Antibody clumps in blood could drive nerve cell death in MS

'Direct link' seen between toxic form of IgGs and cell loss marking progression

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Clusters of immunoglobulin G (IgG) antibodies in the blood of multiple sclerosis (MS) patients appear to contribute to the nerve cell death that marks the neurodegenerative disease, according to a recent study.

IgG antibodies harvested from the blood of MS patients drove nerve cell death in cell cultures, whereas antibodies from healthy people or people with other inflammatory and neurological diseases did not.

Researchers believe their findings could help in developing new therapies that target the underlying mechanisms of MS and prevent its progression.

“This is the discovery of my entire research career,” Xiaoli Yu, PhD, an associate professor in the department of neurosurgery at the University of Colorado School of Medicine and the study’s senior author, said in a university news story.

“I think these findings could represent a paradigm shift in MS research,” Yu added.

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IgGs, a common antibody, formed clumps only in samples from MS patients

The study, “Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis,” was published in Cell Death and Disease

MS is an autoimmune disease marked by the progressive loss of myelin — the fatty substance that surrounds and protects nerve cells — which ultimately leads to cell death in the brain and spinal cord.

Yet, the mechanisms that lead to nerve cell loss in the disease haven’t been completely worked out.

IgGs are the most common type of antibody found in the blood and other bodily fluids. They work to protect against infection, but some self-reactive antibodies that drive autoimmunity also belong to this family.

A growing body of research, initiated several decades ago, has established that most MS patients have elevated levels of IgG in their blood.

“But there’s been no definitive evidence showing whether … those IgG antibodies are toxic or not,” Yu said in a Q&A that accompanied the news story.

Yu and colleagues examined IgGs in blood samples from 190 MS patients, 116 people with other inflammatory or neurological disorders, and 44 healthy people.

They found that IgGs from MS samples formed large clumps, or aggregates. In a series of experiments using cell cultures and mouse brain tissue, the team determined that IgG aggregates in MS blood could trigger apoptosis in nerve cells. Apoptosis, a programmed type of cell death, is normally used by the body to get rid of unwanted or damaged cells.

Astrocytes, a type of nerve support cell, also were vulnerable to apoptosis mediated by the antibody clumps. However, when IgGs were depleted or the aggregates were broken up, apoptosis was blocked. IgG antibodies from people with other diseases or healthy individuals did not drive such cell death.

Additional findings showed that IgGs from MS patients were causing apoptosis through the activation of the complement cascade, an immune signaling pathway that’s been implicated in several autoimmune diseases, including MS.

“The IgG antibody-induced complement activation and neuronal apoptosis may be a novel mechanism for axonal loss and neuronal degeneration in MS,” the researchers noted.

IgG clumps in blood of PPMS patients particularly toxic to nerve cells

Some MS therapies seek to target immune B-cells, the cells responsible for producing antibodies. But to Yu, findings suggest that targeting the toxic antibodies themselves could be a better therapeutic strategy.

“Our study suggests that new therapies should be developed to target the toxic antibodies, the product of B cells, not just the B cells,” Yu said in the Q&A. “We’ve shown that blood plasma antibodies of this kind — unique features distinct in MS — kill astrocytes and mouse brain tissues.”

More research is needed, however, to better understand how the aggregates form and are able to access the brain.

Data also indicated that the IgG aggregates were more toxic to nerve cells the further MS had progressed. Aggregates from people with secondary progressive MS (SPMS), who were generally older and had been living with MS for longer periods, caused significantly more cell death than those from relapsing remitting (RRMS)  or primary progressive (PPMS) patients.

A molecule that can detect these toxic antibodies also “could provide early detection of what potentially might develop into progressive MS,” Yu said.

Because no way currently exists to identify patients who will transition from RRMS to the secondary progressive phase, and progressive MS patients have very few treatment options, the researchers consider their findings particularly relevant.

“We discovered that MS plasma IgG antibodies form aggregates that generate complement-dependent apoptosis in neurons and astrocytes,” the scientists concluded. “Our findings provide a direct link between IgG antibodies and neuron death which may stipulate strategies for novel therapeutics to prevent neurodegeneration and disease progression.”

Screening drug libraries for existing or experimental small compounds “may identify inhibitors preventing MS IgG-induced neuronal apoptosis,” they added.