It is crucial to understand the pathophysiology and causes of multiple sclerosis (MS) by performing systematic analyses of the complex interplay between genetic and environmental factors that regulate immune cell function. However, this is complicated by the variety of environmental and genetic risk factors that affect MS patients.
A new study has been done to overcome this problem. It analyzed molecular signatures and circulating immune cell types in monozygotic identical twins. Twins with the same genetic and environmental risks have both MS. However, only one sibling is affected.
We are looking at the central question of whether the immune system of two identical genetically-engineered individuals can cause significant inflammation and severe nerve damage in one instance and no damage in the other, stated Burkhard Becher (PhD), professor at the Institute of Experimental Immunology, University of Zurich (UZH), who is also the senior author of this study.
The study combines high throughput mass cytometry and cellular indexing transcriptomes and epitopes with sequencing (CITE–seq). It compares epitopes, transcriptomes and T cell clonal population in MS-affected twins. This allowed the team identify changes in myeloid/helper T cells that were found in MS-affected twins, as well as in other MS patients.
The journal published the findings. NatureIn an article titled “Twin study reveals non-heritable immune perturbations in multiple sclerosis.”
MS is characterized by patients’ own immune systems turning against them. This causes progressive neurological deficits and attacks the central and peripheral nervous system. These symptoms begin with tingling and numbness, but gradually progress to cognitive impairments, motor deficits and paralysis. Although MS has been linked to nearly 200 genetic loci as well as many environmental risk factors, including viral infections, low vitamin-D levels, smoking and tobacco, the cause of the disease remains elusive.
MS is driven both by genetics and environmental factors. It is difficult to understand the environmental triggers and their impact on the immune systems. Becher said that previous studies had shown that MS-driven immune signatures were strongly confounded by genetic heterogeneity.
Studies over the past decade have demonstrated the importance of genetic variants for MS development. However, environmental factors play an important role as well. Our study showed that genetics account for about half of the immune system’s composition, according to Florian Ingelfinger (a PhD candidate at UZH Institute of Experimental Immunology).
Becher and his collaborators, Lisa Ann Gerdes and Eduardo Beltrn (both PhD from the Institute of Clinical Neuroimmunology, LMU Klinikum), studied 61 pairs of identical twins to prove that genetic risk factors alone are not enough to trigger MS. Gerdes stated that healthy twins had the highest genetic risk for MS but showed no clinical signs.
Becher said that by studying this unique group, we can eliminate genetic variability and obtain the best immune signature to manifest clinical MS.
Ingelfinger stated that they used a combination mass cytometry with the most up-to-date methods in genetics and machine learning to not just identify the characteristic proteins found in the immune cells in each case but also to decode the totality all of the genes that are activated in these cells.
Bucher stated, “We extracted every bit of information on the single-cell-level using high-parametric, genomics and machine-learning driven data analytics.
The greatest differences in immune profiles between twins with MS and those without it was found to be communication between immune cells. This was mainly due to cytokine receptors. MS patients have an increased sensitivity to certain cytokines, which results in abnormal activation and infiltration of T cells into the brain and spinal chord, causing damage.
Investigators discovered that T cells found in patients showed signs of being recently activated. Becher stated, “We may have discovered the cellular Big Bang of MS hereprecursor cell that gives rise to disease-causing cells.”
Contrary to previous MS studies, which did not account for genetic predisposition, the study on a special cohort of discordant twins will provide insights into the specific influences genetics and environment on MS. It will also help identify the components of immune dysfunction in MS affected by genetic and environmental risk factors.
Bechers team plans to examine the immune signatures of T cells and monocytes identified in this study in upcoming experiments and test their effects on MS patients and preclinical models.