Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis
Eduardo Beltrán, … , Reinhard Hohlfeld, Klaus Dornmair
Eduardo Beltrán, … , Reinhard Hohlfeld, Klaus Dornmair
Published September 30, 2019
Citation Information: J Clin Invest. 2019;129(11):4758-4768. https://doi.org/10.1172/JCI128475.
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Research Article Immunology Neuroscience

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

Abstract

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six “healthy” co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.

Authors

Eduardo Beltrán, Lisa Ann Gerdes, Julia Hansen, Andrea Flierl-Hecht, Stefan Krebs, Helmut Blum, Birgit Ertl-Wagner, Frederik Barkhof, Tania Kümpfel, Reinhard Hohlfeld, Klaus Dornmair

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Figure 3

Analysis of clonally expanded lymphocyte cells.

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Analysis of clonally expanded lymphocyte cells. t-SNE projection of all ...
t-SNE projection of all CSF cells where either CD4+ (A) or CD8+ (B) cells were removed. Cells of the adaptive immune system with at least 1 detectable TCR or BCR chain are shown in light reddish color. Cells of the innate immune system are shown in gray. Expanded clones, i.e., T and B cells that express identical α:β TCR or H:L BCR chains, are highlighted in dark red for CD8+ T cells, blue for CD4+ T cells, and green for B cells. Dot sizes correlate with clonal frequencies: normal-sized dots indicate that the clone was found 2 times; larger dots indicate that it was found 3 or more times.