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Twin study reveals non-heritable immune perturbations in multiple sclerosis.

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 interactions^1,2. 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.

SUBMITTER: Ingelfinger F

PROVIDER: S-EPMC8891021 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Twin study reveals non-heritable immune perturbations in multiple sclerosis.

Ingelfinger Florian F Gerdes Lisa Ann LA Kavaka Vladyslav V Krishnarajah Sinduya S Friebel Ekaterina E Galli Edoardo E Zwicky Pascale P Furrer Reinhard R Peukert Christian C Dutertre Charles-Antoine CA Eglseer Klara Magdalena KM Ginhoux Florent F Flierl-Hecht Andrea A Kümpfel Tania T De Feo Donatella D Schreiner Bettina B Mundt Sarah S Kerschensteiner Martin M Hohlfeld Reinhard R Beltrán Eduardo E Becher Burkhard B

Nature 20220216 7899

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 interactions<sup>1,2</sup>. 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 conj ...[more]

PMID: 35173329

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Project description:Background and objectivesOcrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology.MethodsA first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest.ResultsUsing an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4+ T cells: one corresponding to naive CD4+ T cells was increased, the other clusters corresponded to effector memory (EM) CD4+CCR6- T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8+ T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8+CCR5+ T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells.DiscussionOur study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5.

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Twin study reveals non-heritable immune perturbations in multiple sclerosis.

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Twin study reveals non-heritable immune perturbations in multiple sclerosis.

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