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000295844 0247_ $$2doi$$a10.11588/HEIDOK.00035284
000295844 037__ $$aDKFZ-2024-02661
000295844 1001_ $$0P:(DE-He78)e469468b5d6134e74ede38a064bc0ecc$$aMalapit, Joshua$$b0$$gmale$$udkfz
000295844 245__ $$aInsights into Autoimmune Mechanisms and the Pathogenic Role of Tumor-Infiltrating B Cells in Yo-Associated Paraneoplastic Cerebellar Degeneration
000295844 260__ $$bHeidelberg University Library$$c2024
000295844 3367_ $$2DataCite$$aOutput Types/Dissertation
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000295844 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1734096567_19441
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000295844 502__ $$aDissertation, Universität Heidelberg, 2024$$bDissertation$$cUniversität Heidelberg$$d2024$$o2024-08-01
000295844 520__ $$aParaneoplastic 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
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000295844 650_7 $$2Other$$a570 Life sciences
000295844 773__ $$a10.11588/HEIDOK.00035284
000295844 8564_ $$uhttp://www.ub.uni-heidelberg.de/archiv/35284
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000295844 9141_ $$y2024
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