Systematic analyses of the complex interplay of genetic and environmental factors that regulate immune cells are key in unraveling the pathophysiology of multiple sclerosis (MS). However, the diversity of genetic and environmental risk factors in the patient population confounds such studies.
To overcome this obstacle, a new study has analyzed molecular signatures of circulating immune cell types in identical (monozygotic) twins where both siblings carry the same genetic and early-life environmental risks, but only one sibling is affected by MS.
“We are exploring the central question of how the immune system of two genetically identical individuals leads to significant inflammation and massive nerve damage in one case, and no damage at all in the other,” said Burkhard Becher, PhD, professor at the Institute of Experimental Immunology at the University of Zurich (UZH), who is the senior author of the study.
The study combines high-throughput mass cytometry with cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to compare epitopes, transcriptomes, and T cell clonal populations in twins discordant for MS. This enabled the team to identify changes in myeloid and helper T cells that were present in MS-affected twins and other, non-twin MS patients.
The findings were published in the journal Nature, in an article titled, “Twin study reveals non-heritable immune perturbations in multiple sclerosis.”
In MS, patients’ own immune systems turn against them, progressively attacking the central and peripheral nervous systems and resulting in cumulative neurological deficits. These begin with numbness and tingling but slowly progress to visual impairments, motor deficits, paralysis, and cognitive impairments. Despite nearly 200 genetic loci and several environmental risk factors such as viral infections, low vitamin D levels, and smoking tobacco that have been linked to MS, the cause of the disease is still unclear.
“The fact that MS is driven by both genetics and environmental influences makes it impossible to fully capture the environmental triggers for MS and their effect on the immune system. In previous studies the genetic heterogeneity strongly confounded the effect of the MS-driven immune signature,” said Becher.
Although studies in the past decade have clearly underscored the necessity of genetic variants in developing MS, environmental factors also play a considerable role. “Based on our study, we were able to show that about half of the composition of our immune system is determined by genetics,” said Florian Ingelfinger, a PhD candidate at the UZH Institute of Experimental Immunology.
Becher and his collaborators, Lisa Ann Gerdes, PhD, and Eduardo Beltrán, PhD, of the Institute of Clinical Neuroimmunology at the LMU Klinikum, studied 61 pairs of genetically identical twins to show that genetic risk factors on their own are not sufficient to trigger MS. “Although the healthy twins also had the maximum genetic risk for MS, they showed no clinical signs of the disease,” said Gerdes.
“The study of this unique cohort of ‘MS twins’ allows us to eliminate all genetic variability and to extract the most pure immune signature for the manifestation of clinical MS,” said Becher.
Ingelfinger said, “We used a combination of mass cytometry and the latest methods in genetics paired with machine learning to not only identify characteristic proteins in the immune cells of the sick twin in each case, but also to decode the totality of all the genes that are switched on in these cells.”
Bucher added, “We extracted every bit of information at the single-cell level using high-parametric cytometry, genomics, and machine-learning driven data analysis.”
The team found communication between immune cells, specifically through cytokine receptors, showed the greatest differences between the immune profiles of affected and unaffected twins. In patients with MS, increased sensitivity to specific cytokines results in abnormal activation of circulating T cells that then infiltrate into the brain and spinal cord, causing damage.
The investigators showed T cells in patients bear signatures of being recently activated. Becher said, “We may have discovered the cellular big bang of MS here—precursor cells that give rise to disease-causing T cells.”
In contrast to earlier MS studies that do not control for genetic predisposition, this study on a unique cohort of discordant twins provides insights into the specific influences of genetics and environment on MS and will help pinpoint the components of immune dysfunction in MS that are affected by genetic and environmental risk factors.
In upcoming experiments Becher’s team intends to take a closer look at the pure immune signatures in T cells and monocytes that were identified in this study and test their effects in preclinical models of MS and in clinical samples from therapy trials.
