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Higher Levels of IgG3 Antibodies in Serum, But Not in CSF, Distinguish Multiple Sclerosis From Other Neurological Disorders

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Abstract

Increased intrathecal IgG and oligoclonal bands (OCB) are seminal features of multiple sclerosis (MS). Although no such differences in MS blood total IgG antibodies have been reported, serum OCB are a common and persistent finding in MS and have a systemic source. Recent studies showed that IgG3+ B cells and higher levels of serum IgG3 are linked to the development of MS. Additionally, intrathecal IgG synthesis in MS is associated with IgG3 heavy chain gene single nucleotide polymorphisms, and there is a strong relationship between susceptibility to MS and an IgG3 restriction fragment length polymorphism. These studies support the role of IgG3 in disease pathogenesis. Using multiple immunoassays, we investigated levels of total IgG, IgG1, and IgG3 in sera and CSF of 102 MS patients (19 paired CSF and sera), 76 patients with other neurological disorders (9 paired CSF and sera), and 13 healthy controls. We show that higher levels of total IgG and IgG3 antibodies were detected in MS serum, but not in CSF, which distinguishes MS from other inflammatory and non-inflammatory neurological disorders, with Receiver Operating Characteristic (ROC) Curves 0.79 for both IgG3 & total IgG. Our data support the notion that IgG3 antibodies may be a potential candidate for MS blood biomarker development.

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Acknowledgements

We would like to thank the Neurosurgery Nervous System Biorepository in the Department of Neurosurgery of the University of Colorado Anschutz Medical Campus (https://medschool.cuanschutz.edu/neurosurgery/research-and-innovation) for providing control samples from healthy donors and patients with brain tumors and other non-inflammatory neurological disorders. We thank Accelerated Cure Project (https://www.acceleratedcure.org/) for providing MS and HC samples.

Funding

This work was supported by the Department of Neurosurgery Research Funds, University of Colorado Anschutz Medical Campus. Additional support was from NIH NIMH (5R21MH118174-02) for MWG & XY.

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Author notes

  1. Peter G.E. Kennedy and Michael W. Grander contributed equally to the work

Authors and Affiliations

  1. Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, UK

    Peter G. E. Kennedy

  2. Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Michael W. Graner, Anthony Fringuello, Wenbo Zhou, Kinda Alquatli & Xiaoli Yu

  3. Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Tiffany Pointon & Sara Bisel

  4. Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

    Dianne Langford

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  1. Peter G. E. Kennedy
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Contributions

PGEK, MWG, and XY analyzed data and wrote the manuscript. AF, TP, KA, SB, TC performed experiments. DL provided samples and the revision of the manuscript. XY designed the studies, did data analysis, prepared figures, and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiaoli Yu.

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Kennedy, P.G.E., Graner, M.W., Fringuello, A. et al. Higher Levels of IgG3 Antibodies in Serum, But Not in CSF, Distinguish Multiple Sclerosis From Other Neurological Disorders. J Neuroimmune Pharmacol 17, 526–537 (2022). https://doi.org/10.1007/s11481-021-10048-x

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