New disease model to facilitate development of ALS and MS therapies

April 17, 2018, Karolinska Institutet
Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100. Credit: Marvin 101/Wikipedia

Researchers at Karolinska Institutet in Sweden have developed a new disease model for neurodegenerative diseases such as ALS and MS that can be used to develop new immunotherapies. The model is described in a publication in the scientific journal Nature Immunology.

All of the body's organs contain macrophages, which, as part of the immune system, consume bacteria and other foreign bodies. However, macrophages are also specialised according to the organ in which they operate; in the brain, they are known as microglia, and researchers believe that this specialisation is controlled by the cytokine TGF-β, which is a kind of protein.

In a healthy brain, microglia are involved in interneuronal communication and the renewal of myelin, the insulating sheaths enveloping axons of that enable the transmission of nerve impulses. In diseases like MS and ALS, other immune called monocytes can enter the brain via the blood, be transformed into inflammatory cells and cause damage to the neurons and the myelin sheath.

The researchers behind the current study hypothesized that TGF-β may reprogram inflammatory cellular monocytes into microglia-like cells.

"We already knew that TGF-β is produced in the brain and is important for giving microglia their specialised functions," says first author Harald Lund, doctoral student at the Department of Clinical Neuroscience, Karolinska Institutet. "So we figured that monocytes should also respond to TGF-β when they enter the brain. We were curious to see what would happen if the monocytes lost the ability to respond to TGF-β."

To test this, the researchers first used a mouse in which the animal's own microglia could be removed. This led to a rapid influx of monocytes into the and spinal cord, which gave rise to new microglia-like cells, and the mice displayed no pathological symptoms. But when the researchers then switched off the TGF-β receptors on the new microglia-like cells, they started to consume large parts of the myelin in the . The mice quickly developed a deadly neurodegenerative disease, the symptoms of which were similar to those of ALS.

The disease model can explain a mechanism that is active in neuroinflammatory and , and could be used to develop and test new immunotherapies. Today, there are no effective treatments.

"There are many deadly neurodegenerative diseases in humans, but a lack of experimental models for developing new immunotherapies," says Professor Bob Harris at the Centre for Molecular Medicine, Karolinska University Hospital and the Department of Clinical Neuroscience, Karolinska Institutet. "This new model will be a valuable addition to our research programme and we hope that the next study will result in a new, effective therapy."

Explore further: An immunological memory in the brain

More information: Harald Lund et al, Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling, Nature Immunology (2018). DOI: 10.1038/s41590-018-0091-5

Related Stories

An immunological memory in the brain

April 11, 2018
Inflammatory reactions can change the brain's immune cells in the long term—meaning that these cells have an "immunological memory." This memory may influence the progression of neurological disorders that occur later in ...

Brain immune system is key to recovery from motor neuron degeneration

February 20, 2018
The selective demise of motor neurons is the hallmark of Lou Gehrig's disease, also known as amyotrophic lateral sclerosis (ALS). Yet neurologists have suspected there are other types of brain cells involved in the progression ...

Discovery could let doctors customize brain's immune response to diseases

April 11, 2018
The University of Virginia neuroscience lab that discovered that the brain connects directly to the immune system now has found evidence that doctors could load up the brain with custom blends of immune cells to battle genetic ...

Immune cells of the blood might replace dysfunctional brain cells

October 22, 2012
Blood-circulating immune cells can take over the essential immune surveillance of the brain, this is shown by scientists of the German Center for Neurodegenerative Diseases and the Hertie Institute for Clinical Brain Research ...

Study explains mechanisms behind glioblastoma influence on the immune system

September 12, 2016
Glioblastomas exert an influence on the microglia, immune cells of the brain, which causes them to stimulate cancer growth rather than attacking it. In a study published in the journal Nature Immunology, an international ...

New model may provide insights on neurocognitive disorders caused by HIV

November 8, 2017
HIV infects certain cells in the brain called microglia, and infected microglia release toxic and inflammatory molecules that can impair or kill surrounding neurons. Researchers have been limited in their ability to study ...

Recommended for you

Our intestinal microbiome influences metabolism—through the immune system

June 21, 2018
Research tells us that the commensal or "good" bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies, published June 21 in Cell Metabolism, shows one surprising way they do this.

Human immune 'trigger' map paves way for better treatments

June 21, 2018
A discovery about how human cells are 'triggered' to undergo an inflammatory type of cell death could have implications for treating cancer, stroke and tissue injury, and immune disorders.

Fetal T cells are first responders to infection in adults

June 20, 2018
Cornell University researchers have discovered there is a division of labor among immune cells that fight invading pathogens in the body.

How a thieving transcription factor dominates the genome

June 20, 2018
One powerful DNA-binding protein, the transcription factor PU.1, steals away other transcription factors and recruits them for its own purposes, effectively dominating gene regulation in developing immune cells, according ...

Composition of complex sugars in breast milk may prevent future food allergies

June 12, 2018
The unique composition of a mother's breastmilk may help to reduce food sensitization in her infant, report researchers at the University of California San Diego School of Medicine with colleagues in Canada.

Drug may quell deadly immune response when trauma spills the contents of our cells' powerhouses

June 11, 2018
When trauma spills the contents of our cell powerhouses, it can evoke a potentially deadly immune response much like a severe bacterial infection.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.