抗Hu抗体阳性副肿瘤性边缘叶脑炎1例报告及文献复习

正神经系统副肿瘤综合征(paraneoplastic neurologic syndromes,PNS)是指肿瘤在中枢神经系统和周围神经、肌肉系统出现的远隔效应,是一组针对神经系统某些靶抗原的自身免疫性疾病,如累及大脑边缘叶系统即表现为副肿瘤性边缘叶脑炎~([1])。在一些PNS患者血清和(或)脑脊液中可发现肿瘤神经抗体,特异性抗神经元抗体有抗Hu、抗Yo、抗CV2、抗Ri、抗Ma2等抗体,现将我院收治的1例抗Hu抗体阳性的副肿瘤性边缘叶脑炎患者病例报道如下,并结合相关文献进行     

抗amphiphysin抗体、抗Hu抗体双阳性副肿瘤神经综合征(附1例报告及文献复习)

目的提高临床医生对抗amphiphysin抗体、抗Hu抗体双阳性副肿瘤神经综合征的认知。方法回顾分析1例抗amphiphysin抗体、抗Hu抗体双阳性的副肿瘤神经综合征患者的临床表现、检查及诊疗经过等资料,结合文献复习加以讨论。结果患者男性,71岁。主要临床表现为进行性肢体无力加重,脑脊液检查抗amphiphysin抗体、抗Hu抗体双阳性,纵隔肿物病理显示胸腺神经内分泌癌。手术切除后肢体无力症状得到改善,但预后不良。结论副肿瘤神经综合征少见,其神经症状与肿瘤的关联各不相同。特征性副肿瘤抗体,如抗amphiphysin抗体、抗Hu抗体双阳性,对副肿瘤综合征及相关肿瘤的识别与诊断具有重要价值。     

副肿瘤综合征

副肿瘤综合征是恶性肿瘤的破坏性远隔效应,它可影响神经系统的任何一个部位。多数神经系统副肿瘤综合征是免疫介导的,神经系统异常通常在肿瘤之前出现,症状和体征多种多样,取决于受损的部位。诊断主要依靠临床表现和相关辅助检查。近年来副肿瘤综合征患者血清或脑脊液中特异性抗神经元抗体的发现可作为肿瘤相关疾病的诊断标志,并为癌肿早期甚至超早期诊断提供了依据。治疗主要包括两个方面：一是针对神经系统副肿瘤综合征的免疫治疗;二是针对肿瘤的手术、放疗、化疗等。副肿瘤综合征的神经病理改变及肿瘤发现是否及时是影响预后的重要因素。     

自身抗体对副肿瘤综合征诊断价值的探讨

目的　探讨自身抗体对副肿瘤综合征的诊断价值。方法　利用间接免疫荧光法对 48例疑诊副肿瘤综合征患者进行抗 Yo抗体、抗 Hu抗体、抗 Ri抗体测定和临床随访 ,并与正常人和神经系统其他疾病患者对照。结果　 48例中 ,1例病前有肺癌史 ,2例检查中发现肿瘤 ,4例随访 3～ 1 8个月后发现肿瘤。正常对照组和神经系统其他疾病组自身抗体均为阴性 ,患者组中有 1例呈副肿瘤性脑脊髓炎 ,其抗 Hu抗体阳性 ,相对分子质量为3 80 0 0 ,病理检查证实为小细胞肺癌。结论　自身抗体测定对此病的早期诊断有一定价值 ,但阳性率不高 ,其临床价值尚需进一步随访证实     

