The effect of IgG3 and IgG4 autoantibodies against CNTN1 on the nervous system

• Applicant: Privatdozentin Dr. Kathrin Doppler
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402838542

Inflammatory neuropathies with autoantibodies against paranodal proteins are characterized by severe motor and sensory involvement, often associated with cerebellar tremor. Neuropathic symptoms are supposed to be caused by binding of autoantibodies to the paranodes of peripheral nerves whereas tremor might be a correlate of autoantibody binding to cerebellar neurons. This entity of peripheral neuropathy with central nervous system (CNS) symptoms is of high interest as therapeutic response is different from patients with inflammatory neuropathies without autoantibodies. A reason of this might be that autoantibodies against paranodal proteins mostly belong to the IgG4 subclass of immunoglobulins. The pathogenic mechanisms of IgG4 autoantibodies are largely unknown but are of high relevance as IgG4 autoantibodies are not only found in autoimmune neuropathies but also in myasthenia gravis (anti-MuSK) and limbic encephalitis (anti-Caspr2, anti-LGI1). Inflammatory neuropathies with autoantibodies against the paranodal protein contactin-1 (CNTN1) are an ideal model to study the effect of IgG4 autoantibodies: The existence of patients with different subclasses of anti-CNTN1-IgG allows the comparison of the effect of IgG4 and other subclasses and binding to different structures of peripheral nerves as well as neurons of the CNS allows to compare autoantibody effects to different tissues.In the planned study, we therefore aim to elucidate the effect of IgG4 anti-CNTN1 autoantibodies in comparison with IgG3 autoantibodies on functional properties of CNS neurons as well as structural changes induced by autoantibody binding.By analyzing the function of ion channels of cerebellar and hippocampal neurons after incubation with anti-CNTN1 sera and controls by patch-clamp recordings, we will get information on functional effects of autoantibody binding in vitro. In vivo effects will be studied by intrathecal passive transfer of patients‘ and control IgG to rats and subsequent behavioral testing and nerve conduction studies. Structural changes induced by binding of autoantibodies of different subclasses will be studied by analyzing the distribution of neuronal surface proteins in culture as well as tissue of the passive transfer experiments. Structural analysis will include high resolution microscopy to obtain detailed information on the distribution of proteins and ion channels. As a result of this project, we will obtain detailed information on functional and structural changes induced by IgG4 autoantibodies that will provide a basis for the development of targeted therapies, not only for anti-CNTN1-associated neuropathy but for all IgG4-mediated autoimmune diseases.

• DFG Programme: Research Grants