Paraneoplastic cerebellar degeneration associated with anti-ITPR1 antibodies.
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ABSTRACT:
SUBMITTER: Berzero G
PROVIDER: S-EPMC5292928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Paraneoplastic 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. METHODS:The 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. RESULTS:A 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. CONCLUSIONS:Our 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.
| S-EPMC6035206 | biostudies-literature
Project description:Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
| S-EPMC7808941 | biostudies-literature
Project description:Yo antibodies are associated with paraneoplastic cerebellar degeneration (PCD). We have characterized Yo sera by measuring CDR2 and CDR2L antibodies and the localization of their antigens.Forty-two Yo sera from patients with paraneoplastic neurological syndromes (PNS), 179 sera from ovarian and 114 sera from breast cancer patients without PNS and 100 blood donors were screened for CDR2 and CDR2L antibodies by radioactive immune assay (RIA). Fluorescence microscopy was also used to determine the presence of CDR2 or CDR2L antibodies by staining of HeLa cells transfected with CDR2 or CDR2L fused to green fluorescent protein (GFP). Confocal microscopy was further used to localize the CDR2 and CDR2L proteins.RIA showed that 36 of the 42 Yo positive sera contained CDR2 and CDR2L antibodies whereas 6 sera contained only CDR2 antibodies. Five of the ovarian cancer patients had CDR2L antibodies and 4 of the breast cancer patients had either CDR2 or CDR2L antibodies. Only patients with both antibodies had PCD. RIA and staining of transfected cells showed similar results. Yo antibodies were not present in the 100 blood donors. Confocal microscopy showed that CDR2 and CDR2L were localized to the cytoplasm, whereas CDR2L was also present on the cell membrane.Yo sera usually contain CDR2 and CDR2L antibodies and both antibodies are associated with PCD. Since only CDR2L is localized to the cell membrane it is likely that CDR2L antibodies may be of primary pathogenic importance for the development of PCD.
| S-EPMC3688866 | biostudies-literature
Project description:Patients with isolated ZIC4 antibodies usually have paraneoplastic cerebellar degeneration (PCD) and small cell lung cancer (SCLC) but the frequency is unknown. We analyzed the presence of ZIC1, ZIC2 and ZIC4 antibodies in 27 patients with PCD and SCLC negative for other onconeural antibodies. ZIC antibodies were detected in nitrocellulose filters with phage plaques. Four (15%) PCD sera recognized ZIC2. Three of these positive sera also reacted with ZIC1 and two with ZIC4. Our study suggests that 1) the incidence of isolated ZIC antibodies is low in PCD patients and SCLC and 2) ZIC antibodies are probably directed to epitopes shared by the three ZIC proteins.
| S-EPMC2582201 | biostudies-literature
Project description:BackgroundParaneoplastic cerebellar degeneration (PCD) is a classical tumor-associated, immune-mediated disease typically associated with gynecological malignancies, small-cell lung-cancer or lymphoma.Case presentationHere we present the case of a 38-year old male with an over 12 months rapidly progressive cerebellar syndrome. Extensive diagnostic workup revealed selective hypermetabolism of the right tonsil in whole-body PET. Histological examination after tonsillectomy demonstrated a lymphoepithelial carcinoma of the tonsil and the tongue base strongly suggesting a paraneoplastic cause of the cerebellar syndrome. To the best of our knowledge this is the first case of an association of a lymphoepithelial carcinoma, a rare pharyngeal tumor, with PCD.ConclusionsIn cases of classical paraneoplastic syndromes an extensive search for neoplasms should be performed including whole-body PET to detect tumors early in the course of the disease.
| S-EPMC4016266 | biostudies-literature
Project description:OBJECTIVE: To determine sensitivity and specificity of a standardized recombinant cell-based indirect immunofluorescence assay (RC-IFA) for anti-Tr antibodies in comparison to a reference procedure. METHODS: Delta/Notch-like epidermal growth factor-related receptor (DNER) was expressed in HEK293 and used as a substrate for RC-IFA. HEK293 control cells expressing CDR2/Yo and CDR2L as well as mock-transfected HEK293 cells were used as controls. Serum samples from 38 patients with anti-Tr antibodies (33 with paraneoplastic cerebellar degeneration [PCD] and Hodgkin lymphoma), 66 patients with anti-Tr-negative PCD, 53 patients with Hodgkin lymphoma without neurologic symptoms, 40 patients with rheumatic diseases, and 42 healthy blood donors were tested for anti-DNER reactivity in the RC-IFA. In addition, RC-IFA results were compared to those from a commercial tissue-based IFA using monkey cerebellum. RESULTS: Using the RC-IFA, anti-DNER was detected in all anti-Tr-positive patients but in none of the controls (sensitivity 100%, 95% confidence interval [CI] 92.8%-100%; specificity 100%, 95% CI 98.7%-100%). In comparison, anti-Tr was not detected in 4 samples with low-titer autoantibodies using the commercial tissue-based assay. Preadsorption of sera with either recombinant full-length DNER or its extracellular domain selectively abolished anti-Tr reactivity. CONCLUSION: Anti-Tr antibodies bind to the extracellular domain of DNER and can be detected by RC-IFA using HEK293 cells expressing the recombinant receptor. The new method performs better than a frequently used commercial tissue-based indirect immunofluorescence assay (IFA) in samples with low-titer antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RC-IFA accurately detects anti-Tr as compared to conventional IFA.