多重抗神经元抗体阳性的神经系统副肿瘤综合征临床分析

目的探讨神经系统副肿瘤综合征患者出现多重抗神经元抗体的临床特征及潜在意义。方法检索2015年7月至2019年12月至宣武医院住院治疗并诊断为"神经系统副肿瘤综合征""癌性副肿瘤综合征""副肿瘤相关性周围神经病""边缘性脑炎"及"自身免疫性脑炎"的患者,筛选出两种或两种以上抗神经元抗体均为阳性的患者。结果在134例符合诊断的患者中,6例存在多重抗神经元抗体,包括抗Amphiphysin抗体合并抗γ-氨基丁酸受体B型(GABA_BR)抗体阳性2例[其中1例抗Hu抗体及抗谷氨酸脱羧酶(GAD65)抗体亦呈阳性],以及抗SOX1抗体合并抗Titin抗体阳性、抗Yo抗体合并抗富亮氨酸胶质瘤失活蛋白1(LGI1)抗体阳性、抗接触蛋白相关蛋白2(CASPR2)抗体合并抗LGI1抗体阳性和抗Hu抗体合并抗Ri抗体阳性各1例。6例患者临床表现均符合副肿瘤综合征,4例为周围神经病或肌肉接头病(其中2例合并边缘性脑炎,1例合并亚急性小脑变性),另2例单纯表现为边缘性脑炎;2例对免疫治疗有效;3例明确诊断癌症,分别为乳腺癌、胆管癌、小细胞肺癌。结论多重抗神经元抗体的存在,可导致患者的临床表现复杂多样,免疫治疗可能有效。存在某种抗神经元抗体的患者即使无相应神经综合征,该抗体亦对恶性肿瘤有提示意义。     

抗HU抗体阳性副肿瘤性小脑变性1例及文献复习

副肿瘤性小脑变性(paraneoplastic cerebellar degenertion,PCD)又称亚急性小脑变性(subacute cerebellar degeneration,SCD),是神经系统副肿瘤综合征(praneoplastic neurological syndrome,PNS)引起神经系统的典型损害之一,神经系统副肿瘤综合征(PNS)是一种罕见的副肿瘤综合征,并不是由肿瘤转移或直接浸润到神经系统引起,是由免疫反应的改变引起。是一种与恶性肿瘤相关但原因不明的小脑非转移性病变。本文报道1例以副肿瘤性小脑变性为首发症状的肺癌病例,加强临床医生对该病的认识。该患者即以双下肢行走不稳收入院,表现为小脑受损的症状与体征,脑干受损症状与体征未表现。检查脑脊液生化示,葡萄糖4.73 mmol/L,微量总蛋白548.00 mg/L;脑脊液抗酸、墨汁染色阴性。脑脊液常规示,红细胞数0,白细胞26个/mm~3;副肿瘤相关抗体抗Hu抗体阳性。行胸部增强CT示,左肺上叶前段占位病变,考虑新生物;左肺上叶尖后段纤维条灶索;纵隔内及左肺门区多发淋巴结肿大。结合患者临床表现和辅助检查,临床诊断为副肿瘤性小脑变性。早期诊断副肿瘤性小脑变性对于及时发现和根除宿主体内的肿瘤至关重要,尤其小细胞肺癌、乳腺癌、卵巢癌等。有条件可在血液和脑脊液中检测特定的抗神经元抗体,目前发现许多抗神经元抗体与PCD有关,并且对特定的肿瘤类型的早期诊断提供依据,如抗Hu抗体提示小细胞肺癌,抗Yo抗体提示乳腺、卵巢等肿瘤。该病总体预后不良,应积极采取综合治疗手段,控制肿瘤的转移及复发,以提高患者生存质量,延长生存时间,改善生存率。     

神经元特异性烯醇化酶和抗核抗体在神经系统副肿瘤综合征诊断中的意义

目的 明确神经元特异性烯醇化酶(NSE)、抗核抗体(ANA)、血沉(ESR)、C反应蛋白(CRP)在神经系统副肿瘤综合征诊断中的意义.方法 收集45份神经系统副肿瘤综合征患者血清标本,45例神经系统其它疾病患者作为对照.NSE采用放射免疫法检测,ANA以Hep-2细胞为底物的间接免疫荧光法检测,滴度在1∶80以上为阳性.ESR采用魏氏原理应用光电扫描法测定.CRP的测定采用免疫透射比浊度法测定.结果 结果以χ±s 表示.45例患者中,9例血清NSE升高(20.5%),全部均为肺癌.45例神经系统副肿瘤综合征患者中,27例血清ANA阳性(61.4%),平均滴度1∶640.29例副肿瘤性周围神经病患者中14例(48.3%)血清ANA阳性,平均滴度1∶320.而在对照组血清ANA滴度全部均在1∶40以下.结论 ESR、CRP在副肿瘤综合征患者体内也可以升高,但缺乏特异性.NSE对神经系统副肿瘤诊断无明确意义,但对于ANA阳性的患者,在除外胶原血管病的前提下,应警惕有无神经系统副肿瘤综合征.     

