EFFECTS OF AUTOIMMUNE ANTIBODIES ON NETWORK FUNCTION IN IPSC-DERIVED NEURONAL CULTURES

IgLON5 disease is a recently described neurological disorder, which combines characteristics of autoimmunity as well as neurodegeneration. Patients usually present with a combination of sleep-related disorders, and progressive cognitive and motor dysfunction. Pathologically, the disease is defined by the accumulation of hyperphosphorylated tau in specific brain regions such as the hypothalamus and the brainstem tegmentum as well as the presence of antibodies against the neuronal cell adhesion protein IgLON5. In vitro studies have shown that patient-derived anti-IgLON5 antibodies lead to an impairment of neuronal network function and glutamatergic signaling.
A pivotal factor for a better understanding of this multifactorial disease is to gain a better understanding of the cross-communication of the immune system and the neuronal activity.
To do so, human induced pluripotent stem cell (iPSC)-derived neuronal organoid cultures were incubated with anti-IgLON5 antibodies or an isotype control antibody, and neuronal network activity was recorded. This granted an insight into the impact of these pathological antibodies on network function and excitability.
Results showed a decreased activity in iPSC-derived neuronal organoids after days of incubation with anti-IgLON5 antibodies compared to the isotype control, corroborating the results previously shown in patch-clamp experiments with 2D cell cultures.
The combination of electrophysiological recordings and the correlation to induced structural changes in a human organoid model grants a unique insight into the effect of autoimmune antibodies in the context of IgLON5 disease and possible therapeutic strategies.