Elevated IL-6 Concentrations Seen in Patients With High GADA Titers

Findings from a new study of patients with epilepsy show that concentrations of IL-6 are heightened in those with high glutamic acid decarboxylase (GADA) titers.

The findings from this single-center cross-sectional study, say the researchers in Frontiers in Cellular Neuroscience, suggest that IL-6 signaling may be a promising target for the treatment of patients with GADA-induced autoimmune epilepsy.

Antibodies against GADA are commonly seen in patients with type 1 diabetes, although they have also been detected in patients with various neurological conditions, including epilepsy. Mounting data also show that GADA plays an important role in the autoimmune etiology of epilepsy.

The group found that median (IQR) IL-6 concentrations were significantly higher in the 7 patients who were GADA high positive, at 2.86 (1.90-5.34) pg/mL, than in the 238 patients who were GADA negative, at 1.18 (0.54-2.32) pg/mL. Similar patterns were observed with IL-10, with median cytokine concentrations higher in patients who were GADA high positive than those who were GADA negative: 1.45 (0.53-14.32) vs 0.50 (0.24-1.00) pg/mL, although the difference was not statistically significant.

“Considering the critical role of IL-6–mediated inflammation in autoimmune neurological diseases, increased IL-6 levels in the GADA high-positive group may indicate a role for IL-6 in initiating and propagating autoimmune inflammation in our patients,” explained the researchers. “Moreover, unchanged levels of IL-10 among GADA groups suggest that IL-10 could not contribute adequate anti-inflammatory supply to counteract the excessive inflammation driven by IL-6.”

Citing the impact of IL-6 on B cells and T cells, the researchers suggest that the cytokine could lead to the production of GADA. For example, through the ability to induce B-cell differentiation, IL-6 may cause the secretion of various pathological autoantibodies, including GADA.

The cytokine also affects T cells by amplifying overreactive Th1 activity, known to be responsible for the onset of several organ-specific autoimmune inflammatory diseases like multiple sclerosis. Similarly, explained the researchers, increased and continuous IL-6 production during epileptic seizures could stimulate GADA production.

GADA high-positive patients in the current study had a higher number of other autoimmune diseases, as well as a higher number of other autoantibodies, potentially due to a poly autoimmune etiology of disorder, explained the researchers.

“On the other hand, IL-6–mediated systemic inflammation could also be the result of the presence of GADA. The pathogenic significance of GADA in neuroinflammation is complex. Epilepsy-specific antibodies such as NMDA receptor and voltage-gated potassium channel complex antibodies are regarded as directly pathogenic to the brain,” the study authors wrote. “Previously, in patients with high GADA titers, we found intrathecal synthesis of GADA, suggesting that GADA could be a marker of an ongoing immune response, and in the same patients, we found high levels of IL-6.”

Among all groups of patients—GADA high positive, GADA low positive, and GADA negative—the IL-6 to IL-10 ratio was similar. Median concentration of IL-6 and IL-10 were not different between patients who were GADA negative and patients who were GADA low positive nor were they difference between patients who were GADA low positive and patients who were GADA high positive.

Reference

Basnyat P, Peltola M, Raitanen J, et al. Elevated IL-6 plasma levels are associated with GAD antibodies-associated autoimmune epilepsy. Front Cell Neurosci. Published online March 21, 2023. doi:10.3389/fncel.2023.1129907