| S-EPMC4345632 | biostudies-literature
Project description:Paraneoplastic cerebellar degeneration (PCD) is a rare nonmetastatic neurological complication often associated with ovarian, breast, and other gynecologic cancers. Anti-Yo is one of the antionconeural antibodies found in patients with PCD. It primarily emerges before a malignancy is detected.In this report, we describe an unusual case involving a patient who exhibited anti-Yo-positive PCD 1 year after being diagnosed with ovarian cancer.Histopathology of the resected tissues and Antineuronal antibody testing.The patient was treated with intravenous immunoglobulin (IVIG, 1 g/d) for 1 week and a large-dose of methylprednisolone (0.4 g/kg/d) for 5 days. At the same time, underlying complications were prevented actively, and the peripheral nerves were protected.Although most patients with anti-Yo-positive PCD do not improve after treatment, our patient significantly improved after receiving active and effective treatment.
| S-EPMC5556197 | biostudies-other
Project description:To compare transcriptomic data from ovarian cancers related to PCD with anti-Yo antibodies with control ovarian cancers from published data
2017-10-18 | E-MTAB-5942 | biostudies-arrayexpress
Project description:OBJECTIVE:Identify the subcellular location and potential binding partners of two cerebellar degeneration-related proteins, CDR2L and CDR2, associated with anti-Yo-mediated paraneoplastic cerebellar degeneration. METHODS:Cancer cells, rat Purkinje neuron cultures, and human cerebellar sections were exposed to cerebrospinal fluid and serum from patients with paraneoplastic cerebellar degeneration with Yo antibodies and with several antibodies against CDR2L and CDR2. We used mass spectrometry-based proteomics, super-resolution microscopy, proximity ligation assay, and co-immunoprecipitation to verify the antibodies and to identify potential binding partners. RESULTS:We confirmed the CDR2L specificity of Yo antibodies by mass spectrometry-based proteomics and found that CDR2L localized to the cytoplasm and CDR2 to the nucleus. CDR2L co-localized with the 40S ribosomal protein S6, while CDR2 co-localized with the nuclear speckle proteins SON, eukaryotic initiation factor 4A-III, and serine/arginine-rich splicing factor 2. INTERPRETATION:We showed that Yo antibodies specifically bind to CDR2L in Purkinje neurons of PCD patients where they potentially interfere with the function of the ribosomal machinery resulting in disrupted mRNA translation and/or protein synthesis. Our findings demonstrating that CDR2L interacts with ribosomal proteins and CDR2 with nuclear speckle proteins is an important step toward understanding PCD pathogenesis.
| S-EPMC7664253 | biostudies-literature
Project description:AIM:Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neurone degeneration following paraneoplastic Yo antibody internalization and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D28k malfunction. Therefore, we hypothesized that Yo antibody internalization affects not only calbindin calcium binding capacity, but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neurone death. METHODS:Immunohistochemically, we evaluated cerebellar organotypic slice cultures of rat brains after inducing PCD through the application of Yo antibody-positive PCD patient sera or purified antibodies against CDR2 and CDR2L how pharmacologically biased mitochondrial signalling affected PCD pathology. RESULTS:We found that Yo antibody internalization into Purkinje neurons caused depletion of Purkinje neurone calbindin-immunoreactivity, cannabinoid 1 receptor over-activation and alterations in the actions of the mitochondria permeability transition pore (MPTP), voltage-dependent anion channels, reactive oxygen species (ROS) and Na+ /Ca2+ exchangers (NCX). The pathological mechanisms caused by Yo antibody binding to CDR2 or CDR2L differed between the two targets. Yo-CDR2 binding did not alter the mitochondrial calcium retention capacity, cyclophilin D-independent opening of MPTP or activity of NCX. CONCLUSION:These findings suggest that minimizing intracellular calcium overload toxicity either directly with cyclosporin-A or indirectly with cannabidiol or the ROS scavenger butylated hydroxytoluene promotes mitochondrial calcium homeostasis and may therefore be used as future neuroprotective therapy for PCD patients.
| S-EPMC7379599 | biostudies-literature