TY - JOUR
T1 - Leucine Zipper 4 Autoantibody
T2 - A Novel Germ Cell Tumor and Paraneoplastic Biomarker
AU - Dubey, Divyanshu
AU - Kryzer, Thomas
AU - Guo, Yong
AU - Clarkson, Benjamin
AU - Cheville, John C.
AU - Costello, Brian A.
AU - Leibovich, Bradley C.
AU - Algeciras-Schimnich, Alicia
AU - Lucchinnetti, Claudia
AU - Hammami, M. Bakri
AU - Knight, Andrew M.
AU - Howe, Charles
AU - Lennon, Vanda A.
AU - McKeon, Andrew
AU - Pittock, Sean J.
N1 - Publisher Copyright:
© 2021 American Neurological Association.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
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U2 - 10.1002/ana.26050
DO - 10.1002/ana.26050
M3 - Article
C2 - 33583072
AN - SCOPUS:85101814487
SN - 0364-5134
VL - 89
SP - 1001
EP - 1010
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -