Researchers at the University of Zurich have identified a cell population that likely plays a key role in multiple sclerosis (MS). T helper cells in the blood of MS patients infiltrate the central nervous system, where they can cause inflammation and damage nerve cells.
This discovery opens up new avenues for monitoring and treating MS patients.
In multiple sclerosis (MS), dysregulated immune cells periodically infiltrate the brain of afflicted patients, causing damages to neural transmission and neuronal loss.
If not properly monitored and treated, the disease leads to accumulating disabilities that ultimately greatly restrict the daily life of patients.
Around 2.5 million people, many of whom young adults, suffer from the chronic autoimmune disease.
“Fingerprint” of harmful immune cells identified
There is a long-standing interest in identifying the “fingerprint” of the immune cells that characterize MS.
An international team led by Burkhard Becher at the Institute of Experimental Immunology of the University of Zurich has now achieved this.
“We identified a specific population of white blood cells augmented in the peripheral blood of MS patients that have two properties characteristic of MS:
They can move from the blood to the central nervous system and there they can cause inflammation of the nerve cells,” explains Becher.
Machine learning and high-dimensional cytometry
For their study the researchers used high-dimensional cytometry to characterize the immune cells.
This technology makes it possible to analyze millions of cells in hundreds of patients and determine their immune properties – in other words, their “fingerprints.”
To be able to analyze the enormous amount of data in the first place, the scientists developed an innovative machine-learning algorithm.
“Artificial intelligence and machine learning helps us to greatly reduce the data’s complexity, while the interpretation of results is left to the investigators,” says Burkhard Becher.
Key properties of dysregulated immune cells
Using this interdisciplinary approach the team of medical doctors, biologists and computational scientists was able to identify a population of immune cells in the peripheral blood of MS patients that differ from those in other inflammatory and non-inflammatory diseases.
These dysregulated T helper cells produce a neuroinflammatory cytokine called GM-CSF and high levels of the chemokine receptor CXCR4 and the membrane protein VLA4.
“The cell population we identified therefore has two key properties that are characteristic of MS:
The cytokine causes neuroinflammation, and thanks to the receptors the immune cells can get into the central nervous system,” explains Edoardo Galli, first author of the study.
In addition, the researchers found this characteristic signature to be highly represented in the cerebrospinal fluid and in the brain lesions of MS patients, suggesting a direct contribution to the disease.
Furthermore, effective immunomodulatory therapy strongly reduces this cell population.
Strong hints, but no proof yet
“Our data clearly indicate a stringent association of this signature to MS, and we believe that the identification of such an easily accessible biomarker brings important value for MS monitoring,” says Burkhard Becher.
It is still premature to claim a disease-causing role for this population, according to the researchers.
Further studies are needed to confirm this hypothesis. However, the detailed characterization of this population could provide important hints for new MS-specific treatments to improve the patients’ care.
Multiple Sclerosis (MS) is a leading cause of progressive disability in young adults caused by inflammation, demyelination and axonal loss in the central nervous system (CNS) [1,2]. Patients are typically diagnosed between 20 and 40 years of age with women being affected nearly three times as often as men .
The immune response causes the breakdown of the blood-brain barrier, infiltration of immune cells into the CNS and subsequent development of inflammatory and demyelinating lesions in both brain and spinal cord .
Most MS patients (85–90%) are initially diagnosed with the relapsing-remitting form of MS (RRMS), which is characterized with recurring episodes of acute neurological symptoms (relapses) followed by recovery (remission).
The majority of RRMS patients eventually convert to a progressive form of MS, i.e. secondary progressive MS (SPMS) with accumulating axonal damage and neuronal loss and persistent increase in neurological disability.
Current disease modulatory treatments (DMT) are mainly effective in controlling the early inflammatory stage of the disease, while the therapeutic efficacy in progressive stages is poor, likely due to a shift from mainly adaptive immune mechanism to more complex and currently less defined processes also involving innate and local tissue reactions .
Although the exact cause of MS remains unknown, >200 genomic loci have been associated with the risk of developing the disease with the genes in the HLA class II locus (in particular HLA-DRB1) exerting the strongest influence [, , ].
The risk loci collectively support the immune cause of MS and particularly the role of adaptive immunity and CD4+ T cell pathways in triggering the disease.
While genetic and environmental factors independently confer modest effects, their combined impact conveys a dramatic increase in the risk of developing MS, suggesting interactions on a molecular level .
Thus, studying the epigenetic mechanisms, that integrate instructions from genes and environment to control cellular function on the molecular level, represents one avenue to uncover processes of importance for diseases as complex as MS.
The most commonly studied epigenetic mechanism is DNA methylation, which is the covalent addition of a methyl group to the 5th carbon of cytosine, known as 5-methylcytosine (5mC) in a CpG dinucleotide context .
Generally, DNA methylation within CpG rich promoters of genes is associated with transcriptional repression, while higher methylation in gene bodies has been shown to positively correlate with expression .
We have recently demonstrated that DNA methylation mediates risk of developing MS .
Several studies have compared DNA methylation changes between MS patients and controls in CD4+, CD8+, CD14+, CD19+ cells and bulk peripheral blood mononuclear cells using the same methodology to measure DNA methylation genome-wide, i.e. Illumina methylation arrays [, , , , , , , ].
While each study reports potentially interesting candidates, changes in HLA-DRB1 seem most reproducible likely owing to the strong genetic regulation of methylation in the locus.
This lack of reproducibility is caused by the fact that MS is a heterogeneous disease, thus warranting larger cohorts of sorted cells, which is typically challenging, and new analytical methods.
Here we analyzed DNA methylation in four cell types implicated in MS immunopathology [, , ] that were sorted from peripheral blood of RRMS and SPMS patients and healthy controls.
We show that immune cells from MS patients share epigenetic changes and we demonstrate a statistical framework to identify such changes, thus increasing the power of identifying disease-associated methylation patterns in complex heterogeneous diseases.
More information: Edoardo Galli et al. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis, Nature Medicine (2019). DOI: 10.1038/s41591-019-0521-4
Journal information: Nature Medicine
Provided by University of Zurich