Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis.
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
Author Information
Eduardo Beltrán: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Lisa Ann Gerdes: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Julia Hansen: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Andrea Flierl-Hecht: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Stefan Krebs: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center; and.
Helmut Blum: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center; and.
Birgit Ertl-Wagner: Department of Radiology, Grosshadern Medical Campus; Ludwig Maximilian University of Munich, Munich, Germany.
Frederik Barkhof: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
Tania Kümpfel: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Reinhard Hohlfeld: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
Klaus Dornmair: Institute of Clinical Neuroimmunology, Biomedical Center and Hospital.
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.
