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Multiple Sclerosis l: Introduction

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Multiple sclerosis is a chronic autoimmune disease of the central nervous system (CNS) that affects the brain, spinal cord, and optic nerves. It is an inflammatory demyelinating disorder and a leading cause of neurological disability in young adults.EpidemiologyMS commonly begins between 20 and 40 years of age and is twice as common in women. Its exact cause remains unclear, but genetic susceptibility contributes, with higher risk in first-degree relatives and identical twins. A greater...

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Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis.

Wenbo Zhou¹, Michael Graner¹, Petr Paucek¹

¹Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045, USA.

Cell Death & Disease

|April 8, 2023

Summary

Multiple sclerosis (MS) plasma immunoglobulin G (IgG) forms large aggregates that induce significant neuronal apoptosis, a key factor in MS neurodegeneration and axonal damage.

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Area of Science:

Neuroimmunology
Pathology
Molecular Biology

Background:

Grey matter pathology drives multiple sclerosis (MS) progression.
The specific mechanisms of neurodegeneration in MS are under investigation.

Purpose of the Study:

To investigate the role of MS plasma immunoglobulin G (IgG) aggregates in neuronal apoptosis.
To elucidate the link between MS IgG aggregates, complement activation, and neurodegeneration.

Main Methods:

Annexin V apoptosis assay to quantify neuronal cell death.
Analysis of MS plasma IgG aggregates using transmission electron microscopy and nanoparticle tracking.
Evaluation of complement activation products (C1q, C3b, C5b9) and caspase 3 in neuronal cells.
Inhibition studies using IgG depletion, IdeS enzyme, and caspase inhibitors.

Main Results:

MS plasma IgG forms aggregates (>100 nm) that induce six times higher neuronal apoptosis compared to controls.
MS IgG aggregates trigger complement-dependent neuronal apoptosis, evidenced by co-deposition of IgG, complement components, and active caspase 3.
Neuronal apoptosis is mediated by IgG aggregates and can be inhibited by IgG depletion, IdeS digestion, or caspase inhibition.

Conclusions:

MS IgG aggregates play a pathological role in neurodegeneration.
Complement activation by MS IgG aggregates contributes to neuronal apoptosis and axonal damage.
Apoptosis is a significant mechanism of neurodegeneration in multiple sclerosis.