Blood Factors Impair Metabolism of Blood-brain Barrier in MS, Study Suggests

Blood Factors Impair Metabolism of Blood-brain Barrier in MS, Study Suggests
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Molecules in the blood of multiple sclerosis (MS) patients promote a pro-inflammatory state and impair the metabolism and integrity of the blood-brain barrier, a study suggests.

In MS, the disruption of the blood-brain barrier (BBB) — a highly selective and protective membrane — allows immune cells to reach the central nervous system (CNS, the brain and spinal cord), where they drive inflammation and ultimately lead to neurodegeneration.

The metabolic changes found in BBB cells were similar to those previously reported in immune cells from MS patients, supporting the hypothesis that MS may be considered a chronic metabolic disorder.

The study, “Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier,” was published in the Journal of Neuroinflammation.

The BBB is a complex three-dimensional structure composed mainly of tightly packed endothelial cells (those lining the inside of blood vessels) that prevent large molecules, viruses, and immune cells in the blood from reaching the CNS.

Damage to the BBB occurs in the initial stages of MS, contributing to an inflammatory state in the CNS, immune attacks against myelin (the protective sheath around nerve fibers), and the progression of the disease.

However, the underlying mechanisms of BBB disruption in MS remain poorly understood.

Increasing evidence points to metabolic unbalance as a potential driver of MS, with MS patients showing changes in hormones and processes involved in energy metabolism and some of those being associated with disease severity.

Previous studies showed that relapsing-remitting MS (RRMS) patients have higher levels of pro-inflammatory immune-metabolic molecules in the blood and metabolic changes in T-cells, which are associated with autoimmunity.  (T-cells are a type of immune cell involved in the abnormal immune responses and inflammation characteristic of MS.)

However, the metabolic status of endothelial cells in the BBB remains unknown, as well as the effects of blood factors of MS patients in the BBB.

Researchers at the University of Naples Federico II, in Italy, and Queen Mary University of London, in the U.K., now evaluated whether factors in the blood of RRMS patients affect BBB’s structure, function, and metabolism using an established cellular model of the human BBB.

The model comprises human brain endothelial cells grown in the lab that maintain BBB properties.

The study involved 30 people — newly-diagnosed, untreated RRMS patients and healthy individuals — with a mean age of 37.7 years; 62.3% of them being women. Healthy participants had similar age, body mass index (an indicator of body fat), and sex ratio to that of RRMS patients.

The structure, function, and metabolism of BBB endothelial cells were analyzed in the presence of blood from RRMS patients vs. healthy individuals.

Data showed that BBB cells exposed to blood from RRMS patients had a significant reduction in the levels of key molecules involved in BBB tightness and an increase in BBB permeability, compared with those exposed to blood from healthy donors.

These changes in BBB integrity were accompanied by a significant increase in the levels of molecules known to facilitate the passage of immune cells through the barrier, specifically of certain subsets of T-cells. The team noted that these changes in endothelial cells usually are associated with a pro-inflammatory state.

Moreover, exposing BBB cells to blood from RRMS patients significantly impaired their energy metabolism, outside and inside mitochondria (the cells’ main powerhouses), compared with cells treated with blood from healthy individuals.

These metabolic changes were similar to those previously reported for T-cells in RRMS patients, the researchers noted.

“These data support our hypothesis that factors present in the [blood] of RRMS patients can exert a detrimental impact upon brain [endothelial cells], reducing their energy reserves and placing them in a condition of metabolic stress, effects which contribute to a deterioration in their key physiological role, provision of an effective permeability barrier,” the researchers wrote.

“In MS the BBB disruption may be secondary to circulating [pro-inflammatory] immune factors which are primary to the chain of events contributing to the disease,” they added.

The team suggested that suppressing inflammation and controlling hormones associated with energy metabolism in MS patients may help repair the BBB damage and halt disease progression.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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