Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes

Abstract

We describe a new antibody, called anti-glial nuclear antibody (AGNA), in patients with paraneoplastic neurological syndromes (PNS) and small-cell lung carcinoma (SCLC). AGNA was initially identified in 24 sera of our archives by immunohistochemistry on rat cerebellum. AGNA positive sera showed a characteristic nuclear staining of the Bergmann glia in the Purkinje cell layer. Immunoblots and probing a cerebellar expression library with AGNA sera did not identify the antigen. Twenty of the 24 patients with AGNA had PNS and all but two had lung cancer. AGNA was identified in 13/113 (11.5%) patients with SCLC compared with 0/122 with other types of cancer (p<0.0001). The frequency of AGNA was not higher than expected for the presence of SCLC in the different PNS subtypes except in LEMS (p=0.0002). AGNA was present in 13/30 (43%) of LEMS patients with SCLC, compared with 0/19 of LEMS patients without cancer (p=0.0006). We conclude that the recognition of AGNA is helpful since this antibody is found in PNS associated with SCLC, particularly LEMS, in which other onconeural antibodies are absent.

Fig. 1

(A) Frozen section of paraformaldehyde-fixed rat cerebellum immunoreacted with AGNA positive serum. There is intense labeling of the nuclei of Bergmann glia in the Purkinje cell layer. (B) Higher magnifications of the same section incubated with AGNA. (C) Double labeling study showing that AGNA reacts with the nuclei (red) of Bergmann glia, which are not labeled with NeuN a neuronal nucleus-specific monoclonal antibody (green). Note that NeuN labels the nuclei of granular cells and other cerebellar neurons except Purkinje cells, as previously described (Mullen et al., 1992). Bar=38 μm (A), 18 μm (B), and 24 μm (C). Sections counterstained with hematoxylin in (A) and (B).

Fig. 2

Frozen section paraformaldehyde-fixed rat hippocampus double labeled with biotinylated AGNA IgG (red) and NeuN antibody (green). The nucleus of one neuron coexpress both antigens (yellow) whereas the nucleolus is only labeled with AGNA. Bar=11 μm.

Fig. 3

Paraffin embedded sections of small-cell lung carcinoma (SCLC) immunoreacted with biotinylated AGNA IgG. The robust reactivity of the biotinylated AGNA IgG (A) is abolished by preincubation with an AGNA positive serum (B). Sections counterstained with hematoxylin.