23 Feb 2022
Researchers have investigated the immune system of monozygotic twin pairs to decipher the influence of environment and genetics on multiple sclerosis.
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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The disease is the most common cause of neurological impairments in young adults. In MS, the body’s own immune system attacks the brain and spinal cord. This usually leads to progressive neurological dysfunctions such as vision defects, sensory disturbances, motor impairments (e.g. restricted ambulatory ability), and cognitive impairments. Although the cause of MS has not yet been ascertained, a variety of genetic risk factors and environmental influences have already been linked to the disease.
Studies from the past few years have demonstrated clearly that genetic risk variants are inextricably linked with the development of MS. “Through our study, we managed to show that about half of the make-up of our immune system is determined by genetics,” says Florian Ingelfinger, a PhD candidate at the Institute of Experimental Immunology at the University of Zurich. That these genetic influences are significant but not sufficient to trigger MS is demonstrated by a study carried out jointly with the team of immunologist Burkhard Becher, Professor at the Institute of Experimental Immunology at the University of Zurich and the research groups of PD Dr. Lisa Ann Gerdes and Dr. Eduardo Beltrán from the Institute of Clinical Neuroimmunology at University of Munich Hospital. This study investigated 61 monozygotic – and hence genetically identical – pairs of twins, of which one of the twins in each pair is affected with MS while the twin-sibling was healthy. “Although the healthy twins also had maximum familial risk of developing MS, they showed no clinical signs of having the disease,” says Lisa Ann Gerdes, neuroimmunologist at the Institute of Clinical Neuroimmunology at University of Munich Hospital and principal investigator of the MS TWIN STUDY.
Thanks to this globally unique cohort of monozygotic pairs of twins, it was possible to rule out genetic influences when comparing twins with and without multiple sclerosis. “We’ve tackled the crucial question how the immune system of two genetically identical individuals can lead in one case to this major inflammatory reaction and massive nerve damage, whereas in the other twin there is no damage at all,” explains Becher. Consequently, the international team of scientists is able to very deliberately track and monitor, free from genetic influences, the changes in the immune system that ultimately trigger the MS in one twin, while their twin sister or brother remains unaffected by the disease.
The researchers employ state-of-the-art technologies to describe the so-called immunity profiles of the twin pairs in all their vast detail. “We use a combination of mass cytometry and the latest methods in genetics coupled with machine learning, to not only identify characteristic proteins of the immune cells of sick twins, but also decode the totality of all genes that are activated in these cells,” explains Ingelfinger. Eduardo Beltrán, expert for single-cell genomics at the Institute of Clinical Neuroimmunology and Biomedical Center at University of Munich Hospital, adds: “In this way, we ensure that we extract every last piece of information out of these valuable samples that is technically possible at the present time.” The team utilizes a variety of specially tailored algorithms based on artificial intelligence in order to obtain relevant insights from this immense data set.
“Astonishingly, we found the largest differences in the immunity profiles of MS-affected twins in so-called cytokine receptors; in other words, in the manner in which immune cells communicate with each other. You could describe the cytokine network as the language of the immune system,” explains Ingelfinger. The researchers discovered that increased sensitivity to certain cytokines leads to stronger activation of T cells in the blood of patients with multiple sclerosis. These T cells are very adept at getting into the central nervous system of patients and causing damage there. The identified cells exhibited characteristics of recently activated cells, which were in the process of developing into fully functional T cells. “We might just have discovered the cellular big bang of MS – precursor cells that give rise to pathogenic T cells,” explains Becher.
“The findings of this study are particularly valuable compared to previous studies on MS, which did not control for genetic predisposition,” emphasizes Becher. “Our study disentangles which part of the immune disorder in MS is influenced by genetic components and which by environmental factors. This is fundamentally important for understanding the evolution of the disease.” The twin pairs were recruited for the study as part of the national MS TWIN STUDY at the Institute of Clinical Neuroimmunology at University of Munich Hospital. “We’re indebted to all our patients who volunteered for this study for this unique opportunity to tease apart the influence of genetics and environment in multiple sclerosis,” says Gerdes. Furthermore, the research teams led by Anneli Peters and Lisa Ann Gerdes recently received a highly prestigious research grant for the MS TWINS STUDY. Awarded by the National Multiple Sclerosis Society in the United States, the grant is worth 297,000 US dollars.
Florian Ingelfinger, Lisa Ann Gerdes, Vladyslav Kavaka, Sinduya Krishnarajah, Ekaterina Friebel, Edoardo Galli, Pascale Zwicky, Reinhard Furrer, Christian Peukert, Charles-Antoine Dutertre, Klara Magdalena Eglseer, Florent Ginhoux, Andrea Flierl-Hecht, Tania Kümpfel, Donatella De Feo, Bettina Schreiner, Sarah Mundt, Martin Kerschensteiner, Reinhard Hohlfeld, Eduardo Beltrán & Burkhard Becher: Twin study reveals non-heritable immune perturbations in multiple sclerosis. Nature 2022.