Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy

Epilepsia. 2021 Jan;62(1):176-189. doi: 10.1111/epi.16742. Epub 2020 Nov 2.


Objective: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE).

Methods: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.

Results: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.

Significance: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.

Keywords: CD4 T cells; drug-resistant epilepsy; inflammatory cytokines; serum neurofilament light chain (sNfL).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4 Lymphocyte Count
  • CD4-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Cytokines / immunology*
  • Drug Resistant Epilepsy / immunology*
  • Epilepsy / drug therapy
  • Epilepsy / immunology
  • Female
  • Flow Cytometry
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Immunoassay
  • Inflammation
  • Interferon-gamma / immunology
  • Interleukin-10 / immunology
  • Interleukin-17 / immunology
  • Interleukin-4 / immunology
  • Interleukins / immunology
  • Male
  • Middle Aged
  • Neurofilament Proteins / immunology*
  • Single Molecule Imaging
  • Th17 Cells / immunology
  • Th2 Cells / immunology
  • Tumor Necrosis Factor-alpha / immunology
  • Young Adult


  • CSF2 protein, human
  • Cytokines
  • IFNG protein, human
  • IL10 protein, human
  • IL17A protein, human
  • IL4 protein, human
  • Interleukin-17
  • Interleukins
  • Neurofilament Proteins
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • neurofilament protein L
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • interleukin-22

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