副肿瘤性神经元中间丝自身免疫。

Paraneoplastic neuronal intermediate filament autoimmunity.

机构信息

From the Departments of Laboratory Medicine and Pathology (E.B., T.J.K., S.R.H., S.J.P., V.A.L., A.M.), Neurology (N.Z., Y.G., D.D., E.E.B., C.F.L., S.J.P., V.A.L., A.M.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN.

出版信息

Neurology. 2018 Oct 30;91(18):e1677-e1689. doi: 10.1212/WNL.0000000000006435. Epub 2018 Oct 3.

OBJECTIVE

To describe paraneoplastic neuronal intermediate filament (NIF) autoimmunity.

METHODS

Archived patient and control serum and CSF specimens were evaluated by tissue-based indirect immunofluorescence assay (IFA). Autoantigens were identified by Western blot and mass spectrometry. NIF specificity was confirmed by dual tissue section staining and 5 recombinant NIF-specific HEK293 cell-based assays (CBAs, for α-internexin, neurofilament light [NfL], neurofilament medium, or neurofilament heavy chain, and peripherin). NIF-immunoglobulin Gs (IgGs) were correlated with neurologic syndromes and cancers.

RESULTS

Among 65 patients, NIF-IgG-positive by IFA and CBAs, 33 were female (51%). Median symptom onset age was 62 years (range 18-88). Patients fell into 2 groups, defined by the presence of NfL-IgG (21 patients, who mostly had ≥4 NIF-IgGs detected) or its absence (44 patients, who mostly had ≤2 NIF-IgGs detected). Among NfL-IgG-positive patients, 19/21 had ≥1 subacute onset CNS disorders: cerebellar ataxia (11), encephalopathy (11), or myelopathy (2). Cancers were detected in 16 of 21 patients (77%): carcinomas of neuroendocrine lineage (10) being most common (small cell [5], Merkel cell [3], other neuroendocrine [2]). Two of 257 controls (0.8%, both with small cell carcinoma) were positive by both IFA and CBA. Five of 7 patients with immunotherapy data improved. By comparison, the 44 NfL-IgG-negative patients had findings of unclear significance: diverse nervous system disorders ( = 0.006), as well as limited ( = 0.003) and more diverse ( < 0.0001) cancer accompaniments.

CONCLUSIONS

NIF-IgG detection by IFA, with confirmatory CBA testing that yields a profile including NfL-IgG, defines a paraneoplastic CNS disorder (usually ataxia or encephalopathy) accompanying neuroendocrine lineage neoplasia.

目的

描述副肿瘤神经元中间丝（NIF）自身免疫。

方法

通过组织基础间接免疫荧光检测法（IFA）评估存档的患者和对照血清及脑脊液标本。使用 Western blot 和质谱鉴定自身抗原。通过双重组织切片染色和 5 种基于重组 NIF 特异性的人胚肾 293 细胞基础测定（CBA，用于α-中间丝蛋白、神经丝轻链[NF-L]、神经丝中间链、神经丝重链和外周蛋白）来确认 NIF 特异性。NIF-免疫球蛋白 G（IgG）与神经系统综合征和癌症相关联。

结果

在 65 例通过 IFA 和 CBA 检测为 NIF-IgG 阳性的患者中，有 33 例为女性（51%）。中位症状发作年龄为 62 岁（范围 18-88 岁）。患者分为两组，一组为 NfL-IgG 阳性（21 例，这些患者大多检测到≥4 种 NIF-IgG），另一组为 NfL-IgG 阴性（44 例，这些患者大多检测到≤2 种 NIF-IgG）。在 NfL-IgG 阳性的患者中，19/21 例有≥1 种亚急性起病的中枢神经系统疾病：小脑共济失调（11 例）、脑病（11 例）或脊髓病（2 例）。在 21 例患者中发现了 16 例癌症（77%）：神经内分泌谱系癌（10 例）最为常见（小细胞癌[5 例]、默克尔细胞癌[3 例]、其他神经内分泌癌[2 例]）。257 例对照中有 2 例（0.8%，均为小细胞癌）在 IFA 和 CBA 检测中均为阳性。5 例有免疫治疗数据的患者得到改善。相比之下，44 例 NfL-IgG 阴性患者的神经系统疾病表现无明显意义：多样化的神经系统疾病（=0.006），以及有限的（=0.003）和更多样化的（<0.0001）癌症伴随情况。