Microtubule‐associated protein 1B: Novel paraneoplastic biomarker

Abstract

Objective: To report the identification of microtubule-associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA-2) antibody, its frequency, and clinical, oncological, and serological associations. Methods: Archival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA-2-IgG-seropositive patients identified during 1993-2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments. Results: IgG in 95 of 96 patients' serum or CSF (but in none of 98 healthy or disease control subjects' serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients' IgG also bound to MAP1A. PCA-2 was often accompanied by additional neural autoantibody markers of small-cell carcinoma, including collapsin responsemediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA-1) IgG (also known as antiHu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small-cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA-2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA-2 (also known as anti-Ri; 0.016%) and PCA-Tr (also known as delta/notch-like epidermal growth factor-related receptor [DNER]; 0.006%). Interpretation: MAP1B, the PCA-2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. ANN NEUROL 2017;81:266-277 I n 2000, Vernino and Lennon 1 reported 10 patients with neurological autoimmunity, 9 of whom had imaging or histopathologic evidence of lung cancer (8 biopsyproven small-cell lung carcinoma [SCLC]). Their serum IgG bound to a protein of 280kDa mass in both rodent brain and a SCLC line and yielded a characteristic staining pattern on rodent neural tissues. The autoantibody was named Purkinje cell cytoplasmic antibody type 2 (PCA-2), to distinguish it from a biomarker of ovarian and breast cancer-related cerebellar degeneration, PCA-1 (also known as anti-Yo). 2 The neurological associations initially reported for PCA-2 were mixed, of subacute onset and predominantly central (brainstem and limbic encephalitis, cerebellar ataxia), but some patients had peripheral manifestations (Lambert-Eaton myasthenic syndrome [LEMS] or autonomic or motor neuropathy). 1 Our study extends the immunochemical characteristization of PCA-2 IgG an...

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

“…37 The SCLC-related IgGs identified most commonly are specific for SOX transcription factor proteins (SOX1 and SOX2), Hu proteins (antineuronal nuclear autoantibody [ANNA] type 1), voltage-gated calcium channels (VGCCs; P/Q type and N type), collapsin response-mediator protein 5 (CRMP5), metabotropic g-aminobutyric acid (GABA) type B receptors, amphiphysin, and microtubule-associated protein 1B (antigen of Purkinje cell cytoplasmic autoantibody [PCA] type 2). 37,38 Antineuronal nuclear autoantibody type 1-IgG is a biomarker of several classically recognized SCLC-associated syndromes, such as sensory neuronopathy, limbic encephalitis, and gastrointestinal dysmotility. 37,39 CD8 þ T cells specific for peptides derived from the Hu protein (the antigen of ANNA1 IgG) have been demonstrated in peripheral blood of ANNA1 -IgGeseropositive SCLC patients.…”

“…Its antigen is the microtubule-associated protein 1B. 38 Thymic Epithelial Tumors Thymoma is highly associated with neurologic, rheumatologic, hematologic, endocrine, and cutaneous autoimmune disorders. 45,46 Remarkably, myasthenia gravis is predicted to develop in 25% of all patients with thymoma.…”

Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes

“…Briefly, patient samples (serum/CSF) were tested on a mouse composite tissue slide with an indirect immunofluorescence assay for IgG binding corresponding to the anti-Hu or anti-Yo pattern, as previously described. 29 The results were confirmed with western blot analysis on rat cerebellum preparations.…”

“…In total, 798 individual IPs (including all three rounds of enrichment) were performed on 130 CSF and serum samples from patients with anti-Yo or anti-Hu antibodies identified by the Mayo Clinic Neuroimmunology Laboratory with CLIA and New York State approved methodology, as previously described (see Methods). 29…”

Identity of the Purkinje cell cytoplasmic antibody type 2 autoantibody antigen is finally revealed

“…In the February issue of Annals of Neurology Gadoth and colleagues characterized the PCA‐2 autoantibody using biochemical, molecular, and histological approaches, and evaluated >100 serum and human CSF samples from the Mayo Clinic Neuroimmunology Laboratory. Samples were further evaluated using mass spectroscopy to unequivocally assign MAP1B as the main antigen for the PCA‐2 antibody.…”