Genetic and Environmental Factors Influence MS in Monozygotic Twin Pairs

In monozygotic twin pairs discordant for multiple sclerosis (MS), genetically and environmentally determined features of an MS-associated immune signature are detectable with matched-pair analysis of the extended twin, according to a study published recently in Nature. Twins with MS exhibited a shift in their circulating monocyte compartment towards inflammatory monocytes.

Genetic risk factors and environmental triggers of MS have undefined interactions. The etiology of MS remains essentially unknown. Therefore, “investigating how genetic predisposition and environmental triggers shape the interactions of individual immune cells is vital to understand the pathophysiology of autoimmune diseases, including MS,” the researchers explained.

The objective of the current study was to understand the genetic predisposition and environmental on monozygotic twin pairs discordant for MS, meaning both siblings carried the same genetic and early-life environmental risks, but only one sibling had MS.

In their analysis, the researchers looked at the peripheral immune signature of 61 monozygotic twin pairs discordant for MS. This group was part of the MS TWIN STUDY at the Institute of Clinical Neuroimmunology at the LMU Klinikum in Munich, Germany. Twin pairs were interviewed and received neurological examination, blood sampling, and MRI between May 2012 and May 2020.

MS diagnosis was confirmed with medical records and MRI scans and then the participants were randomized then analyzed by mass cytometry. The cellular indexing of transcriptomes and epitopes (CITE-seq) analysis of the myeloid compartment was also conducted.

Researchers integrated data on the immune profiles of healthy monozygotic and dizygotic twin pairs, enabling them to estimate the variance in the IL-2 receptor alpha chain to be largely driven by genetic and shared early environmental influences.

Among the twins, higher sensitivity to specific cytokines led to a higher activation of T cells that may have infiltrated the central nervous system and potentially caused tissue damage and neurological deficits.

“The expanding helper T cells of twins with MS, which were also elevated in nontwin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25 (CD25 represents a major genetic MS risk allele)–IL-2 axis, and their proliferative capacity positively correlated with MS severity,” the researchers wrote.

Study limitations included a larger fraction of younger twins with less severe disease severity; participants with more than one family member affected with MS may have introduced a higher familial risk bias; heterogeneity regarding age, disease course, and treatments; disease modifying treatment of the MS affected twin; and may include mass cytometry analysis that was carried out in two independent runs, but was not repeated due to limited precious sample material.

“The observation that some of the findings revealed in this study have previously been reported in cross-sectional studies of MS… whereas other features demonstrated opposite trends of what has previously been described, highlights the importance of discerning genetic predisposition from environmentally induced alterations in MS,” the researchers concluded.

Reference

Ingelfinger F, Gerdes LA, Kavaka V, et al. Twin study reveals non-heritable immune perturbations in multiple sclerosis. Nature. Published online February 16, 2022. doi:10.1038/s41586-022-04419-4