Abstract
Background and Objectives In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation.
Methods To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85).
Results Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS.
Discussion Our data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.
Glossary
- CM=
- central memory;
- CTLA-4=
- cytotoxic T lymphocyte–associated protein 4;
- DMT=
- disease-modifying therapy;
- DNAM-1=
- DNAX accessory molecule-1;
- EAE=
- experimental autoimmune encephalomyelitis;
- EDSS=
- Expanded Disability Status Scale;
- EM=
- effector memory;
- HD=
- healthy donor;
- IFN-γ=
- interferon-gamma;
- KLRG1=
- killer cell lectin-like receptor subfamily G member 1;
- LAG3=
- lymphocyte-activation gene 3;
- MFI=
- mean fluorescence intensity;
- MS=
- multiple sclerosis;
- NIC=
- noninflammatory control;
- NK=
- natural killer;
- PB=
- peripheral blood;
- PBMC=
- peripheral blood mononuclear cell;
- PPMS=
- primary progressive multiple sclerosis;
- RA=
- rheumatoid arthritis;
- RRMS=
- relapsing-remitting multiple sclerosis;
- sNfL=
- serum neurofilament light chain;
- SLE=
- systemic lupus erythematosus;
- TNF-α=
- tumor necrosis factor alpha
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this work as first authors.
↵† These authors contributed equally to this work as last authors.
The Article Processing Charge was funded by the authors.
- Received March 5, 2021.
- Accepted in final form August 30, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
