Reprinted with the kind permission of Cort Johnson and Health Rising
Why should a blog focused on chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) be interested in multiple sclerosis? Because some distinct similarities exist between the three diseases, and when diseases like ME/CFS and FM aren’t getting much research, sometimes it pays to pay attention to diseases that are. You never know what insights might open up.
For the record, while multiple sclerosis is not as disabling as ME/CFS (yes – studies indicate that ME/CFS is more disabling than MS), MS is considered one of the most fatiguing diseases known. (Dr. Light’s study actually found more fatigue in MS but much less post-exertional malaise ME/CFS.)
Additionally, MS like ME/CFS and FM, mostly strikes women in mid-life. Plus, having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and one suspects, FM as well. Infections often trigger relapses in both MS and ME/CFS. Pregnancy also often brings a respite for women with either MS or ME/CFS (often unfortunately followed by a relapse.) Central nervous system involvement is present in all three diseases. In fact, Simmaron’s spinal fluid study found similar levels of immune dysregulation in ME/CFS and multiple sclerosis.
A New Multiple Sclerosis Study Breaks Through
Proc Natl Acad Sci USA. 2018 Feb 13; 115(7):E1520-E1529. doi: 10.1073/pnas.1710401115. Epub 2018 Jan 29. Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility. Russi AE, Ebel ME, Yang Y, Brown MA.
A new MS study highlights a vital aspect of medical research – an animal model – that both chronic fatigue syndrome and fibromyalgia lack. It illuminates how researchers can use animal models to crack complex medical mysteries. Tantalizing leads are present in both FM and ME/CFS, but no one has been able to meld them into a bonafide breakthrough. That appears to have happened in MS.
Let’s see what happens in a well-studied, well-funded disease. As a bonus, we’ll see that the hopeful breakthrough in MS could even have relevance to ME/CFS and FM.
One of the huge questions facing ME/CFS, fibromyalgia, MS and many autoimmune diseases is why so many more women than men get ill. Women don’t just get more autoimmune diseases; they tend to get them earlier than men and tend to have more severe cases. No one knows why, but researchers have been scratching around a possible answer for at least a decade.
The gender divide in MS has been well explored. The fact that puberty sparks an increase in MS incidence in females suggests a strong hormonal component is present. A 2015 review agreed that sex hormones probably play a major role. Another noted that the autoimmune component of MS is greatly increased in women.
A Serendipitous Mistake Sparks a Major Finding
As so often happens in research, a serendipitous mistake sparked this discovery. It began when a Northwestern University graduate student accidentally used a male mouse instead of a female mouse in an experiment. (Female mice are apparently hard to distinguish from male mice.) The researchers were using female mice to find genetic mutations that could help prevent the progression of MS – a female dominated disease.
When they ran the experiment, they found, to their great surprise, that the genetic mutation that was protective in female mice actually made things worse for the male mice. (Talk about a gender divide.) Digging deeper, the team found that the genetic mutation in male mice blocked the activity of immune cells (ILC2) that are protective against multiple sclerosis in female mice. These cells halt the production of TH17 T-cells that initiate the attack on the myelin sheaths of neurons in MS.
Mast Cells Make Good
Mast cells are usually associated with allergic responses and in ME/CFS/FM with a condition called mast cell activation syndrome (MCAS) but this study revealed that mast cells can have a protective side as well.
A male hormone, testosterone, then reared its head. In men testosterone triggers mast cells to produce a substance called IL-33 which stops the production of the TH17 cells in their tracks. In fact, when the Northwestern University researchers removed the mast cells from the male mice their neurons came under attack and they developed mouse MS. In the presence of testosterone, then, mast cells are a very nice thing to have.
Female mice, which have seven to eight times less testosterone than male mice, don’t produce enough testosterone to induce their mast cells to produce IL-33. Instead, female mast cells produce cytokines which increase inflammation and the TH17 T-cells that have been fingered in MS.
Testosterone has been on MS researchers’ radar for quite some time. A recent review of hormonal related changes in MS asserted that there is “compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system.”