神经系统副肿瘤综合征抗体

神经系统副肿瘤综合征(PNS)是指神经系统抗原在肿瘤组织异位表达后产生相关抗体,通过自身免疫反应对神经和/或肌肉系统产生的远隔效应,不包括肿瘤直接浸润、转移、继发营养障碍及感染、高凝等原因所致神经系统损害,其诊断主要依据2004年Graus等提出的标准,此标准认为副肿瘤综合征抗体在该疾病的诊断中具有重要意义.本文将从副肿瘤综合征抗体的分类、引起神经系统损伤的机制、相应抗原的特点及对临床的指导意义方面进行综述.     

特异性神经元抗体对神经系统副肿瘤综合征筛检价值的研究

目的　探讨特异性神经元抗体 (尤其是抗 Hu抗体 )对国内人群神经系统副肿瘤综合征 (paraneoplasticsyndromesofnervoussystem ,PNSNS)筛检诊断的特异性和灵敏性。方法　采用免疫组织化学ABC法和Westernblot对 2 0例PNSNS和 12 0例非PNSNS患者的血清进行检测 ,并采用流行病学筛检公式计算出特异度和灵敏度。结果　PNSNS组和非PNSNS组ABC法阳性结果差异有统计学意义 (χ2 =33 4 5 ,P <0 0 1) ,特异性神经元抗体筛检诊断PNSNS的灵敏度为 95 % ,特异度为 72 5 % ;PNSNS组和非PNSNS组Westernblot法阳性率差异有统计学意义 (χ2 =117 12 ,P <0 0 1) ,抗 Hu抗体筛检诊断的PNSNS的灵敏度为 95 % ,特异度为 98 3%。结论　血清特异性神经元抗体 (尤其是抗 Hu抗体 )是国内人群中PNSNS患者较敏感和特异性的血清标志物 ,在神经元的免疫损伤中具有重要作用     

抗SOX-1抗体阳性副肿瘤性脊髓病一例

目的探讨副肿瘤性脊髓病(PM)的临床特点,以提高对该病的诊断水平。方法分析1例PM患者的病历资料。结果 62岁男性患者以双下肢麻木无力起病,呈亚急性进展,脑脊液副肿瘤综合征抗体示:抗SOX-1抗体IgG阳性(+),结合CT及增强磁共振(MRI)等检查,诊断为PM。结论 副肿瘤性脊髓病是由于全身性或潜在的恶性肿瘤的远隔效应从而造成脊髓损伤的一种神经系统副肿瘤综合征,提高对该病的认识,有助于早期诊断,通过检测相关特异性抗体指导疾病的早期治疗。     

Tumor progression and serum anti-HuD antibody concentration in patients with paraneoplastic neurological syndromes

The aim of this study was to investigate whether there are clues for a correlation between tumor progression and serum anti-Hu antibody concentration in patients with anti-Hu-associated paraneoplastic neurological syndromes (PNS). 19 patients with anti-Hu-associated PNS were assigned to three groups according to the course of tumor progression. Group 1 corresponds to patients with rapid tumor progression [n = 5; mean survival in months/standard deviation (SD); 24/10]; in group 2 patients with a favorable tumor prognosis were included (n = 7; mean/SD 79/25, 6 patients still alive); group 3 consisted of patients in whom tumor progression could not be assessed (n = 7; mean/SD 23/20). The anti-Hu antibody concentrations in sera were measured in a recombinant HuD-ELISA. In sera from patients of group 1 the anti-Hu antibody concentration was modest (mean OD 0.56, SD 0.08) whereas a significantly higher anti-Hu antibody concentration was detected in sera from patients with a favorable tumor prognosis (group 2, mean OD 1.86, SD 0.34). These results hint at a negative correlation between tumor progression and the anti-Hu antibody concentration in sera from patients with PNS. These findings confirm and extend previous reports of more indolent tumor growth in patients with an anti-Hu immune response.     

