Human-derived Monoclonal Autoantibodies As Interrogators of Cellular Proteotypes in the Brain

Overview

Journal Trends Neurosci

Specialty Neurology

Date 2024 Sep 6

PMID 39242246

Authors

Matthew L Baum

Christopher M Bartley

Affiliations

Soon will be listed here.

Abstract

A major aim of neuroscience is to identify and model the functional properties of neural cells whose dysfunction underlie neuropsychiatric illness. In this article, we propose that human-derived monoclonal autoantibodies (HD-mAbs) are well positioned to selectively target and manipulate neural subpopulations as defined by their protein expression; that is, cellular proteotypes. Recent technical advances allow for efficient cloning of autoantibodies from neuropsychiatric patients. These HD-mAbs can be introduced into animal models to gain biological and pathobiological insights about neural proteotypes of interest. Protein engineering can be used to modify, enhance, silence, or confer new functional properties to native HD-mAbs, thereby enhancing their versatility. Finally, we discuss the challenges and limitations confronting HD-mAbs as experimental research tools for neuroscience.

References

Gibson L, McKeever A, Coutinho E, Finke C, Pollak T . Cognitive impact of neuronal antibodies: encephalitis and beyond. Transl Psychiatry. 2020; 10(1):304. PMC: 7463161. DOI: 10.1038/s41398-020-00989-x. View

Andrzejak E, Rabinovitch E, Kreye J, Pruss H, Rosenmund C, Ziv N . Patient-Derived Anti-NMDAR Antibody Disinhibits Cortical Neuronal Networks through Dysfunction of Inhibitory Neuron Output. J Neurosci. 2022; 42(15):3253-3270. PMC: 8994542. DOI: 10.1523/JNEUROSCI.1689-21.2022. View

Trubetskoy V, Pardinas A, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli T . Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022; 604(7906):502-508. PMC: 9392466. DOI: 10.1038/s41586-022-04434-5. View

Ly L, Kreye J, Jurek B, Leubner J, Scheibe F, Lemcke J . Affinities of human NMDA receptor autoantibodies: implications for disease mechanisms and clinical diagnostics. J Neurol. 2018; 265(11):2625-2632. PMC: 6182686. DOI: 10.1007/s00415-018-9042-1. View

Otchy T, Wolff S, Rhee J, Pehlevan C, Kawai R, Kempf A . Acute off-target effects of neural circuit manipulations. Nature. 2015; 528(7582):358-63. DOI: 10.1038/nature16442. View

Wolff S, Olveczky B . The promise and perils of causal circuit manipulations. Curr Opin Neurobiol. 2018; 49:84-94. PMC: 5957484. DOI: 10.1016/j.conb.2018.01.004. View

Nguyen D, Saney C, Hentenaar I, Cabrera-Mora M, Capric V, Woodruff M . Majority of human circulating IgG plasmablasts stop blasting in a cell-free pro-survival culture. Sci Rep. 2024; 14(1):3616. PMC: 10864258. DOI: 10.1038/s41598-024-53977-2. View

Langlieb J, Sachdev N, Balderrama K, Nadaf N, Raj M, Murray E . The molecular cytoarchitecture of the adult mouse brain. Nature. 2023; 624(7991):333-342. PMC: 10719111. DOI: 10.1038/s41586-023-06818-7. View

Itaya K, Inoue M, Iizuka N, Shimizu Y, Yuki N, Ichikawa H . A case of a 17-year-old male with neurofascin-155 antibody-positive chronic inflammatory demyelinating polyradiculoneuropathy presenting with tremor and ataxia. Rinsho Shinkeigaku. 2016; 56(9):633-6. DOI: 10.5692/clinicalneurol.cn-000853. View

10.

Hansen J, Baum A, Pascal K, Russo V, Giordano S, Wloga E . Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science. 2020; 369(6506):1010-1014. PMC: 7299284. DOI: 10.1126/science.abd0827. View

11.

Binks S, Uy C, Honnorat J, Irani S . Paraneoplastic neurological syndromes: a practical approach to diagnosis and management. Pract Neurol. 2021; 22(1):19-31. DOI: 10.1136/practneurol-2021-003073. View

12.

DeGiorgio L, Konstantinov K, Lee S, Hardin J, Volpe B, Diamond B . A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med. 2001; 7(11):1189-93. DOI: 10.1038/nm1101-1189. View

13.

Siletti K, Hodge R, Mossi Albiach A, Lee K, Ding S, Hu L . Transcriptomic diversity of cell types across the adult human brain. Science. 2023; 382(6667):eadd7046. DOI: 10.1126/science.add7046. View

14.

Wang E, Mao T, Klein J, Dai Y, Huck J, Jaycox J . Diverse functional autoantibodies in patients with COVID-19. Nature. 2021; 595(7866):283-288. DOI: 10.1038/s41586-021-03631-y. View

15.

Unterauer E, Boushehri S, Jevdokimenko K, Masullo L, Ganji M, Sograte-Idrissi S . Spatial proteomics in neurons at single-protein resolution. Cell. 2024; 187(7):1785-1800.e16. DOI: 10.1016/j.cell.2024.02.045. View

16.

Marino M, Holt M . AAV Vector-Mediated Antibody Delivery (A-MAD) in the Central Nervous System. Front Neurol. 2022; 13:870799. PMC: 9039256. DOI: 10.3389/fneur.2022.870799. View

17.

Chan K, Nestor J, Huerta T, Certain N, Moody G, Kowal C . Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory. Nat Commun. 2020; 11(1):1403. PMC: 7075964. DOI: 10.1038/s41467-020-15224-w. View

18.

Hikosaka O, Yasuda M, Nakamura K, Isoda M, Kim H, Terao Y . Multiple neuronal circuits for variable object-action choices based on short- and long-term memories. Proc Natl Acad Sci U S A. 2019; 116(52):26313-26320. PMC: 6936452. DOI: 10.1073/pnas.1902283116. View

19.

Hoffmann L, Jarius S, Pellkofer H, Schueller M, Krumbholz M, Koenig F . Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases. J Neurol Neurosurg Psychiatry. 2008; 79(7):767-73. DOI: 10.1136/jnnp.2007.118588. View

20.

Hodge R, Bakken T, Miller J, Smith K, Barkan E, Graybuck L . Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019; 573(7772):61-68. PMC: 6919571. DOI: 10.1038/s41586-019-1506-7. View