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Twin study reveals non-heritable immune perturbations in multiple sclerosis
Florian Ingelfinger1,2, Lisa Ann Gerdes3,4,5, Vladyslav Kavaka3,4
1Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Nature
|February 17, 2022
Summary
This study reveals key immune alterations in twins with multiple sclerosis (MS), identifying specific T cell changes independent of genetic predisposition. These findings help distinguish genetic and environmental factors contributing to MS immune signatures.
Area of Science:
- Immunology
- Neuroimmunology
- Genetics
Background:
- Multiple sclerosis (MS) is a chronic central nervous system inflammatory disorder with complex genetic and environmental origins.
- The precise interplay between genetic predisposition and environmental triggers in MS pathogenesis remains incompletely understood.
- Investigating discordant monozygotic twins offers a unique model to disentangle genetic and environmental influences on MS immune signatures.
Purpose of the Study:
- To investigate peripheral immune signatures in monozygotic twin pairs discordant for MS.
- To dissect the influence of genetic predisposition versus environmental factors on MS-related immune alterations.
- To identify specific immune cell populations and pathways associated with MS development.
Main Methods:
- Utilized multimodal, high-throughput, and high-dimensional single-cell technologies.
- Employed data-driven computational tools for analysis.
- Analyzed immune profiles from 61 monozygotic twin pairs discordant for MS, alongside healthy monozygotic and dizygotic twin pairs.
Main Results:
- Identified an inflammatory shift in monocytes and a population of IL-2 hyper-responsive transitional naive helper T cells in twins with MS.
- Found CD25 expression variance in naive helper T cells largely driven by genetic and shared early environmental influences.
- Observed expanding helper T cells, expressing CNS-homing receptors and exhibiting a dysregulated CD25-IL-2 axis, were independent of individual genetics and correlated with MS severity.
Conclusions:
- Matched-pair analysis in twins successfully distinguished genetically determined from environmentally determined features of MS immune signatures.
- Identified specific T cell populations and their dysregulated cytokine axis as key MS-associated immune alterations.
- The findings provide insights into the complex etiology of MS, separating genetic predisposition from environmentally driven immune responses.
