Identification of the CNTN1/CASPR complex as the target of autoantibodies in a patient with chronic inflammatory demyelinating polyneuropathy (P5.138)

Objective: To identify the target of autoantibodies in a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Background: Autoantibodies against the nodes of Ranvier occasionally appear in CIDP, a frequent but heterogeneous neuropathy. We discovered an unspecified IgG reactivity on brain tissue in a patient’s serum and identified the corresponding neuronal target antigens. Design/Methods: The Caucasian male (46y) underwent neurological, neuroimaging and laboratory investigation. Serum and cerebrospinal fluid (CSF) were analyzed by indirect immunofluorescence assay (IFA). Histo-immunoprecipitates obtained by incubation of the serum with rat and porcine cerebellum were subjected to mass spectrometric analysis. The antigens were expressed in HEK293 and used for IFA. The patient presented with a history of progressive distal-symmetric flaccid sensorimotor tetraparesis for 12 months. MRI of the head was unremarkable but revealed contrast enhancement of spinal nerve roots and the cauda equina. Nerve conduction studies showed pronounced demyelination and axonal damage. Electromyography demonstrated widespread pathologic spontaneous activity. CSF analysis showed albuminocytological dissociation with normal cell count and an elevation of CSF total protein with disruption of the blood-CSF barrier function. Known causes of polyneuropathy were ruled out using standard techniques. Results: IFA revealed a granular IgG3 staining of the hippocampal and cerebellar molecular layers. The corresponding autoantigens were identified as CNTN1 and CASPR. HEK293 co-expressing human CNTN1 and CASPR showed a specific reaction with the patient serum. However, cells expressing the individual proteins or 32 established neural autoantigens, including CNTN2 and CASPR2, did not react. In a neutralization experiment, recombinant CNTN1/CASPR abolished the tissue reactivity of the samples. Anti-CNTN1/CASPR-IgG was neither detectable in 29 disease controls nor in 48 healthy controls. Conclusions: The discovery of anti-CNTN1/CASPR-IgG confirms an earlier report of autoantibodies against this complex that is expressed on the axonal surface in nodes of Ranvier. It remains to be assessed whether these antibodies carry pathogenic potential. Disclosure: Dr. Kade has received personal compensation for activities with Euroimmun AG as an employee. Dr. Strippel has nothing to disclose. Dr. Teegen has nothing to disclose. Dr. Miske has received personal compensation for activities with Euroimmun AG as an employee. Dr. Scharf has nothing to disclose. Dr. Denno has nothing to disclose. Dr. Probst has nothing to disclose. Dr. Radzimski has received personal compensation for activities with Euroimmun AG as an employee. Dr. Stocker has nothing to disclose. Dr. Melzer has nothing to disclose. Dr. Komorowski has nothing to disclose.