Cytokines & the Blood-Brain Barrier
–Fibromyalgia Neuroimmune Mechanisms
Principal Investigator: Eva Kosek, M.D., Ph.D.
Uppsala University and Karolinka Institute, Sweden
The microglia are morphed into an activated state in fibromyalgia, causing neuroinflammation.1 Normally, these immune cells go on high alert to protect the brain against threats. But there is nothing normal about chronically spooked microglia that disrupt brain function. Prof. Kosek suspects immune system alterations coupled with changes in the blood-brain barrier (BBB) are partly to blame in fibromyalgia.
“The BBB protects the brain by preventing harmful substances in the circulation from entering the central nervous system,” says Kosek. However, certain processes impair the integrity of the BBB and they need to be investigated.
This project examines the roles of the immune system and the BBB in producing the symptoms of fibromyalgia. To do so, blood and cerebral spinal fluid (CSF) will be analyzed. It’s a tag-on project to a much larger study involving an overnight sleep evaluation (polysomnography), brain imaging, and completion of 17 symptom questionnaires.
Why Examine the BBB?
“Communication over the BBB may be an important way to send signals to the brain about what happens in the rest of the body,” says Kosek. This is how cells in the blood can communicate with those in the brain. But a leaky BBB allows substances to seep through uncontrolled, and Kosek offers three findings in fibromyalgia patients to suggest the BBB is more porous:
- Activation of brain’s microglia, causing a state of neuroinflammation
- Disturbed sleep
- Elevated levels of inflammation-promoting cytokine chemicals in the CSF
“A leaky BBB is implicated in a number of diseases characterized by neuroinflammation,” say Kosek. Examples include multiple sclerosis and Alzheimer’s disease. When the brain’s immune cells are activated, it’s natural to suspect that substances in the blood are entering the brain unchecked across a porous BBB. Yet despite the presence of neuroinflammation in fibromyalgia, the BBB integrity has not been investigated.
Disturbed sleep occurs in more than 90 percent of patients. And in animal models, sleep disruption makes the BBB more porous.
“Some cytokines have the ability to increase the permeability of the BBB,” says Kosek. She was the first to show CSF elevations of IL-8, a cytokine known to impair the BBB integrity.2 Other cytokines known to irritate the BBB have also been reported.
Cytokine Crosstalk
Your systemic blood circulation and CSF communicate across your BBB using small protein molecules called cytokines. Kosek is analyzing hundreds of cytokine concentrations in both the blood and CSF. The goal is to better understand the crosstalk between the blood and the CSF.3
“I suspect the immune environment in both the blood and CSF is altered, and that elevated cytokines in the blood will trigger increases in the CSF,” says Kosek. It’s one way of peripheral to central communication. She also expects enhanced BBB permeability will contribute to greater cytokine concentrations in the CSF.
Signs the BBB is Leaky
The most common test to determine if your BBB is leaky involves measuring albumin in both the blood and CSF. Albumin is the most abundant protein in the blood and it’s very large. Due to size, it does not cross a healthy BBB into the CSF. However, if the barrier is leaky, the CSF will contain excessive amounts of albumin. So, Kosek is comparing the amount of albumin in the CSF to that in the blood. This ratio is a measure of BBB integrity, with higher ratios indicating a more porous BBB.
Albumin assays are one measure, but looking at cytokines captures a more complete picture. These small molecules easily seep through a leaky BBB to cause problems in the brain. On the other hand, the activated microglia in fibromyalgia patients can pump out cytokines into the CSF. Kosek is performing various measures, with the goal of determining which cytokines are increased in the CSF and whether they are associated with a leaky BBB.
Symptoms, Cytokines & BBB
Kosek is evaluating how cytokine concentrations in the blood and CSF relate to key symptoms in patients. She is also determining if specific cytokines are associated with increased BBB permeability. With regards to fibromyalgia symptoms and the BBB, she expects enhanced permeability to correspond with more disturbed sleep. Greater pain and fatigue may also be tied to the BBB findings.
“A more porous BBB potentially underlies altered function of the central nervous system and contributes to symptoms,” says Kosek. But the relationship between the BBB’s role and fibromyalgia symptoms is not straightforward. Sleep disorders contribute to enhanced pain, greater fatigue, and immune system changes that alter cytokines. “We need to disentangle how key symptoms relate to one another from an immunological perspective and the BBB function,” says Kosek.
Antibody Relationship
The immunoglobulin (IgG) portion of your blood contains antibodies that fend off pathogens. But when IgG from fibromyalgia patients (but not healthy people) is injected into mice, it induces a fibromyalgia-like state in the animals.4 Examining the mice shows the IgG antibodies bind to the satellite glial cells (SGCs). They are special immune cells that reside just outside the spinal cord.
Most importantly, Kosek, in collaboration with others, found SCG IgG antibodies in fibromyalgia patients correlated with pain intensity and the overall disease severity.5 So, it’s essential to understand the role played by these antibodies.
Do the SGC antibodies correlate with altered concentrations of cytokines in either the blood or CSF? And what about the BBB? Is this barrier more severely impaired in patients with higher SGC antibodies? “We don’t suspect the antibodies themselves are directly causing enhanced BBB permeability,” says Kosek. “However, they might trigger other changes in blood cytokines that alters the BBB.”
Significance
“Identification of specific cytokine patterns related to key fibromyalgia symptoms (pain, fatigue and sleep) could be the starting point for developing clinically relevant biomarkers,” says Kosek. Recently, her team found a cytokine in the CSF that correlated with fatigue independently of pain, sleep and depression.6 The subjects had chronic back or knee pain (not fibromyalgia), but this demonstrates the usefulness of the cytokine measurements.
Aside from looking at potential biomarkers, cytokine assays offer insight into disease mechanisms. More specifically, they illuminate how the immune system in the periphery signals to the central nervous system.
“Our results can potentially pave the way for developing totally new treatment strategies,” says Kosek. “One possible avenue would be the development of biological treatments. This would be analogous to the success story in rheumatology, where antibodies against cytokines are used to treat inflammatory diseases.”
Finally, if a leaky BBB is documented in fibromyalgia, this elevates the severity and legitimacy of the disease.
Research holds the key to better treatments. AFSA funded six projects in the past two years. Help us keep the momentum going!
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References for Cytokines & the BBB
- Albrecht DS, Loggia ML, et al. Brain Behav Immun 75:72-83, 2019. Free Article
- Kadetoff D, Lampa J, et al. J Neuroimmunol 242(1-2):33-8, 2012. Abstract
- Employing OLINK technology to measure cytokines.
- Goebel A, Kosek E, et al. J Clin Invest. 131(13):e144201, 2021. Free Article
- Krock E, Morado-Urbina CE, et al. Pain 164:1828-1840, 2023. Free Article
- Rosenstrom AHC, Ahmed AS, et al. Brain Behav Immun 128:54-64, 2025. Free Article