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We agree that our results do not show the mechanism(s) causing the Purkinje cell death; however, our main finding is that Yo antibodies detected in paraneoplastic cerebellar degeneration (PCD) patients bind endogenous CDR2L, and not endogenous CDR2. However, we would point out that we found similar results with a mouse CDR2 antibody raised toward the full-length protein.1 Greenlee and Carlson have reported that recombinant CDR2 and CDR2L were both able to prevent antibody-mediated cytotoxicity,2 which could indicate that antibodies toward a common epitope are needed for PCD pathology. We have previously shown that adsorption with recombinant CDR2 only partially removes Yo antibody staining of Purkinje cells, whereas adsorption with recombinant CDR2L completely removes all staining.3 We agree with Greenlee and Carlson that the roles of CDR2 and CDR2L in antibody-mediated Purkinje cell death have not been definitively established, and we concluded as much in our paper. [Extracted from the article]

CD20 SP + sp T cells constitute about 5% of all circulating T cells. Success of anti-CD20 therapy has placed B cells center stage, to an extent that T cells are becoming perceived as minor players in the pathogenesis of multiple sclerosis (MS). [Extracted from the article]

Objective: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood.Methods: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model.Results: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals.Interpretation: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561. [ABSTRACT FROM AUTHOR]

The pathogenesis of Yo-mediated paraneoplastic cerebellar degeneration (PCD) is unclear. We applied cerebrospinal fluid and serum from PCD patients as well as CDR2 and CDR2L antibodies to neuronal tissue, cancer cell lines, and cells transfected with recombinant CDR2 and CDR2L to elucidate which is the major antigen of Yo antibodies. We found that Yo antibodies bound endogenous CDR2L, but not endogenous CDR2. However, Yo antibodies can bind the recombinant CDR2 protein used in routine clinical testing for these antibodies. Because Yo antibodies only bind endogenous CDR2L, we conclude that CDR2L is the major antigen of Yo antibodies in PCD. ANN NEUROL 2019;86:316-321. [ABSTRACT FROM AUTHOR]