Multiple sclerosis (MS), a chronic inflammatory disease that affects the central nervous system, is the leading cause of neurological impairment in young adults. MS occurs when the brain and spinal cord are attacked by the patient’s immune systems. This can lead to neurological deficits such damaged sight, sensory disturbances, motor problems, and other symptoms. Cognitive impairment and a limitation in the ability to walk. Although the cause is not yet known, MS has been linked to several environmental factors and genetic risk factors.
MS can’t be caused by genetic predisposition.
Recent research has clearly shown that multiple sclerosis is a condition that can only be developed by inheriting genetic risk variants. Florian Ingelfinger is a PhD candidate at UZH Institute of Experimental Immunology. “Based on our research, we were able… to show that approximately half of the composition of the immune system is determined through genetics,” he says. The study by the team led by immunologist Burkhard Becher, professor at the Institute of Experimental Immunology at UZH, and the research groups of Lisa Ann Gerdes and Eduardo Beltrán of the Institute of Clinical Neuroimmunology at the LMU Klinikum, shows that these genetic influences, while always present in MS patients, are not on their own sufficient to trigger multiple sclerosis. The study involved 61 pairs where one twin was diagnosed with MS, while the other twin was healthy. The twins were therefore identical from a genetic perspective. Lisa Ann Gerdes explains that healthy twins had the highest MS risk, but they showed no clinical signs.
Twin study eliminates genetic influences
This unique group of identical twins allowed researchers to exclude genetic influences through comparing twins with multiple sclerosis and those without. Burkhard Bercher says, “We are trying to understand how the immune systems of two genetically identical individuals lead to significant inflammation and major nerve damage in one instance and no damage whatsoever in the other.” The international team of scientists was able to use identical twins to determine if there was a genetic influence on MS and track the immune system changes that ultimately led to the onset of MS in one twin.
Artificial intelligence and single-cell technologies at the cutting edge
The researchers use state-of-the art technologies to detail the immune profiles of twins. Florian Ingelfinger explained that the researchers use a combination o mass cytometry and modern genetics paired together with machine learning to not just identify the immunogenic proteins of the sick twin but also to decode all the genes that are activated in these cells. Eduardo Beltrán, an expert in single-cell genomics, adds: “This ensures that we obtain as much information as currently technically possible from these valuable samples.” To extract the relevant insights from this vast dataset, the team uses a variety if tailored algorithms that are based on artificial Intelligence.
A mistake in the communication between immune cells
“Surprisingly we found the greatest differences in the immune profiles MS affected twins to be in the Cytokine Receptors. The way that immune cells communicate with each other. Ingelfinger states that the cytokine networks are like the language of our immune system.” Researchers discovered that patients with multiple-sclerosis are more sensitive to certain cytokines and have higher activation rates of T cells in their blood. These T cells are more prone to migrate into patients’ central nervous systems and cause damage. The cells that were identified showed characteristics of newly activated cells. These cells were in the process to becoming fully functional T cells. Becher believes that we may have discovered the cellular Big Bang of MS — precursor cells that can give rise to disease-causing, T cells.
Understanding the impact of genes and environment on MS is an important foundation
Burkhard Becher says that the findings of this study are especially valuable in comparison with previous MS studies which did not control for genetic predisposition. “We are now able to determine which part MS’ immune dysfunction is influenced more by genetic than environmental factors. This is fundamental in understanding the progression of the disease. The LMU Klinikum recruited twins for the study. Lisa Ann Gerdes said, “This unique opportunity of unraveling the influence genetics and environment on multiple sclerosis was entirely thanks to our patients that agreed to join the study.”
Funding
The Study was supported by the Deutsche ForschungsgemeinschaftWithin the framework of the German Excellence Strategy, the Munich Cluster for Systems Neurology, and by the Gemeinnützige Hertie StiftungThe Bayerischer Landesverband der Deutschen Multiple Sklerose Gesellschaft(DMSG), Bundesverband der DMSGThe Dr. Leopold und Carmen Ellinger StiftungThe Verein zur Therapieforschung für MS Kranke e.V., the Swiss National Science Foundation Studienstiftung des deutschen Volkesunder the Horizon 2020 research programme.
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