Quantification of circulating anti-Hu antibody in serial samples from patients with paraneoplastic neurological syndromes: Possible correlation of antibody concentration and course of neurological symptoms

Serial samples, spanning an observation period of 4 to 10 years, from five patients with anti-Hu associated paraneoplastic neurological syndromes (PNS) were investigated with an enzyme linked immunosorbent assay (ELISA) employing recombinant HuD protein as antigen. In one patient the anti-Hu antibody concentration converted from negative to highly positive levels after the onset of neurological symptoms. These findings argue in favour of the idea that an autoimmune process, which is generated at the beginning of the neurological disease, causes the anti-Hu associated PNS. Serum samples obtained shortly after the beginning of the PNS were available from two other patients. The anti-Hu antibody levels in these latter patients increased from modest to highly positive anti-Hu antibody in follow up samples. In two patients a clear decrease of the anti-HuD antibody concentration together with an improvement of paraneoplastic neurological symptoms after successful tumour treatment were seen. Overall these data suggest that there might be a correlation between the anti-HuD antibody level and the clinical course of paraneoplastic neurological symptoms which supports further the hypothesis that an autoimmune process is responsible for the anti-Hu associated paraneoplastic neurological symptoms. Received: 16 March 2001, Received in revised form: 6 July 2001, Accepted: 10 July 2001     

副肿瘤综合征抗Hu抗体对培养神经细胞的直接影响

目的研究副肿瘤综合征(PNS)自身抗体(抗Hu抗体)对培养神经细胞的直接影响。方法抗Hu抗体阳性PNS患者血清IgG、对照组血清IgG添加到由胎鼠脑分离出的培养神经细胞,观察有无细胞的凋亡。对照组血清IgG为：(1)AB型健康人标准血清；(2)无神经损害症状的抗Hu抗体阴性痛患者血清；(3)重组Hu蛋白吸附后的抗Hu抗体阳性患者血清。结果添加抗Hu抗体阳性PNS患者血清IgG的培养神经细胞互相融合,由粗而长的突起相互连接,而对照组未看到上述变化。各组均未发现凋亡的神经细胞。结论抗Hu抗体未能引起神经细胞的凋亡或死亡,推测是诱导了接触因子的表达促进了细胞的分化。     

Anti-Hu antibody titre and brain metastases before and after treatment for small cell lung cancer

OBJECTIVES: To follow up the level of anti-Hu antibody titres during chemotherapy and to compare the pattern of metastases and other neurological complications before and after chemotherapy in patients with small cell lung cancer (SCLC) with and without low titre anti-Hu antibodies. Seventeen per cent of patients with SCLC without paraneoplastic syndromes have a low titre of anti-Hu antibodies in their serum. Previous studies suggested that these antibodies correlate with a more indolent tumour growth. METHODS: The serum of 52 consecutive patients with SCLC were studied before and during chemotherapy, and the correlation with stage of disease and pattern of metastases was examined. All serum samples were investigated using western blot and enzyme linked immunosorbent assay (ELISA) with HuD recombinant protein. All patients with SCLC were investigated using MRI of the brain, CSF, bone marrow aspiration, ultrasound of the abdomen, and radionuclide bone scan. RESULTS: Nine (17%) of 52 SCLC serum samples were positive by western blot. At the time of diagnosis none of the anti-Hu positive patients had either CNS (brain or leptomeningeal), epidural, adrenal, or bone marrow metastases and 56% had limited disease. In eight of 43 anti-Hu negative patients CNS metastases were found at the time of diagnosis, and only 30% had limited disease. The prevalence of bone and liver metastases was similar in both groups. Survival was 11 (SD ) months for the 43 anti-Hu negative and 10 (SD 6) months for the nine anti-Hu positive patients. Male:female ratio in the anti-Hu negative group was 4.4:1, and in the anti-Hu positive group 2:1. CONCLUSIONS: No anti-Hu antibody positive serum, as tested by western blot, became negative during chemotherapy. Anti-Hu positive and anti-Hu negative patients had similar survival, but anti-Hu positive patients tended to be women, had limited disease at the time of tumour diagnosis, and initially metastases seemed to spare the nervous system.     

Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome

Previous study has shown that the anti-Hu antibody titre ofserum samples from patients with paraneoplasticencephalomyelitis/paraneoplastic sensory neuronopathy (PEM/PSN) wassignificantly higher than that from patients with small cell lungcancer without neurological disturbances (non-PEM/PSN). The aims ofthis study were (1) to identify the fine epitopes on HuD recognised bythe anti-Hu antibody, (2) to determine if the pattern of epitopicreactivity differed between antibodies from patients with and withoutPEM/PSN, and (3) to determine if the pattern of epitopic reactivitycorrelated with the clinical features. Recombinant full length HuD andnine deletion fragments were constructed and immunoreacted by western blot analysis with 14 anti-Hu serum samples from eight patients withPEM/PSN and six without PEM/PSN. All anti-Hu serum samples reacted withthe deletion fragments containing amino acids (aa) 90-101 or aa171-206. Some anti-Hu samples reacted with the deletion fragmentscontaining aa 223-234, aa 235-252, or aa 354-373. There was nodifference in the pattern of epitopic reactivity between patients withand without PEM/PSN. There was no correlation between the pattern ofepitopic reactivity and the clinical features. The anti-Hu antibodytitre from patients with PEM/PSN was significantly higher than frompatients without PEM/PSN, but there was overlap of their titreconcentrations. In conclusion, aa 90-101 and aa 171-206 are the majorepitopes with which all anti-Hu serum samples react, and aa 223-234,aa 235-252, and aa 354-373 are the minor epitopes with which onlysome anti-Hu serum samples react. The analyses suggested that thepattern of epitopic reactivity of the anti-Hu antibody on HuD was not acritical factor for the development or clinical features of PEM/PSN.

     

Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis

We looked for the presence of the anti-Hu antibody in the sera from 50 normal subjects; 44 patients with small cell lung cancer, not associated with paraneoplastic disease; and 25 patients with small cell lung cancer associated with paraneoplastic sensory neuropathy, encephalomyelitis, or both. Using the avidin-biotin immunoperoxidase method and a highly sensitive quantitative Western blot analysis, the anti-Hu antibody was not detected in the 50 normal human sera. Seven of the 44 patients with small cell lung cancer but no paraneoplastic syndrome had detectable levels (average titer, 76 U/ml) of anti-Hu antibody on Western blot. These levels are significantly lower than the average titer of the 25 patients who had small cell lung cancer and paraneoplastic sensory neuropathy or encephalomyelitis (average titer, 4,592 U/ml). In the group with nonparaneoplastic small cell lung cancer (low anti-Hu titer) there was a predominance of women (5 women: 2 men), and all patients had "limited" disease when diagnosed. In the antibody-negative group the sex ratio was 16 women to 21 men and 51% of the patients had "extensive" disease. None of the 7 patients with a low-titer anti-Hu antibody developed a paraneoplastic syndrome by the time of writing. The anti-Hu antibody appears, when present, to be a good marker for small cell lung cancer and, when present at high titer, for small cell lung cancer associated with a paraneoplastic syndrome.     

Paraneoplastic anti-Hu serum: studies on human tumor cell lines

Patients with low titers of anti-Hu, the paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/PSN) antibody, have a better tumor prognosis that those who do not harbor these antibodies. Accordingly, we examined the effects of serum from patients with anti-Hu antibodies on human tumor cell lines, in order to determine: (1) if the serum was toxic (growth inhibition or cytolysis) to tumor cells with or without complement, and (2) if anti-Hu antibodies contributed to tumor toxicity. The serum of 14 patients with anti-Hu associated PEM/PSN, 22 patients with small-cell lung cancer (SCLC) without anti-Hu antibodies, and 20 normal individuals were studied. Three cell lines (NT-2, BE(2)-C, and SH.SY5Y) that express Hu proteins, and one cell line (SAOS-2) that does not, were studied. We examined the effects of whole serum, IgG-depleted serum, and purified IgG in the presence or absence of complement. A higher percentage of anti-Hu sera were toxic (71%) compared with sera from anti-Hu negative SCLC patients (23%) (p<0.0001). No correlation existed between the titer of anti-Hu antibodies and toxicity. The toxic effects were observed in all tumor cell lines including the cell line that does not express Hu antigens. Toxicity persisted in serum depleted of IgG. Purified anti-Hu IgG in the presence and absence of complement, was not toxic. Our findings indicate that anti-Hu serum is toxic for human tumor cell lines, but this toxicity does not appear to be mediated by anti-Hu antibodies.     

