With mini-antibodies against rheumatism and Co: Nanobodies inhibit chronic inflammation

Our immune system is essential for life. It defends our body against the influences of bacteria, viruses, and other foreign bodies that enter from the outside. But it can also harm our bodies. The immune system is heavily involved in diseases such as gout, rheumatism, inflammatory bowel disease, or circular hair loss. Researchers have now been able to demonstrate that custom antibody fragments can help treat these diseases and chronic inflammation in general.

When infected cells rupture (purple), they release ASC speckles (light blue). The nanobodies (yellow) used in the study break down the blubber – the inflammation goes away.

ASC complexes and autoimmune diseases

Diseases in which the immune system accidentally attacks its own tissue with antibodies or special messengers and proteins of the innate defense are called autoimmune diseases. Large protein complexes, called ASC speckles, play a key role in this.

These ASC complexes usually serve to fight pathogens and kill infected cells. However, they also occur in chronic inflammation, destroy cell membranes, and release large amounts of inflammatory messengers. Senior author Bernardo Franklin of Bonn University Hospital explains this as follows: At some point, it nearly explodes and all its contents are emptied into the tissue. This triggers the immune system to mount a strong inflammatory response.

The suspicion that ASC complexes also play an important role in autoimmune diseases has been around for some time. It is suspected that the ASC spots are even involved in Alzheimer’s disease. ASC in the brain promotes the formation of amyloid beta plaques and may thus contribute to the development of inflammation in the brain. †There is therefore great interest in preventing the extracellular pro-inflammatory activity of ASC speckles the researchers said.

Nanobodies disrupt extracellular ASC complexes

The team has now been able to test a new approach to prevent the formation of ASC complexes in mouse and human cell cultures. Use was made of so-called nanobodies or antibody fragments that can bind to parts of the ASC complexes. Due to their small size, these nanobodies can also reach hard-to-reach places on the ASC molecules. They are also easier to produce than normal antibodies.

In preliminary tests with normal antibodies, the researchers were also able to show that although these sometimes work against the ASC complexes, they also provoke unwanted immune reactions. This was not the case in the experiments with nanobodies.

Nanobodies limit inflammatory reactions

In experiments, the scientists tested the antibody fragments on mice suffering from symptoms of rheumatism and gout.

After administration of the nanobodies, the rodents’ inflammation, and health status improved significantly“, first author Damien Bertheloot of the University Hospital Bonn summarizes the results. After just a few hours, the symptoms of the inflammation disappeared, leaving the animals largely symptom-free. In addition, the concentration of immune cells and inflammatory messengers in the tissue decreased.

In cell culture experiments, the researchers were also able to observe that the nanobodies prevented the formation and proliferation of extracellular ASC complexes. Like prions or misdirected amyloid proteins, these complexes can also cause ASC proteins to clump together. This leads to an increase in ASC complexes, which could, however, be prevented by using the nanobodies. At the same time, the desired function of the intracellular ASC molecules is preserved.

Also, working with Alzheimer’s?

The team sees the potential to fight chronic inflammation in their results and the nanobodies. In further research steps, they now want to investigate whether these nanobodies also work against ASC spots in the brain and thus limit the formation of amyloid plaques that are typical of Alzheimer’s disease. †Perhaps it is possible to slow down this process using our nanobodies said, Franklin.