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Abstract
Objective: To assess changes in the T-cell receptor (TCR) repertoire in peripheral venous blood and CSF of patients with multiple sclerosis (MS) treated with natalizumab and the potential implication for developing progressive multifocal leukoencephalopathy (PML) and PML–immune reconstitution inflammatory syndrome (IRIS).
Methods: The TCR repertoire in blood and CSF was assessed by complementarity determining region 3 spectratyping in 59 patients with MS treated with natalizumab for at least 18 months, 5 cases of natalizumab-associated PML, 17 age- and sex-matched patients with MS not treated with natalizumab, and 12 healthy controls.
Results: Patients with MS presented with peripheral TCR repertoire expansions in blood, which appeared less prominent during therapy with natalizumab. TCR repertoire restrictions observed in CSF were most pronounced in patients with MS treated with natalizumab. In patients who developed PML with longitudinal samples available, new identical TCR receptor length expansions in blood and CSF were observed following plasma exchange, and preceded the development of IRIS.
Conclusions: Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration.
GLOSSARY
- AUC=
- area under the curve;
- CI=
- confidence interval;
- EDSS=
- Expanded Disability Status Scale;
- Gd=
- gadolinium;
- IRIS=
- immune reconstitution inflammatory syndrome;
- JCV=
- JC polyomavirus;
- MS=
- multiple sclerosis;
- PLEX=
- plasma exchange;
- PML=
- progressive multifocal leukoencephalopathy;
- TCR=
- T-cell receptor
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Editorial, page 1372
Supplemental data at www.neurology.org
- Received March 1, 2013.
- Accepted in final form June 12, 2013.
- © 2013 American Academy of Neurology
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