Cytotoxic T lymphocyte-mediated cell death in paraneoplastic sensory neuronopathy with anti-Hu antibody.

Paraneoplastic sensory neuronopathy (PSN) has been shown to harbor characteristic anti-neuronal autoantibody 'anti-Hu' in their sera and cerebrospinal fluid. Creation of animal models exhibiting clinical or pathological features seen in PSN by means of passive transfer of anti-Hu positive IgG has not been achieved. Although, anti-Hu antibody was shown to induce neuronal cell lysis in vitro, this result has not been reproduced so far. Since prominent T cell infiltration are seen in the central nervous system and posterior spinal ganglion of the patients with anti-Hu syndrome, we studied cytotoxic T cell (CTL) activity in peripheral mononuclear cells from a patient with PSN harboring anti-Hu antibody. The activated CD8+ T cells from the patient's venous blood were shown to lyse her own fibroblasts which were incubated with interferon-gamma to induce HLA class I molecules on their surface and the recombinant HuD protein was injected into the cells by microinjector. This is the first report showing the existence of CTL in a patient with PSN.     

Effects of antineuronal antibodies from patients with paraneoplastic neurological syndrome on primary-cultured neurons

Some patients with paraneoplastic neurological syndrome (PNS) produce autoantibodies against tumor and neuronal tissues of symptom-relevant areas. These characteristic antibodies are detected at early stages of the neurological disorder and are reliable markers for the diagnosis of PNS and underlying cancers. These antibodies are thought to be related directly to neuronal damage. However, the passive transfer of antibodies to rodents has been succeeded only in those in which the target antigens were expressed on the cell surface, like Lambert-Eaton myasthenic syndrome. The serum IgGs from patients with PNS and anti-Yo or anti-Hu antibody were not shown to induce the disease by passive transfer or active immunization with these antigen proteins to date. Instead, cytotoxic T lymphocytes (CTLs) against these antigen peptides-presenting targets could be induced in the peripheral blood of PNS patients. However, there is no direct proof of CTLs killing neurons. In this study, we examined the effects of the anti-Yo or anti-Hu antibody on mouse-brain-derived neurons in a primary culture system and found that these antibodies did not kill neurons, but induced the expression of cell adhesion molecules and accelerated neuronal differentiation. These effects of serum IgG fractions containing the anti-Yo or the anti-Hu antibody on the cultured neurons were the same, suggesting that their effects were not through the binding of the antibody to specific antigens, but to some other factors contained in IgG fractions.     

观察副肿瘤神经综合征患者抗Hu抗体对培养胎鼠神经细胞N-cadherin的表达及意义

目的观察副肿瘤神经综合征(PNS)患者自身抗体(抗Hu抗体)对胎鼠培养神经细胞的直接影响及N-cadherin的表达,探讨PNS免疫学的发病机制。方法实验组抗Hu抗体阳性PNS患者血清IgG、对照组血清IgG添加到由胎儿鼠脑分离出的培养神经细胞,观察细胞的变化,通过免疫组化观察N-cadherin的表达。结果实验组添加抗Hu抗体阳性IgG的培养神经细胞可见细胞互相融合,突起出现粗而长相互连接的形态变化,免疫组化发现大量N-cadherin的表达;而对照组未看到上述细胞形态的变化,免疫组化也未发现N-cadherin的表达;各组均未发现凋亡的神经细胞。结论抗Hu抗体可能通过诱导N-cadherin的表达,或者在抗Hu抗体IgG片段中存在着另外的某种物质,从而促进神经细胞聚集及突起的增粗伸长,因而影响了神经细胞的正常功能。这种效应推测抗Hu抗体不是直接与对应抗原发生了免疫反应引起发病,而可能是在血清抗体IgG片段中存在着抗体以外的致病因子参与了PNS的发病过程。