LAUSR

We read with great interest the article by the group of Kråkenes et al, “CDR2L Is the Major Antibody Target in Paraneoplastic Cerebellar Degeneration.” We have previously demonstrated, as has that same group, that anti-Yo antibodies are taken up by cerebellar Purkinje cells in rodent slice cultures and are able to cause neuronal death, possibly by interference with calcium signaling The observations by Kråkenes et al correlate well with recent work demonstrating that ovarian tumors from anti-Yo–positive patients show high rates of genetic alterations in CDR2 and, to a greater extent, CDR2L Yo antigens, suggesting that tumor expression of one or both of these proteins may be a key event in breaking immunological tolerance and initiating Purkinje cell destruction. We have two observations concerning Kråkenes et al’s article. First, the work, although of high importance, does not actually demonstrate whether anti-CDR2L antibodies or anti-CDR2 antibodies are capable of causing Purkinje cell death. This could be readily tested using rodent cerebellar slice cultures and methods in use by the authors and other investigators. Such studies would be important in establishing the roles of these two proteins in disease pathogenesis. Second, we would note that the authors, in their work investigating CDR2 immunoreactivity, relied heavily on a commercial polyclonal rabbit antibody raised by immunization with a peptide that contains only 123 of the 454 amino acids of the complete protein. It is not clear whether antibody raised against this peptide fragment duplicates the immunoreactivity that might have been seen using antibody generated against the entire CDR2 protein. We make this observation because, in our own studies, adsorption of anti-Yo IgG with intact CDR2 protein completely abolished both nuclear and cytoplasmic staining of Purkinje cells in slice culture and prevented antibody-mediated cytotoxicity, suggesting that CDR2 may be an important antigenic target as well. The authors’ work comparing reactivity of anti-Yo antibodies with a commercial antibody to CDR2L represents an important finding. However, it may be premature to dismiss CDR2 as a potential autoantigen at this point. We would submit that the roles of the CDR2 and CDR2L proteins in antibody-mediated Purkinje cell death have not been definitively established, and that further analyses will be needed to elucidate the role of antibody to each antigen in disease pathogenesis.