亮氨酸拉链 4 自身抗体：一种新型的生殖细胞瘤和副肿瘤生物标志物。

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

机构信息

Department of Neurology, Mayo Clinic, Rochester, NY.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, NY.

出版信息

Ann Neurol. 2021 May;89(5):1001-1010. doi: 10.1002/ana.26050. Epub 2021 Feb 28.

DOI:10.1002/ana.26050

PMID:33583072

Abstract

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.

摘要

目的

本研究旨在描述一种新的生殖细胞肿瘤生物标志物和相关的副肿瘤神经系统综合征（PNS）。

方法

对伴有生殖细胞肿瘤 PNS 的患者的存档血清进行评估。我们通过 Western blot 和质谱法在人睾丸癌细胞系（TCam-2）中鉴定出一种常见的自身抗原。通过重组蛋白 Western blot、酶联免疫吸附试验（ELISA）和基于细胞的测定法确认其身份。通过分析各种对照血清/脑脊液来确认自身抗体的特异性。

结果

在 28 例患者的血清中检测到亮氨酸拉链 4（LUZP4）-免疫球蛋白 G（IgG），其中 26 例（93%）为男性。神经症状发作的中位年龄为 45 岁（范围为 28-84 岁）。中位效价（ELISA）为 1:300（1:50 至>1:6,400，正常值<1:50）。在 18 例中鉴定出同时存在 kelchlike 蛋白 11-IgG（64%）。最常见的表现型为脑桥脑炎（17/28，61%）。其他表现包括边缘脑炎（n=5，18%）、癫痫发作和/或脑炎（n=2，7%）以及运动神经元病/多神经根病（n=4，14%）。在接受癌症评估的 PNS 患者中，最常见的恶性肿瘤是精原细胞瘤（21/27，78%）。在 21 例通过全身氟脱氧葡萄糖正电子发射断层扫描（PET）检测到的精原细胞瘤中，有 9 例（43%）为睾丸外。两名女性患者均患有卵巢畸胎瘤。在 4 例患者中发现了消退的睾丸生殖细胞肿瘤。与暴露于 vehicle 和健康对照培养物的 CD4+和 CD8+T 细胞相比，来自慢性免疫抑制-naive LUZP4-IgG 血清阳性患者的 T 细胞-树突状细胞共培养物暴露于重组 LUZP4 蛋白后，CD69 的表达明显增加。