Neuronal Uptake of Paraneoplastic and Other IgGs is Mediated by the Fc Portion of the IgG Molecule and Involves Previously Uncharacterized Neuronal FcγRI Receptors: Implications for Antibody-Mediated Neuronal Injury

Objective To investigate the mechanisms by which neurons take up paraneoplastic and other antibodies. Background Our laboratory has previously demonstrated that neurons can take up both normal and paraneoplastic IgGs and that paraneoplastic autoantibodies such as anti-Yo and anti-Hu can bind to their intracellular target antigens to produce neuronal death. In this study we investigated how neuronal antibody uptake occurs. Design/Methods We first compared neuronal uptake of normal and paraneoplastic Fab fragments with that of normal IgG Fc fragments or whole paraneoplastic IgGs. To determine whether neurons expressed receptors capable of binding the Fc portion of the IgG molecule, paraformaldehyde-fixed mouse and rat brains sections were probed with antibodies for the three major types of Fc receptors: FcγRI (CD64), FcγRII, (CD32) and FcγRIII (CD16). Neuronal uptake of antineuronal IgGs was compared between wild type mice and knockout mice lacking the FcγRI receptor. We also investigated whether neuronal IgG uptake could be blocked by normal IgG. Results Neurons incorporated the Fc fragment of normal IgG but not the Fab fragment. Intact paraneoplastic IgGs were taken up by neurons, but immunospecific Fab fragments were excluded. Neurons throughout cerebrum, cerebellum, and brainstem showed immunolabeling for FcγRI, but only rare neurons expressed FcγRII or FcγRIII. Uptake of paraneoplastic IgG and neuronal death were not observed in cultures from FcγRI knockout mice but were extensive in cultures from wild type controls. Paraneoplastic antibody uptake could be inhibited by normal IgG. Conclusions Neuronal uptake of normal and paraneoplastic IgGs requires the interaction of the Fc portion of the IgG molecule with previously uncharacterized neuronal FcγRI receptors. Our study provides a mechanism through which antibodies reactive with intracellular neuronal proteins could gain access to their target antigens to cause neuronal injury and neurological disease. The observation that neuronal antibody uptake can be blocked by normal IgG has possible implications for patient treatment.