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Original Investigation |

Antibodies to Delta/Notch-like Epidermal Growth Factor–Related Receptor in Patients With Anti-Tr, Paraneoplastic Cerebellar Degeneration, and Hodgkin Lymphoma

Maxwell Greene, MD1; Yongjie Lai, MD1; Nicolle Baella2; Josep Dalmau, MD, PhD1,3,4; Eric Lancaster, MD, PhD1
[+] Author Affiliations
1Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia
2currently an undergraduate at the University of Pennsylvania, Philadelphia
3Department of Neurology, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
4Department of Neurology, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
JAMA Neurol. 2014;71(8):1003-1008. doi:10.1001/jamaneurol.2014.999.
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Published online

Importance  The anti-Tr immune response is associated with paraneoplastic cerebellar degeneration and Hodgkin lymphoma (HL). One case series has reported that the Delta/notch-like epidermal growth factor–related receptor (DNER) is the actual target for anti-Tr antibodies, but this result has not been replicated.

Objective  To describe a patient with anti-Tr and confirm that DNER is the autoantigen for a series of patients with anti-Tr.

Design, Setting, and Participants  Observational study and analysis of biological samples for antibodies to DNER at the hospital of the University of Pennsylvania. We examined a cerebrospinal fluid sample from 1 patient with anti-Tr and serum and/or cerebrospinal fluid samples from 5 other patients with anti-Tr.

Exposure  Transfection of HEK293T and Hela cells to express DNER coupled to an enhanced green fluorescent protein tag using a plasmid previously used to detect human DNER antibodies.

Results  A man in his 30s with paraneoplastic cerebellar degeneration and anti-Tr underwent treatment with corticosteroids and intravenous immunoglobulin, resulting in clinical improvement before chemotherapy. Despite close oncologic follow-up, a biopsy, positron emission tomography, and computed tomography, he was not diagnosed as having HL until 6 months after symptom onset. The cerebrospinal fluid sample from this patient reacted with cells transfected to express DNER, as did cerebrospinal fluid and/or serum samples from 5 other patients with paraneoplastic cerebellar degeneration, HL, and anti-Tr. Only 4 of the 5 serum samples reacted to permeabilized cells enough to be distinguished from background, but all 5 serum samples convincingly labeled live cells, which had considerably less background. All 6 control serum samples and 1 serum sample from a patient previously diagnosed as having anti-Tr (but without HL or cerebellitis) did not recognize DNER.

Conclusions and Relevance  This case demonstrates the importance of testing for the anti-Tr immune response in patients with cerebellar degeneration. The strong association of anti-Tr with HL requires careful surveillance for this tumor. We also confirm that DNER is the target antigen of the anti-Tr immune response. Screening for DNER antibodies against living transfected cells may offer an improved signal-to-noise characteristic compared with immunostaining of fixed, permeabilized cells.

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Figure 1.
Recognition of Cells Transfected to Express Delta/Notch-like Epidermal Growth Factor–Related Receptor (DNER) by Patients’ Antibodies

We transfected HEK293T cells to express DNER. A, Immunostaining with patient cerebrospinal fluid (CSF) (1:20). B, Immunostaining with a goat DNER antibody. C, Merged images show the patient CSF in red, the goat antibody in green, and nuclei stained blue with 4′,6-diamidino-2-phenylindole (DAPI). The patient’s CSF reacts strongly with DNER-expressing cells.

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Figure 2.
Transfection of Live Cells to Express Delta/Notch-like Epidermal Growth Factor–Related Receptor (DNER) for Antibody Detection

Cultured Hela cells were transiently transfected to express DNER coupled to an enhanced green fluorescent protein tag (EGFP) (green). A, Immunostaining of fixed cells. B, Immunostaining of live cells. Immunostaining consisted of human serum (red) from patients with paraneoplastic cerebellar degeneration, anti-Tr, and Hodgkin lymphoma (serum samples 1-5) and from a patient with neuropathy and anti-Tr (serum sample 6). In merged images, nuclei are stained blue with 4′,6-diamidino-2-phenylindole (DAPI). Staining of live cells produced improved signal-to-noise compared with fixed cells, showing that serum samples 1 through 5 label surface epitopes of DNER, whereas serum 6 showed negative findings. A panel of control serum samples (not shown) likewise showed negative results. DNER appeared to cluster on the surface of cells.

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Figure 3.
Recognition of Delta/Notch-like Epidermal Growth Factor–Related Receptor (DNER) by Patients’ Antibodies on Cultured Neurons

A, Cultured embryonic rat hippocampal neuron immunostained with patient cerebrospinal fluid (CSF) (1:20). B, The hippocampal neuron immunostained with a goat DNER antibody (1:200). C, Merged images show the patient CSF staining in green and the goat DNER antibody in red to demonstrate colocalization.

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