Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions1,2. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25–IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.
Highlights
Over 200 risk loci with moderate-to-subtle effects have been described, including HLA-DRB1*15:01, IL2RA and IL7R genes[3,9]
Exploring the monocyte reference nodes in proximity to the differential state node in the cohort of twins with Multiple sclerosis (MS), we further revealed that the frequency of non-classical monocytes among total myeloid cells was significantly reduced in twins with MS compared with their unaffected twin siblings
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[40], highlights the importance of discerning genetic predisposition from environmentally induced alterations in MS
Summary
TCCDDM8CoTuDb8ElMeT-pEoMCsRDiAti8veTTDnaocNeulbKlslTe-cnγeeδlglTsaCctDiev5lelCs6dTDimc5e6NblrlisKghct eNllsK cellsUpnMDMaCesamssrigogirnnyeaNdBl zacoivenelels-BlikceePTlrBllaassncCmseillatalisIbosnslntaeiacsrNlamtsBolenmcd-eocialnllatsoescsmyictoeanslomcoyDtneeosncdyrtietisc cells c 1,400 total immune features. Similar to previous reports[17,37,38], we observed that approximately 50% of the variance across all identified immune populations was attributable to genetic influences, 40% to unique environmental factors and 10% to a shared early environment (Fig. 4c) This method was applied to identify the influences associated with modulation of CD25 expression in TH cells overlapping with a naive phenotype. The expression of CD25 in phenotypically naive TH cells is largely regulated through heritable influences, the elevated expression of CD25 in transitional, quasi-naive TH cells in MS is a disease-specific effect driven by unique environmental influences To further solidify this concept, we analysed the expression of CD25 in a cross-sectional validation cohort of 30 untreated patients with RRMS and 29 genetically unrelated healthy donors[14] (cohort of non-twins with MS) (Fig. 4e, Extended Data Table 1). We show that elevated expression of CD25 in TH cells that display a naive phenotype is part of the heritable (cross-sectional) and non-heritable (twins) immune signature of MS
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