pattern of immune inhibition found in the longer duration patients but for the first time match between blood and spinal fluid study was found: the same issues appeared to be occurring in both the central nervous system and the body.

The number of downregulated immune factors – twenty-one in all (vs 13 in the blood study) in the spinal fluid of longer duration ME/CFS patients relative to healthy controls was notable and suggested that the closer one moves to the brain the more evidence of immune exhaustion one may find.

Both ME/CFS and MS patients exhibited immune exhaustion compared to healthy controls but the degree of immune exhaustion seen in ME/CFS was greater than that seen in MS. Demonstrating how complex the immune system is, the two diseases differed more from each other than from the healthy controls.

In one perhaps important way, though, they were quite alike. A chemokine called CXCL10 that clears the way for the entry of natural killer cells and T lymphocytes into the brain in response to a viral infection was increased in both disorders. Increased levels of that chemokine in conjunction with the different kinds of immune exhaustion found in both disorders suggests that either different viruses could be present or a different response to the same virus has occurred.

The fact that infectious mononucleosis or glandular fever increases the risk of coming down with either ME/CFS or multiple sclerosis is intriguing in this regard. Could ME/CFS and MS simply reflect differing responses to the same virus?

Jarred Younger recently suggested that MS may be a more damaging form of ME/CFS. Neuroinflammation is present in both, but in one (MS) the neurons are damaged and in the other (ME/CFS) they are not.

Very high levels of CXCL10, such as appear to be present in MS, are associated with nerve damage. More moderately raised levels, such as seen in ME/CFS, are not. CXCL10 levels may also be able to tell us which patients respond better to antivirals. Hepatitis C and HIV patients with higher CXCL10 levels responded less well to antivirals than patients with lower levels.

The Lipkin spinal fluid study is looking more and more like it could end up being a seminal study. It highlighted a new subset – “the Peterson subset” and validated and expanded on the dramatic immune downregulation seen in the earlier blood study.

A follow-up Simmaron Research/Lipkin/Hornig spinal fluid study is in the works.

The spinal fluid study wasn’t the end of the trend towards immune downregulation, though; right on its heels came the large Landi-Houghton blood study.

The Simmaron Research Foundation Australian Spinal Fluid Study



Mediators Inflamm. 2015;2015:929720. doi: 10.1155/2015/929720. Epub 2015 Mar 5.Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis.

The Simmaron Research Foundation also participated with Sonya Marshall-Gradisnik at Griffith University in a small pre-pilot spinal fluid study. In this smaller study only one immune factor, IL-10, significantly differed between the ME/CFS patients and the healthy controls but the trend was the same; IL-10 was significantly reduced in the ME/CFS patients.

This study may tell us how immune depletion in one area can lead to immune activation in another. Because IL-10 is an anti-inflammatory, reduced IL-10 levels in the cerebral spinal fluid could reflect a brain with inflammation.

The Houghton-Landi Blood Study

Cytokine. 2016 Feb;78:27-36. doi: 10.1016/j.cyto.2015.11.018. Epub 2015 Nov 28. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Landi A1, Broadhurst D2, Vernon SD3, Tyrrell DL4, Houghton M5.

Michael Houghton isn’t just any researcher. A Lasker award winner, he got bit by the ME/CFS bug during the XMRV saga. (He got bit so hard that the Solve ME/CFS Initiative even got him onto the federal advisory panel for ME/CFS ( CFSAC) for a while.) Researchers of his ilk are a real asset to our community and it’s good to see him remaining engaged. In this study he worked with Bateman-Horne Center’s “Research Czarista” Suzanne Vernon.

The Landi-Houghton study examined 34 immune and growth factors in no less than 100 longer duration ME/CFS patients. This study also found little evidence of overt immune activation. Instead, a cluster of down-regulated immune factors ( IL-16, IL-7 and VEGF-A) popped up which suggested ME/CFS – at least in its later stages – was more characterized by immune depletion. They also suggested that ME/CFS patients might be a aging a bit more rapidly than normal.

Early Aging?

IL-7 plays a critical role in NK and T-cell proliferation and induction and IL-7 levels are associated with cognitive declines during aging. The authors suggested that the immune signature they found could mimic aging. It’s not the first result to suggest early aging may be present in either ME/CFS or FM.

One FM study found cognitive declines suggestive of people who were twenty years older. Reduced telomere lengths (a sign of aging) were found in the white blood cells for FM patients and the CDC has reported finding reduced telomere length in chronic fatigue syndrome as well.

