Basnyat Pabitra, Peltola Maria, Raitanen Jani, Liimatainen Suvi, Rainesalo Sirpa, Pesu Marko, Peltola Jukka
Department of Neurology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Neurology, Tampere University Hospital, Tampere, Finland.
Front Cell Neurosci. 2023 Mar 21;17:1129907. doi: 10.3389/fncel.2023.1129907. eCollection 2023.
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.
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.
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 ( = 238), GADA low positive (antibody titers < 1,000 RU/mL, = 5), and GADA high positive (antibody titers ≥ 1,000 RU/mL, = 4).
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; = 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 ( = 0.110). Neither IL-6 nor IL-10 concentrations were different between GADA-negative and GADA low-positive patients ( > 0.05) or between GADA low-positive or GADA high-positive patients ( > 0.05). The IL-6/IL-10 ratio was also similar among all the study groups.
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.
抗谷氨酸脱羧酶（GADA）抗体存在于多种神经学表现中，如僵人综合征、小脑共济失调、边缘叶脑炎和癫痫。越来越多的数据支持GADA作为癫痫自身免疫病因的临床意义，然而，尚无确凿证据证实GADA与癫痫之间的致病联系。
白细胞介素-6（IL-6）是一种促惊厥和神经毒性细胞因子，白细胞介素-10（IL-10）是一种抗炎和神经保护细胞因子，它们是大脑中关键的炎症介质。IL-6产生增加及其与癫痫疾病谱的关联已得到充分证实，提示癫痫中存在慢性全身炎症。因此，在本研究中，我们调查了耐药性癫痫患者血浆中IL-6和IL-10细胞因子浓度及其比值与GADA的关联。
采用酶联免疫吸附测定法（ELISA）检测血浆中IL-6和IL-10浓度，并在一个横断面队列中计算IL-6/IL-10比值，该队列中有247例癫痫患者，此前已检测其GADA滴度以评估其在癫痫中的临床意义。根据GADA滴度，将患者分为GADA阴性（=238）、GADA低阳性（抗体滴度<1000 RU/mL，=5）和GADA高阳性（抗体滴度≥1000 RU/mL，=4）。
GADA高阳性患者的IL-6浓度中位数[2.86 pg/mL，四分位数间距（IQR）=1.90 - 5.34 pg/mL]显著高于GADA阴性患者[1.18 pg/mL，四分位数间距（IQR）=0.54 - 2.32 pg/mL；P = 0.039]。同样，GADA高阳性患者的IL-10浓度[1.45 pg/mL，四分位数间距（IQR）=0.53 - 14.32 pg/mL]也高于GADA阴性患者[0.50 pg/mL，四分位数间距（IQR）=0.24 - 1.00 pg/mL]，然而，差异无统计学意义（P = 0.110）。GADA阴性和GADA低阳性患者之间（P>0.05）或GADA低阳性和GADA高阳性患者之间（P>0.05）的IL-6和IL-10浓度均无差异。所有研究组的IL-6/IL-10比值也相似。
癫痫患者中循环IL-6浓度升高与高GADA滴度相关。这些数据为IL-6提供了额外的病理生理学意义，并有助于进一步描述GADA相关自身免疫性癫痫发病机制中涉及的免疫机制。
