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@PHDTHESIS{Malapit:295844,
      author       = {J. Malapit$^*$},
      title        = {{I}nsights into {A}utoimmune {M}echanisms and the
                      {P}athogenic {R}ole of {T}umor-{I}nfiltrating {B} {C}ells in
                      {Y}o-{A}ssociated {P}araneoplastic {C}erebellar
                      {D}egeneration},
      school       = {Universität Heidelberg},
      type         = {Dissertation},
      publisher    = {Heidelberg University Library},
      reportid     = {DKFZ-2024-02661},
      year         = {2024},
      note         = {Dissertation, Universität Heidelberg, 2024},
      abstract     = {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},
      keywords     = {570 Life sciences (Other)},
      cin          = {D130},
      cid          = {I:(DE-He78)D130-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.11588/HEIDOK.00035284},
      url          = {https://inrepo02.dkfz.de/record/295844},
}