Testosterone levels that drop as men age track with an increased incidence of MS in later life. (Interestingly the men who do get MS tend to have a tougher time with it than women.) Lower testosterone levels in men with multiple sclerosis are also associated with greater disability. Some similar findings have been found in women. Women with MS tend to have lower testosterone levels, and increased lesions were associated with reduced testosterone levels in one study.
A very small clinical trial suggested testosterone supplementation might be able to increase white matter volume in the brains of men with MS. If that finding is validated in larger studies, testosterone might be the first substance found that can reverse some of nervous system damage found in MS.
Testosterone, ME/CFS and FM
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A few studies have implicated testosterone in two other gender-imbalanced diseases – chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).
Two studies have found low levels of testosterone in fibromyalgia, and testosterone levels have strongly been linked to pain sensitivity in animal models. One recent study suggested that lower levels of testosterone in combination with other factors was associated with increased rates of depression and poorer sexual functioning in FM. Recently, Jarred Younger’s small “good-day, bad-day” FM study found that lower levels of two hormones, testosterone and progesterone, were associated with more severe FM symptoms.
Despite concerns about the use of testosterone in women, White found that a 28 day course of testosterone gel reduced pain significantly in women with FM. (More about that later.)
In ME/CFS Broderick’s modeling efforts suggest that testosterone in men is protective. Plus the high rate of gynecological issues in ME/CFS and fibromyalgia suggest that sex hormones are involved in ME/CFS.
Testosterone and Autoimmunity
No one knows if ME/CFS and FM are autoimmune diseases, but both could be and the link could have something to do with testosterone. The evidence that testosterone is protective against some autoimmune diseases is building.
Adding the gut contents of male mice to female mice (another mouse model) reduced their risk of type I diabetes – an autoimmune disease. Interestingly, the protective element again appeared to be testosterone, the levels of which were highly influenced by the composition of the mice gut flora.
Declining testosterone levels in men as they age increases their risk for rheumatoid arthritis. Declining testosterone levels may also be responsible for the gender parity seen in RA by age 75, and could explain why men tend to get multiple sclerosis at a later age than women. Low androgen levels in both men and women also appear to put them at risk for autoimmune disorders.
The gender divide extends to opioid use. Regular opioid use suppresses testosterone in men but not in women.
A TH17 Connection
ME/CFS may share another connection with multiple sclerosis – a deranged TH17 response. TH17 T – cells defend against extracellular pathogens and have been found to play a significant role in the development of inflammatory and autoimmune disorders. TH17 cells appear to help initiate attack on the neuronal sheaths in MS.
Several studies from Dr. Klimas’s group suggest a TH17 associated process may be in play in ME/CFS. Exercise provoked a Th17 response in both ME/CFS and Gulf War Syndrome patients. Broderick’s modeling effort found that as few as five cytokines associated with TH17 activation could identify approximately 80% of ME/CFS patients with an infectious trigger. TH17 cytokines showed up again prominently in Broderick’s network analysis study which found they functioned as “preprogrammed immune component.”
The question now is how induce a testosterone-like response in women without actually using testosterone. Drug studies suggest that testosterone can be helpful in MS but the study authors stated that women can’t take much of it without becoming masculinized and experiencing other significant side effects.
Instead this new MS study’s importance lies in the discovery of a key cytokine (IL-33) that can apparently turn off the destructive nerve processes in MS and even restore the nerves. If researchers can develop a way to promote IL-33 activity without using testosterone in women, they may have gotten a handle not just on MS but possibly on other gender imbalanced autoimmune diseases as well.
A New Approach to Autoimmunity?
The authors were quick to suggest that the findings may apply to other autoimmune diseases as well and could ultimately signal an entirely new approach to them. That’s welcome news given the harsh side effects of many of the immune suppressants used in autoimmune diseases.
“This suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females. These findings could lead to an entirely new kind of therapy for MS, which we greatly need.” Melissa Brown, PhD.
Perhaps it will lead to new direction in research for ME/CFS or FM.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.