Antineuronal Autoantibodies: Molecular Characterization and Clinical Implication

Neurological autoimmune disorders associated with antineuronal autoantibodies result from an immune reaction directed at neuronal self-antigens. When affecting the central nervous system these can be divided into two subgroups: ‘classical’ paraneoplastic neurological syndromes (PNS) and autoimmune encephalitides (AIE). Chapter 1 focusses on the differences between ‘classical’ PNS and AIE. Whereas ‘classical’ PNS occur in elderly patients with cancer, AIE occur in patients of all ages with or without an underlying tumor. The autoantibodies in ‘classical’ PNS are directed at intracellular antigens, non-pathogenic and are probably an epiphenomenon of a T-cell mediated immune response. Patients with ‘classical’ PNS generally do not respond to immunotherapy. Autoantibodies in AIE are pathogenic by directly targeting antigens on the plasma membrane. The symptoms respond well to immunotherapy. Given the conformational nature of the epitopes, the detection of AIE antibodies requires different laboratory techniques than PNS antibodies, which are discussed in detail in chapter 3. Suitable techniques are immunohisto- and cytochemistry and cell-based assays (CBA) in which the conformation of the antigen is maintained. In chapter 2 we reviewthe evidence for pathogenicity of autoantibodies in AIE. Circumstantial evidence including similarity of symptoms between AIE and genetic or pharmacological disruption of the antigen exists for most AIE antigens. In vitro experiments have shown that antigenic modulation is the predominant pathophysiological mechanism for ionotropic receptors such as the NMDA receptor. Induction of symptoms similar to AIE by active or passive immunization would provide prove of pathogenicity has not been shown for most of the AIE antigens. In chapter 4 we screen a population of schizophrenia patients for the presence of antibodies against surface antigens. We show that autoimmunity against neuronal cell surface antigens is not a common finding in patients with schizophrenia. In chapter 5-7 we identify and characterize three novel autoantigens; (1) Plasticity related gene 5 (PRG5), a protein involved in the formation of dendritic spines, in a patient with paraneoplastic cerebellar degeneration. The patient’s antibodies induce internalization of PRG5, however no changes in spines occur upon exposure of hippocampal neurons to anti-PRG5 antibodies. (2) Antibodies to the axon initial segment protein TRIM46 are associated with CNS symptoms and an underlying small cell lung carcinoma (SCLC). (3) We describe the clinical phenotype of 23 patients with anti-GABAB receptor antibodies and show that they have a limbic encephalitis with prominent seizures, in addition we show that anti- GABAB antibodies have a direct functional effect on the GABABR. In chapter 8 we study the effect of mutations in the dynein adaptor protein Bicaudal D2 (BICD2) in patients with spinal muscular atrophy lower extremity predominance (SMALED) on cultured hippocampal neurons. We reveal accumulation of the dynein-dynactin complex in the cell body, Golgi fragmentation and impaired dendritic development. These data suggest that SMALED-BICD2 mutants impair specific dynein-dependent pathways in neurons. Chapter 9 provides a general discussion of the results in this thesis and describes possible future directions in the research field