The effect of IgG3 and IgG4 autoantibodies against CNTN1 on the nervous system
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
Anti-contactin autoantibodies were first described in 2013 in patients with autoimmunemediated neuropathies. The patients suffer from an acute-onset, severe dysfunction of the peripheral nerves with pareses, sensory disturbances and gait ataxia. Some patients also experience tremor. Contactin is a cell adhesion protein that is localized in the paranodal region of the nodes of Ranvier, i.e. in the area directly adjacent to the nodal gap. Anti-contactin autoantibodies are supposed to induce conduction failure at the nodes of Ranvier. Since the antibodies predominantly belong to the IgG4 subclass which does not induce inflammation autoantibody binding is considered to directly affect impaired nerve conduction. In addition to the paranodal region, contactin is also found on the cell surface of neurons in the dorsal root ganglia, the cerebellum and the hippocampus. The current project aimed to investigate effects of anti-contactin autoantibodies to these neurons. For this purpose, serum and purified IgG of patients with anti-contactin autoantibodies that had been stored in our department were used. In addition, 11 new patients with anticontactin autoantibodies were identified during the course of the project and included into the study. To investigate the effect of anti-contactin autoantibodies on dorsal root ganglion neurons and cerebellar neurons, the nerve cells were cultured and patient serum was added. It turned out that this resulted in a reduction of contactin at the surface of the cells and contactin was hardly detectable after four days. When the autoantibodies were removed, contactin reappeared on the cell surface. We were also able to show that the autoantibodies can induce cell death of neurons. Electrophysiological recordings demonstrated a decrease of sodium currents after the addition of the autoantibodies. In another part of the project, he autoantibodies were injected into the spinal canal of rats but did not induce any effect: There were no abnormalities in the animals' behavior or morphological abnormalities of the nerves or impaired nerve conduction detectable. For comparison, we injected autoantibodies against neurofascin, another paranodal protein, in the same way, which caused weakness in the hind paws. Furthermore, we examined the accessibility of the autoantibodies to the paranodal protein complex by incubating the unfixed and non-permeabilized nerve fibers with the autoantibodies. There were differences between the patients with anti-contactin and anti-neurofascin autoantibodies: While anti-contactin patients bound weakly to the paranodes, slight nodal binding was demonstrated for the sera with anti-neurofascin autoantibodies. In summary, the project demonstrated that the pathogenicity of anti-contactin autoantibodies may not be restricted to the paranodal region, but might also affect cell bodies of sensory fibers by reducing surface expression of contactin and sodium currents and could possibly have a cytotoxic effect. Furthermore, it was shown that anti-contactin and anti-neurofascin- 155 autoantibodies differ in terms of their effect on the nerves and the accessibility of the paranodal region. The project thus shows that paranodal autoantibodies may not only cause symptoms due to binding of the paranodal protein complex, but that their pathogenicity is more complex.
Publications
-
Anti–contactin-1 Antibodies Affect Surface Expression and Sodium Currents in Dorsal Root Ganglia. Neurology Neuroimmunology & Neuroinflammation, 8(5).
Grüner, Julia; Stengel, Helena; Werner, Christian; Appeltshauser, Luise; Sommer, Claudia; Villmann, Carmen & Doppler, Kathrin
-
Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies. Neurology Neuroimmunology & Neuroinflammation, 9(3).
Appeltshauser, Luise; Messinger, Julia; Starz, Katharina; Heinrich, David; Brunder, Anna-Michelle; Stengel, Helena; Fiebig, Bianca; Ayzenberg, Ilya; Birklein, Frank; Dresel, Christian; Dorst, Johannes; Dvorak, Florian; Grimm, Alexander; Joerk, Alexander; Leypoldt, Frank; Mäurer, Mathias; Merl, Patrick; Michels, Sebastian; Pitarokoili, Kalliopi ... & Doppler, Kathrin
-
Pathophysiological effects of anti-neurofascin-155 IgG3 and IgG4 in vivo. J Peripher Nerv Syst 27 (3): S54-S55, Meeting-Abstract, Annual Meeting of the Peripheral Nerve Society, Miami, 2022
Hecker K., Sommer C. & Doppler K.
-
Pathophysiological effects of autoantibodies against the paranodal protein neurofascin155 in vivo. Eur J Neurol 29 (1): 302, Meeting Abstract, 8th Congress of the European Academy of Neurology, Wien, 2022
Hecker K., Sommer C. & Doppler K.
-
Different binding and pathogenic effect of neurofascin and contactin–1 autoantibodies in autoimmune nodopathies. Frontiers in Immunology, 14.
Hecker, Katharina; Grüner, Julia; Hartmannsberger, Beate; Appeltshauser, Luise; Villmann, Carmen; Sommer, Claudia & Doppler, Kathrin
