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

O'Donovan, B. D.; Mandel-Brehm, C.; Vazquez, S. E.; Liu, J.; Parent, A. V.; Anderson, M. S.; Kassimatis, T.; Zekeridou, A.; Hauser, S. L.; Pittock, S. J.; Chow, E.; Wilson, M. R.; DeRisi, J. L.

doi:10.1101/502187

bioRxiv · 10.1101/502187

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

O'Donovan, B. D.·Mandel-Brehm, C.·Vazquez, S. E.·Liu, J.·Parent, A. V.·Anderson, M. S.·Kassimatis, T.·Zekeridou, A.·Hauser, S. L.·Pittock, S. J.·Chow, E.·Wilson, M. R.·DeRisi, J. L.

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Abstract

Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.

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O'Donovan, B. D., Mandel-Brehm, C., Vazquez, S. E., Liu, J., Parent, A. V., Anderson, M. S., Kassimatis, T., Zekeridou, A., Hauser, S. L., Pittock, S. J., Chow, E., Wilson, M. R., DeRisi, J. L.. 2018-12-20. Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes. https://doi.org/10.1101/502187

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