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. 2013;8(3):e60438.
doi: 10.1371/journal.pone.0060438. Epub 2013 Mar 25.

Antibody Repertoire in Paraneoplastic Cerebellar Degeneration and Small Cell Lung Cancer

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Free PMC article

Antibody Repertoire in Paraneoplastic Cerebellar Degeneration and Small Cell Lung Cancer

Lidia Sabater et al. PLoS One. .
Free PMC article

Abstract

The goal of this study is to determine whether patients with paraneoplastic cerebellar degeneration (PCD) and small-cell lung cancer (SCLC) have a specific repertoire of antibodies, if SOX1 antibodies (SOX1-ab) can predict the presence of SCLC, and if antibodies to cell surface antigens occur in this syndrome. Antibody analysis was done using immunohistochemistry on rat brain, immunoblot with recombinant antigens, screening of cDNA expression libraries, and immunolabeling of live neurons in 39 patients with PCD and SCLC. VGCC-ab were measured by RIA, and SOX1-ab, Hu-ab, and ZIC4-ab by immunoblot. Lambert-Eaton myastenic syndrome (LEMS) was present in 10 of 23 patients with electrophysiological studies. At least one antibody was detected in 72% of patients. The individual frequencies were: 49% SOX1-ab, 44% VGCC-ab, 31% Hu-ab, and 13% ZIC4-ab. SOX1-ab occurred in 76% of patients with VGCC-ab and 27% of those without VGCC-ab (p = 0.0036). SOX1-ab were not found in 39 patients with sporadic late-onset cerebellar ataxia, 23 with cerebellar ataxia and glutamic acid decarboxylase antibodies, and 73 with PCD and cancer types other than SCLC (31 without onconeural antibodies, 25 with Yo-ab , 17 with Tr-ab). Five patients (13%) had antibodies against unknown neuronal cell surface antigens but none of them improved with immunotherapy. One serum immunoreacted against the axon initial segment of neurons and another serum against ELKS1, a protein highly expressed in the cerebellum that interacts with the beta4-subunit of the VGCC. In conclusion, 72% of patients with PCD and SCLC had one or more antibodies that indicate the presence of this tumor. In these patients, VGCC-ab and SOX1-ab occur tightly associated. SOX1-ab are predictors of SCLC in ataxia patients with a specificity of 100% and sensitivity of 49%. Unlike limbic encephalitis with SCLC, antibodies to cell surface antigens other than VGCC-ab, are infrequent and do not predict response to treatment.

Conflict of interest statement

Competing Interests: Dr. Dalmau has a research grant from Euroimmun, and receives royalties from patents for the use of Ma2 and NMDAR as autoantibody tests. He has no financial competing interests such as ownership of stocks or shares, paid employment or consultancy, board membership, travel grants and honoraria for speaking or participation at meetings, products in development or marketed products, or gifts of any kind etc. The relation of Dr. Dalmau with the company Euroimmun does not alter the authors‚ adherence to all the PLOS ONE policies on sharing data and materials. None of the other contributors have any conflicts of interest.

Figures

Figure 1
Figure 1. Graphic representation of the SOX1, VGCC, Hu, and ZIC4 antibodies in PCD associated with SCLC.
Distribution of SOX1-, VGCC-, Hu-, and ZIC4-ab in our patient cohort. Each row represents a patient and when positive the cell is filled in color.
Figure 2
Figure 2. Association of VGCC and SOX1 antibodies.
Bar graph representation of the correlation between SOX1-ab and VGCC-ab. (Fisher exact test p = 0.0036).
Figure 3
Figure 3. Identification of new antibodies.
A. Antibodies against hillock of the neurons of rat cerebellum. Immunohistochemistry on rat sagittal cerebellum sections. Note the strong atypical reactivity of a PCD SCLC serum against the hillock axon of the neurons, mainly in Purkinje cells. Nuclei are counterstained with hematoxilin. B. Immunofluorescence on live hippocampal neurons. Hippocampal neurons incubated with CSF 1/5 diluted of a PCD SCLC patient. Reactivity of the patient against the membrane of the neuron is seen in green and MAP2 staining in red to ensure the neuronal lineage. Nuclei are seen blue with DAPI. (objective 100x oil)

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