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Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L . Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of neurologic syndromes associated with primary tumors. It is postulated that the immune system targets a tumor antigen that is also expressed endogenously in the nervous system. The majority of these patients are diagnosed with breast cancer or gynecological cancer, while it is exceedingly rare in lung squamous cell carcinoma (LUSC) patients. Here we reported a rare case of anti-Yo antibody-positive PCD in a patient with LUSC and got successfully treated via immunotherapy and oncological treatment. The patient’s ataxia symptoms alleviated following the administered treatments, suggesting that early immunotherapeutic intervention may have potential value in mitigating neurological deterioration. Furthermore, active and timely management of the primary carcinoma is crucial.

Paraneoplastic cerebellar degeneration (PCD) is a rapidly progressive, immune-mediated syndrome characterized by the degeneration of Purkinje cells, often associated with the presence of antibodies targeting intracellular antigens within these cells. These autoantibodies are implicated in the induction of cytotoxicity, leading to Purkinje cell death, as demonstrated in in vitro models. However, the precise roles of antibodies and T lymphocytes in mediating neuronal injury remain a subject of ongoing research, with T cells appearing to be the main effectors of cerebellar injury. Notably, at least 50% of PCD cases involve anti-Yo autoantibodies, also referred to as anti-PCA1 (Purkinje cell antigen 1) antibodies, which specifically target cerebellar degeneration-related protein 2 (CDR2) and its paralogue, CDR2-like (CDR2L). Another recognized antigen is CDR 34, a 34 kDa Purkinje cell antigen characterized by tandem repeats and a B-cell epitope; its detection in non-cerebellar tissues necessitates further in situ hybridization studies. Onconeural antigens are expressed in both Purkinje cells and tumour cells, where they localize in the cytoplasm and associate with membrane-bound and free ribosomes, playing critical roles in regulating transcription and calcium homeostasis. Recent studies suggest that the breakdown of immune tolerance is linked to genetic alterations in tumour cell antigens, leading to the formation of neoantigens that can elicit autoreactive T cells, which may underscore the function of Yo antibodies. In vitro studies indicate that anti-Yo antibodies can induce cell death independent of T lymphocytes. The disease progresses by initial lymphocytic infiltration, followed by a rapid loss of Purkinje cells without significant inflammation. However, in vivo models showcase that anti-Yo PCD is primarily T-cell mediated, with antibodies serving as biomarkers rather than direct effectors of neuronal death. This review examines the mechanisms underlying PCD, focusing on the roles of CDR2 and CDR2L in tumour development and their potential role in the degeneration of cerebellar Purkinje neurons. A comprehensive understanding of these processes is essential for advancing diagnostic, prognostic, and therapeutic strategies for PCD and associated malignancies.

Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies represents a rare immune-mediated paraneoplastic neurological syndrome. Its diagnosis and management remain clinically challenging. Here, we present a case of PCD with confirmed anti-Yo antibodies, validated through anti-cerebellar degeneration protein 2 (CDR2) and anti-CDR2-like antibodies detection, which demonstrated a favorable response to ofatumumab therapy. The patient initially manifested with dizziness, nystagmus, dysarthria, and ataxia. Initial testing revealed weakly positive anti-Yo antibodies, accompanied by positive serum tissue-based assay result for cerebellum. Following one course of intravenous immunoglobulin and methylprednisolone pulse therapy, improvement of the patient’s dizziness was observed. Oral prednisone was prescribed for maintenance therapy. However, after discharge, the patient experienced progressive deterioration of symptoms, including worsening dizziness, dysarthria, and limb ataxia. Upon readmission to our hospital, further immunological testing confirmed the presence of anti-CDR2 and anti-CDR2-like antibodies. When a second course of methylprednisolone pulse therapy proved ineffective, treatment was switched to ofatumumab. After two doses, the patient achieved partial symptomatic relief.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

BackgroundParaneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger.MethodsThe transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis.ResultsA prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures.ConclusionsOur data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.

Objective Anti-IgLON5 disease is a rare autoimmune mediated disease. It is mainly featured by sleep-related disturbance, parkinsonism, chorea and limb ataxia. Previous studies had clarified its clinical manifestations and predisposing genes. However, as far as we know, anti-IgLON5 disease combined with paraneoplastic cerebellar degeneration (PCD) with the detection of anti-Sulfatide IgG antibody, masquerading as meningoencephalitis had not been reported before. Case presentation A 57-year-old Chinese female presented with walking unsteadily for 12 days and logagnosia for 2 days and was admitted to our hospital. She had a past history of breast cancer. Magnetic resonance imaging (MRI) revealed leptomeningeal enhancement (prominent in cerebellar hemisphere). Arterial spin labeling (ASL) perfusion showed hyperperfusion in the cerebellar hemisphere and interhemispheric fissure cistern. MRI and ASL indicated the diagnosis was meningoencephalitis. However, IgG anti-IgLON5 antibody was positive in both serum and cerebrospinal fluid. Therefore, the diagnosis was anti-IgLON5 disease. In addition, the patient combined with PCD due to positive anti-Yo-antibody in serum fluid . Conclusions Whereas sleep disturbance is the most common feature in patients with anti-IgLON5 disease, our case presented with walking unsteadily and logagnosia. Anti-IgLON5 disease combined with PCD with the detection of anti-Sulfatide IgG antibody, masquerading as meningoencephalitis is very rare. Therefore, if meningoencephalitis did not recover with conventional treatment, anti-IgLON5 disease and PCD should be considered as the differential diagnosis.

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome caused by a remote effect or immune response involving the cerebellum due to tumor. Here, we report a rare case of PCD secondary to ovarian cancer, presenting clinically with cerebellar tremor. The patient presented with involuntary movements affecting the head, neck, and limbs, along with ataxia and horizontal nystagmus. After conventional medical treatments proved ineffective, the patient underwent a multidisciplinary assessment and received approval from the Institutional Review Board at Affiliated Nanjing Brain Hospital, Nanjing Medical University, to consent to deep brain stimulation (DBS) targeting the ventral intermediate nucleus (VIM) of the thalamus. During the 18-month follow-up, the frequency and amplitude of the tremor significantly improved, with the TRS (1–9) total score decreasing to 23, a 64.06% improvement compared to preoperative levels. The ADL scale score increased from 10 preoperatively to 35, indicating a significant improvement in quality of life. Additionally, the patient’s cognitive and ataxic symptoms did not worsen. These results suggest significant improvement in symptoms compared to baseline, with enhanced daily life activities and improved quality of life.

Background Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. Methods Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. Results Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. Conclusion CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues.