Anti-Yo antibodies are
immunoglobulin G (
IgG)
autoantibodies reactive with a 62 kDa Purkinje cell cytoplasmic
protein. These
antibodies are closely associated with
paraneoplastic cerebellar degeneration in the setting of gynecological and breast
malignancies. We have previously demonstrated that incubation of rat cerebellar slice cultures with patient sera and cerebrospinal fluid containing
anti-Yo antibodies resulted in Purkinje cell death. The present study addressed three fundamental questions regarding the role of
anti-Yo antibodies in disease pathogenesis: 1) Whether the Purkinje cell cytotoxicity required binding of
anti-Yo antibody to its intraneuronal 62 kDa target
antigen; 2) whether Purkinje cell death might be initiated by antibody-dependent cellular cytotoxicity rather than intracellular antibody binding; and 3) whether Purkinje cell death might simply be a more general result of intracellular antibody accumulation, rather than of specific antibody-
antigen interaction. In our study, incubation of rat cerebellar slice cultures with anti-Yo
IgG resulted in intracellular antibody binding, and cell death. Infiltration of the Purkinje cell layer by cells of macrophage/microglia lineage was not observed until extensive cell death was already present. Adsorption of anti-Yo
IgG with its 62 kDa target
antigen abolished both antibody accumulation and cytotoxicity.
Antibodies to other intracellular Purkinje cell
proteins were also taken up by Purkinje cells and accumulated intracellularly; these included
calbindin,
calmodulin, PCP-2, and patient anti-Purkinje cell
antibodies not reactive with the 62 kDa Yo
antigen. However, intracellular accumulation of these
antibodies did not affect Purkinje cell viability. The present study is the first to demonstrate that
anti-Yo antibodies cause Purkinje cell death by binding to the intracellular 62 kDa Yo
antigen.
Anti-Yo antibody cytotoxicity did not involve other
antibodies or factors present in patient serum and was not initiated by brain mononuclear cells. Purkinje cell death was not simply due to intraneuronal antibody accumulation.