TY  - GEN
A1  - Malapit, Joshua Reginald
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/35284/
ID  - heidok35284
N2  - Paraneoplastic cerebellar degeneration (PCD) is an autoimmune neurological disorder that impairs motor function through the immune-mediated death of cerebellar neurons. PCD is frequently diagnosed among ovarian or breast cancer patients, where the tumor aberrantly expresses antigens typically restricted to the cerebellum. Yo-associated PCD is the most common subtype, characterized by serum- or cerebrospinal fluid (CSF)-derived Yo antibodies. They serve 
as a diagnostic marker, and prompts the search for an associated tumor. Yo antibodies have been 
classically defined to target the canonical Yo antigen Cerebellar Degeneration-related protein 2 
(CDR2), whose expression is normally restricted to Purkinje cells of the cerebellum. Much 
contention however exists surrounding the specificity of these autoantibodies and their 
contribution to the progression of the disorder. In my dissertation, I used single-cell 
immunoglobulin sequencing to examine the repertoire of tumor-infiltrating B cells and antibody?secreting cells from an ovarian carcinoma patient who presented with anti-Yo paraneoplastic 
cerebellar degeneration (Yo-PCD). Here, I show across different reactivity assays that CDR2L 
(Cerebellar Degeneration Related Protein 2 Like), is also a target of Yo antibodies, and may be 
the predominant Yo antigen. I also show that these Yo antibodies are secreted by highly-activated 
and somatically hypermutated antibody-secreting cells that infiltrate the tumor, and likely derive 
from protracted autoreactive germinal center responses. I could also show that these Yo 
antibodies can be taken up by Purkinje cells in vitro. Finally, I could show that after continuous 
intrathecal delivery of monoclonal Yo antibodies in mice, they are also taken up by Purkinje cells 
in vivo, and normal motor function, evaluated through rotarod assays, is affected. My results 
demonstrate that tumor-derived Yo antibodies mainly target CDR2L, and have a potential 
pathogenic contribution to the progression of Yo-PCD. Resolving the relevant Yo antigen and 
dissecting the epitope specificities of Yo autoantibodies may help improve the diagnosis of this 
disorder, and the early detection of the associated tumor. Furthermore, deeply characterizing Yo 
autoantibodies and elucidating antibody-mediated pathogenic mechanisms may fine-tune the 
prognosis for Yo-PCD, and expand current paradigms for the role of antibodies targeting 
intracellular antigens
Y1  - 2025///
TI  - Insights into Autoimmune Mechanisms and the Pathogenic Role of Tumor-Infiltrating B Cells in Yo-Associated Paraneoplastic Cerebellar Degeneration
CY  - Heidelberg
AV  - restricted
ER  -