Two Factors Stand Out

VEGF-A – VEGF-A promotes the survival and stability of endothelial cells lining the blood vessels, stimulates muscle and blood vessels and has neuroprotective factors. It also promotes neuron growth by stimulating epithelial cells to release BDNF – which appears to be low in ME/CFS.

VEGF-A is becoming a factor to look out for in ME/CFS. For one thing it affects the blood vessels. For another reduced VEGF-A levels also popped up in the Simmaron Foundation/Lipkin/Hornig spinal fluid study and in a Gulf War Syndrome study .

Eotaxin – Eotaxin has suddenly appeared on the ME/CFS scene. It was one of only two factors upregulated in the spinal fluid study. Remarkably, high eotaxin levels have been found in long duration patients in three recent studies.

Increased levels of eotaxin have been associated with impaired learning, memory deficits and reduced neuron production in mice as they age.

These consistently increased eotaxin levels could signify either an allergic response a central nervous system infection.

FIBROMYALGIA

The results of immune studies in FM are mixed but three recent studies suggest a scenario of immune depletion may be occurring in FM as well.

A 2012 study found that immune cells from FM patients that were stimulated with an antigen failed to respond as readily as did those of healthy controls. The dramatic reductions – from 1.5 fold to 10-fold of normal – were found across a wide range of immune factors (IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β, MCP-1 and MIP1-α).

Another fibromyalgia study found a “stark decrease: in the levels of three Th2 cytokines (IL-4, IL-5, and IL-13). Because the cytokines with lowered levels had anti-inflammatory effects the authors speculated that inflammation might be increased in FM. Note that reductions of these anti-inflammatory cytokines (and IL-10 in ME/CFS) might be all that is needed for normal levels of pro-inflammatory cytokines to produce inflammatory effects.

Similar trends toward reduced levels of anti-inflammatory cytokines has also been found in depression.

Exercise Study Reveals Immune Depletion

J Neuroimmunol. 2014 Dec 15;277(1-2):160-7. doi: 10.1016/j.jneuroim.2014.10.003. Epub 2014 Oct 18.Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia. Torgrimson-Ojerio B1, Ross RL2, Dieckmann NF3, Avery S4, Bennett RM5, Jones KD6, Guarino AJ7, Wood LJ8.

Another fibromyalgia study found a marked difference between the immune and hormonal responses of healthy controls during exercise and FM patients. Four anti-inflammatory factors (IL-6, IL-10, ACTH, and cortisol) increased and two pro-inflammatory factors (TNF-a, IL-8) decreased during exercise in the healthy controls.

The anti-inflammatory response, however, was blunted in FM patients (ACTH, cortisol, and IL-10) during exercise.

This study also found normal IL- 6 levels which was a surprise given the reductions in IL-10 (another anti-inflammatory cytokine) found. (IL-6 production by the muscle cells during exercise is believed to trigger IL-10 production.)

That odd finding suggested another way to inhibit anti-inflammatory activity. The authors speculated that FM patients’ muscles may be pumping out normal levels of IL-6, but the signal IL-6 produces to create anti-inflammatory products is simply not getting through.

They suggested that a reduced anti-inflammatory response during exercise could very well play a role in the pain FM patients associate with exercise. Anti-inflammatory cytokines stop the pain receptors on nerves from being activated. Take away those cytokines and FM patients could experience increased pain during exercise.

The authors proposed that a quick immune hit during exercise could be responsible for lasting pain, stiffness and fatigue FM patients experience after exercise.

Conclusion

While some studies differ, recent studies suggest a broad pattern of immune exhaustion may be taking place in both chronic fatigue syndrome and fibromyalgia. That exhaustion is most likely caused by what Lipkin and Hornig called an “exuberant stimulation” of the immune system due to an auto-inflammatory process or a chronic infection.

It’s possible that exhaustion in one part of our carefully balanced immune systems could lead to undue prominence of another part. Lipkin and Hornig suggested the immune reductions in the spinal fluid found suggested that immune activation might be occurring in the central nervous system. Likewise the FM study suggested the depletion of Th2 factors suggested immune activation could be occurring even though levels of pro-inflammatory cytokines were not increased.

Immune exhaustion is a serious issue in several diseases and efforts are being made to battle it. How the medical profession is tackling immune exhaustion is a subject for another blog.