Elevated IL-6 plasma levels are associated with GAD antibodies-associated autoimmune epilepsy

Pabitra Basnyat; Maria Peltola; Jani Raitanen; Suvi Liimatainen; Sirpa Rainesalo; Marko Pesu; Jukka Peltola

doi:10.3389/fncel.2023.1129907

Elevated IL-6 plasma levels are associated with GAD antibodies-associated autoimmune epilepsy

Front Cell Neurosci. 2023 Mar 21:17:1129907. doi: 10.3389/fncel.2023.1129907. eCollection 2023.

Authors

Pabitra Basnyat^{1

2}, Maria Peltola³, Jani Raitanen^{4

5}, Suvi Liimatainen^{2

6}, Sirpa Rainesalo⁷, Marko Pesu^{8

9

10}, Jukka Peltola^{1

2}

Affiliations

¹ Department of Neurology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
² Department of Neurology, Tampere University Hospital, Tampere, Finland.
³ Department of Psychiatry, Tampere University Hospital, Tampere, Finland.
⁴ Faculty of Social Sciences (Health Sciences), Tampere University, Tampere, Finland.
⁵ UKK Institute for Health Promotion Research, Tampere, Finland.
⁶ Administration Centre, Tampere University Hospital, Tampere, Finland.
⁷ Division of Acute Treatment, Emergency Department, Intensive Care and Anesthesia, Tampere University Hospital, Tampere, Finland.
⁸ Laboratory of Immunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁹ Fimlab Laboratories, Tampere, Finland.
¹⁰ Gilead Sciences, Vantaa, Finland.

Abstract

Background: Antibodies against glutamic acid decarboxylase (GADA) are present in multiple neurological manifestations, such as stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. Increasing data support the clinical significance of GADA as an autoimmune etiology of epilepsy, however, there is not yet definitive evidence to confirm the pathogenic link between GADA and epilepsy.

Objective: Interleukin-6 (IL-6), a pro-convulsive and neurotoxic cytokine, and interleukin-10 (IL-10), an anti-inflammatory and neuroprotective cytokine, are crucial inflammatory mediators in the brain. Increased production of IL-6 and its association with epileptic disease profiles are well established, suggesting the presence of chronic systemic inflammation in epilepsy. Therefore, in this study, we investigated the association of plasma cytokine concentrations of IL-6 and IL-10 and their ratio with GADA in patients with drug-resistant epilepsy.

Methods: Interleukin-6 and IL-10 concentrations were measured by ELISA in plasma, and the IL-6/IL-10 ratio was calculated in a cross-sectional cohort of 247 patients with epilepsy who had their GADA titers measured previously for their clinical significance in epilepsy. Based on GADA titers, patients were grouped as GADA negative (n = 238), GADA low positive (antibody titers < 1,000 RU/mL, n = 5), and GADA high positive (antibody titers ≥ 1,000 RU/mL, n = 4).

Results: Median IL-6 concentrations were significantly higher in patients with high GADA positivity [2.86 pg/mL, interquartile range (IQR) = 1.90-5.34 pg/mL] than in GADA-negative patients [1.18 pg/mL, interquartile range (IQR) = 0.54-2.32 pg/mL; p = 0.039]. Similarly, IL-10 concentrations were also higher in GADA high-positive patients [1.45 pg/mL, interquartile range (IQR) = 0.53-14.32 pg/mL] than in GADA-negative patients [0.50 pg/mL, interquartile range (IQR) = 0.24-1.00 pg/mL], however, the difference was not statistically significant (p = 0.110). Neither IL-6 nor IL-10 concentrations were different between GADA-negative and GADA low-positive patients (p > 0.05) or between GADA low-positive or GADA high-positive patients (p > 0.05). The IL-6/IL-10 ratio was also similar among all the study groups.

Conclusion: Increased circulatory concentrations of IL-6 are associated with high GADA titers in patients with epilepsy. These data provide additional pathophysiological significance of IL-6 and help to further describe the immune mechanisms involved in the pathogenesis of GADA-associated autoimmune epilepsy.

Keywords: GAD antibodies; IL-10; IL-6; autoimmunity; cytokines; epilepsy.