With nanobodies against rheumatism and Alzheimer’s

New research shows that mini-antibodies can curb chronic inflammation. Due to their production and size, they have significant advantages over normal antibodies. Researchers now hope that with the help of nanobodies, the human defense system will have to be less weakened

New approach: Tests on mice suggest that tailor-made antibody fragments can curb chronic inflammation and thus fight diseases such as rheumatism, arthritis or possibly even Alzheimer’s disease.

In these, the so-called “nanobodies” neutralized alarm molecules of the immune system and thus improved the symptoms of animals suffering from gout and arthritis. This opens up new opportunities to treat those diseases caused by an incorrect reaction of the immune system.

Whether gout, rheumatism, circular hair loss or inflammatory bowel diseases: all these diseases are not caused by pathogens or other external influences, but by our own immune system .

It mistakenly attacks its own tissue with antibodies or special messengers and innate defense proteins – the inflammasome. The central components are proteins that aggregate into large complexes, the so-called ASC grains.

Protein complexes as inflammatory auxiliaries

The problem: These ASC complexes, which are normally intended to defend against pathogens and kill infected cells, also mediate chronic inflammation and ensure the destruction of cell membranes and the release of large quantities of inflammatory messengers.

“At some point it almost explodes and empties its entire contents into the tissues,” says lead author Bernardo Franklin of University Hospital Bonn. “This causes the immune system to launch a strong inflammatory response.”

It has therefore been suspected for some time that ASC complexes also play an important role in autoimmune diseases such as gout, arthritis and rheumatism and possibly even in Alzheimer’s disease.

Because studies show that ASC in the brain can promote beta-amyloid plaque formation and contribute to brain inflammation. “There is therefore a great interest in preventing the extracellular pro-inflammatory activity of ASC spots,” explain Franklin and his colleagues.

Antibody fragments against gout and arthritis

The team has now successfully tested a new approach with mice and human cell cultures. To do this, they used nanobodies, antibody fragments that can be tailored to bind to parts of ASC complexes.

Unlike normal antibodies, these nanobodies are small enough to attach to hard-to-reach areas of the ASC molecule. Moreover, these antibody fragments are easier to produce and more durable.

Another important point: in preliminary tests with normal antibodies, some of them acted against the ASC complexes, but in turn triggered an immune reaction which further intensified the chronic inflammation. As scientists have discovered, this is not the case with nanobodies.

For their current study, they tested the antibody fragments on mice with two common inflammatory autoimmune diseases: “In our experiments, the mice showed symptoms similar to rheumatism and gout,” says first author Damien Bertheloot from the University Hospital of Bonn.

Symptoms cured, ASC complexes resolved

The result: “After the administration of the nanobodies, the inflammation and the state of health of the rodents improved considerably”, reports Bertheloot. After just a few hours, the swelling and pain caused by the inflammation had subsided and the mice were largely asymptomatic.

At the same time, the number of immune cells and inflammatory messengers in the tissues decreased, as the analyzes showed.

Also positive: in cell cultures, the researchers observed that the nanobodies already prevented the formation and proliferation of complexes of extracellular ASC molecules.

Similar to prions or misfolded amyloid proteins, these complexes can also cause dissolved ASC proteins to clump together. However, this “replication” of the ASC complexes could be prevented in the tests by the antibody fragments, as the team reports.

However, since nanobiodies only attack extracellular ASC complexes, the desired and normal defense function of ASC proteins in cells is maintained at the same time, which is important for defense against pathogens.

A new way to fight chronic inflammation

According to Bertheroot and his colleagues, nanobodies open up a promising new way to fight chronic inflammation without having to weaken the entire immune system.

“Nanobodies are the first biological products capable of dissolving existing inflammasomes, while retaining their defense function against pathogens”, write the researchers.

However, further studies are still needed to further investigate the effect and possible uses of such antibody fragments against chronic inflammation.

The team’s next steps also include investigating whether the nanobodies also help fight ASC spots in the brain that promote the formation of the amyloid plaques typical of Alzheimer’s disease. “Perhaps it is possible to slow down this process with the help of our nanobodies,” says Franklin.

Source: Rheinische Friedrich-Wilhelms-Universität Bonn

This article was written by Nadja Podbregar