Leucine Zipper 4 Autoantibody: A Novel Germ Cell Tumor and Paraneoplastic Biomarker

Divyanshu Dubey, Thomas Kryzer, Yong Guo, Benjamin Clarkson, John C. Cheville, Brian A. Costello, Bradley C. Leibovich, Alicia Algeciras-Schimnich, Claudia Lucchinnetti, M. Bakri Hammami, Andrew M. Knight, Charles Howe, Vanda A. Lennon, Andrew McKeon, Sean J. Pittock

Research output: Contribution to journalArticlepeer-review


Objective: This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). Methods: Archival sera from patients with germ cell tumor–associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam-2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant-protein Western blot, enzyme-linked immunosorbent assay (ELISA), and cell-based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. Results: Leucine zipper 4 (LUZP4)–immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28–84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11–IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole-body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T-cell–dendritic-cell cocultures from chronic immunosuppression-naïve LUZP4-IgG–seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle-exposed and healthy control cultures. Interpretation: LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+ T-cell–mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001–1010.

Original languageEnglish (US)
Pages (from-to)1001-1010
Number of pages10
JournalAnnals of neurology
Issue number5
StatePublished - May 2021

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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