In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 11 ( 2021-03-16)
Abstract:
Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell–mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4 + T cells expressing Eomes (Eomes + Th cells) in SPMS pathogenesis—a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes + Th cells circulate in RRMS patient peripheral blood ( n = 44), primary progressive MS (PPMS) patients ( n = 25), or healthy controls ( n = 42), but Eomes + Th cells were significantly increased in SPMS ( n = 105, P 〈 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4 + T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes + Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases ( P 〈 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes + T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.2021818118
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2021
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
