Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis
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PROVIDER: S-EPMC10546956 | biostudies-literature | 2023 Jan
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Project description:Focal Opercular Myoclonic - Anarthric Status Epilepticus (OMASE) is a rare form of focal motor status epilepticus caused by several etiologies. It is characterized by fluctuating dysarthria and epileptic myoclonus involving the bilateral glossopharyngeal musculature. We present the case of a 52-year-old woman who experienced gradual and progressive paralysis and myoclonus of facial and bulbar muscles; additional tests revealed the presence of right breast ductal adenocarcinoma and positive serum anti-Hu and anti-GAD65 antibodies. High doses of steroid pulses, anti-seizure therapy, and rituximab partially controlled myoclonus; the tumor resection improved dysphagia and dysarthria.
| S-EPMC11372628 | biostudies-literature
Project description:ObjectiveTo describe paraneoplastic neuronal intermediate filament (NIF) autoimmunity.MethodsArchived 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.ResultsAmong 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 (p = 0.006), as well as limited (p = 0.003) and more diverse (p < 0.0001) cancer accompaniments.ConclusionsNIF-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.
| S-EPMC6207411 | biostudies-literature
Project description:BackgroundParaneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab.MethodsTwenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive.ResultsThe median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%).ConclusionsNatalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed.Trial registrationhttps://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL.
| S-EPMC8528262 | biostudies-literature
Project description:Paraneoplastic neurological disorders are immune-mediated diseases understood to manifest as part of a misdirected anti-tumor immune response. Paraneoplastic neurological disorder-associated autoantibodies can assist with diagnosis and enhance our understanding of tumor-associated immune processes. We designed a comprehensive library of 49-amino-acid overlapping peptides spanning the entire human proteome, including all splicing isoforms and computationally predicted coding regions. Using this library, we optimized a phage immunoprecipitation and sequencing protocol with multiple rounds of enrichment to create high-resolution epitope profiles in serum and cerebrospinal fluid (CSF) samples from patients suffering from two common paraneoplastic neurological disorders, the anti-Yo (n = 36 patients) and anti-Hu (n = 44 patients) syndromes. All (100%) anti-Yo patient samples yielded enrichment of peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients enriched peptides deriving from the nELAVL (neuronal embryonic lethal abnormal vision like) family of proteins, the anti-Hu autoantigenic target. Among the anti-Hu patient samples that were positive for nELAVL, we noted a restricted region of immunoreactivity. To achieve single amino acid resolution, we designed a novel deep mutational scanning phage library encoding all possible single-point mutants targeting the reactive nELAVL region. This analysis revealed a distinct preference for the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, phage immunoprecipitation sequencing identified several known autoantigens in these same patient samples, including peptides deriving from the cancer-associated antigens ZIC and SOX families of transcription factors. Overall, this optimized phage immunoprecipitation sequencing library and protocol yielded the high-resolution epitope mapping of the autoantigens targeted in anti-Yo and anti-Hu encephalitis patients to date. The results presented here further demonstrate the utility and high-resolution capability of phage immunoprecipitation sequencing for both basic science and clinical applications and for better understanding the antigenic targets and triggers of paraneoplastic neurological disorders.
| S-EPMC7425417 | biostudies-literature
Project description:BackgroundSeveral lines of evidence suggest a T cell-mediated immune response in paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS). In order to investigate whether suppression of T cell-mediated immune responses in Hu-PNS patients improved their neurological outcome, we performed a prospective open-label, single-arm study on sirolimus.MethodsSeventeen progressive Hu-PNS patients were treated with sirolimus with an intended treatment duration of 8 weeks. Primary outcome measures were (i) functional improvement, defined as a decrease of one or more points on the modified Rankin Scale (mRS), and (ii) improvement of neurological impairment, defined as an increase of one or more points on the Edinburgh Functional Impairment Tests (EFIT).ResultsOne patient showed improvement on both clinical scales (mRS and EFIT). This patient presented with limbic encephalitis and improved dramatically from an mRS score of 3 to mRS 1. Another patient, with subacute sensory neuronopathy, remained stable at mRS 2 and improved one point on the EFIT scale. The other patients showed no improvement on the primary outcome measures. Median survival was 21 months.ConclusionWe conclude that treatment of Hu-PNS patients with sirolimus may improve or stabilize their functional disabilities and neurological impairments. However, the effects of this T cell-targeted therapy were not better than reported in trials on other immunotherapies for Hu-PNS. Trial Registration https://www.clinicaltrialsregister.eu/ctr-search/trial/2008-000793-20/NL.
| S-EPMC4483045 | biostudies-literature
Project description:Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB∗01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.
| S-EPMC10551040 | biostudies-literature
Project description:Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-gamma-producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen-specific T cells to this unusual noncytolytic phenotype.
| S-EPMC2701858 | biostudies-literature
Project description:BackgroundThe clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non-small-cell lung cancer (NSCLC) are not well known.ObjectiveTo review the clinical and immunological features of patients with PCD, NSCLC and without well-characterised onconeural antibodies.MethodsThe clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen.ResultsNine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47-73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar-expression library resulted in the isolation of protein kinase Cgamma (PKCgamma). PKCgamma immunoreactivity was not observed in the serum of 170 patients with non-paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small-cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCgamma at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCgamma antibodies expressed PKCgamma.ConclusionPCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.
| S-EPMC2077410 | biostudies-literature
Project description:BackgroundSeptins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination.MethodsSera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression.ResultsImmunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies' specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient.ConclusionsSeptin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.
| S-EPMC10061979 | biostudies-literature
Project description:Paraneoplastic syndromes are a group of rare disorders that can be triggered by an abnormal immune response to proteins from tumors of the lung, ovary, lymphatics, or breast. Paraneoplastic clinical syndromes affect < 1% of patients with cancer; however, the frequency of subclinical levels of paraneoplastic autoantibodies in asymptomatic patients with cancer is unknown. Numerous studies have reported that ovarian cancer patients show signs of paraneoplastic neurological syndromes (PNSs) before or after their cancers are diagnosed. PNSs arise from a tumor-elicited immune response against onconeural antigens that are shared by tissues of nervous system, muscle, and tumor cells. Studies on the serum IgGs obtained from ovarian cancer patients have indicated the presence of onconeural antibodies in the absence of any PNS symptoms. The occurrence of PNSs is low in ovarian cancer patients and it can be accompanied by onconeural antibodies. The diagnosis of PNSs is accompanied by a suspicion of a malignant tumor such that neurologists typically refer such patients for a tumor diagnostic workup. There will be tremendous utility if subclinical levels (without paraneoplastic neurological symptoms or myositis) of these autoantibodies to paraneoplastic antigens can be exploited to screen asymptomatic high-risk patients for ovarian cancer, and used as biomarkers in immunoassays for the early detection or recurrence of ovarian cancer. Ovarian cancer overall survival is likely to be improved with early detection. Therefore, a panel of onconeural antigens that can detect paraneoplastic autoantibodies in patient sera should provide diagnostic utility for an earlier therapeutic intervention. Here we review the usefulness of PNS and other paraneoplastic syndromes and their association with paraneoplastic antigens to exploit these autoantibody biomarkers to form diagnostic multi-analyte panels for early detection of ovarian cancer.
| S-EPMC5476453 | biostudies-literature