Multiple sclerosis (MS) is a neurodegenerative autoimmune disease in which the body’s own T cells attack the central nervous system (CNS). One major obstacle in this process comprises the so-called blood-brain barrier, which T cells have to cross before they can penetrate the brain. Researchers try to decipher this mechanism in order to develop new medications addressing this particular step of disease development. A group of researchers at the University Medical Center of Johannes Gutenberg University Mainz (JGU) has now discovered a mechanism that enables T cells to cross the blood-brain barrier more easily and to invade the CNS. Dr. Florian Kurschus of the Institute for Molecular Medicine at the Mainz University Medical Center and his team have discovered that a protein called EBI2 on the surface of T cells plays a significant role in this process. Their findings have recently been published in the journal Cell Reports.
EBI2 acts as a receptor or target protein for a certain molecule, a ligand known as 7α,25-dihydroxycholesterol. This ligand is synthesized from cholesterol by specific enzymes. EBI2 allows immune cells to enter the brain more easily and more efficiently. The higher the concentration of the ligand, the more rapidly and efficiently immune cells can enter the brain and damage tissue there.
Dr. Florian Kurschus’ team came to this conclusion when they were able to show that particularly large numbers of cells with high levels of the receptor EBI2 had accumulated in the inflamed brain areas of MS patients. "This data allowed us to conclude that in humans the receptor and an elevated ligand concentration promote infiltration by T cells and thus the development of CNS-disease," emphasized Dr. Florian Wanke, who was mainly in charge of the experimental research carried out by Kurschus’ team.
As a first step, the researchers investigated the inflammation processes in an animal model of MS. They were able to show that a higher amount of enzymes relevant to ligand production is present in the CNS at the onset of inflammation. “The more of these enzymes are active, the greater the number of ligands that are able to channel T cells across the blood-brain barrier,” explained Kurschus. "So we were able to conclude how actually increased ligand is produced in the inflamed CNS tissue."
So-called G-protein-coupled receptors, such as EBI2, can readily be targeted for appropriate medication. Therefore they are of great interest in MS research. "Several potential therapeutic approaches for EBI2 are already described and we plan to explore their efficacy in future experiments in models of MS. In addition to MS, this receptor may also play a role in other autoimmune diseases. This is because EBI2 is produced by particularly dangerous cells known as Th17 cells, which are a sub-group among the T helper cells,” added Kurschus. T helper cells are white blood cells that are actually supposed to combat pathogens. In autoimmune diseases such as psoriasis or MS, however, they have the opposite effect. They are thus regarded as pathogenic immune cells, in other words, they precipitate disorders because they wrongly identify physiological structures as alien and combat them.
The work of Dr. Florian Kurschus and his team was mainly carried out at the Institute for Molecular Medicine at the Mainz University Medical Center. These findings are the result of a close collaboration with Professor Ari Waisman and Dr. Stefano Casola who initiated this project in the laboratory of Professor Klaus Rajewsky. Several other laboratories in Germany and abroad were additionally involved in the investigations. Researching neurodegenerative diseases and particularly MS constitutes a special focus of Johannes Gutenberg University Mainz and its University Medical Center. The German Research Foundation (DFG) is sponsoring research into MS at the Mainz University Medical Center by providing funding to Transregional Collaborative Research Center TR128 on "Initiating/effector versus regulatory mechanisms in Multiple Sclerosis—progress towards tackling the disease."
Wanke F, Moos S, Croxford AL, Heinen AP, Gräf S, Kalt B, Tischner D, Zhang J, Christen I, Bruttger J, Yogev N, Tang Y, Zayoud M, Israel N, Karram K, Reißig S, Lacher SM, Reichhold C, Mufazalov IA, Ben-Nun A, Kuhlmann T, Wettschureck N, Sailer AW, Rajewsky K, Casola S, Waisman A and Kurschus FC. EBI2 is highly expressed in multiple sclerosis lesions and promotes early CNS migration of encephalitogenic CD4 T cells. Cell Reports 18, 1–15, 31 January 2017
Dr. Florian Kurschus
Institute for Molecular Medicine
Mainz University Medical Center of Johannes Gutenberg University Mainz, Germany
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