Injecting antibodies from healthy people into people with rheumatoid arthritis can reduce inflammation and slow bone degeneration, but how this happens has been largely unknown until now. For the first time, researchers have discovered the molecular pathway behind this process, opening the door to new treatments for autoimmune and inflammatory diseases.
Autoimmune diseases such as rheumatoid arthritis (RA) occur when a person’s immune system mistakenly attacks its own body. In RA, the immune system produces autoantibodies that attack the lining of the joints, causing pain and swelling, bone erosion and joint deformities.
The most abundant type of antibody floating around in our bodies is Immunoglobulin G (IgG). IgG is very potent, uniquely able to link foreign particles to other immune cells in the body and initiate an inflammatory response. On the other hand, when IgG from healthy people is given intravenously (IVIg) to people with autoimmune diseases, it can exert anti-inflammatory effects and slow down the self-destructive disease of bone and cartilage in people with RA .
This has played out enormously in the clinical setting, where IVIg has been used to treat a variety of autoimmune and inflammatory diseases. How IgG suppresses inflammation is largely unknown, prompting researchers from the Friedrich-Alexander-Universität Erlangen and the Universities of Ulm and Würzburg to investigate it in more detail.
Using two RA mouse models, an autoantibody model and a pro-inflammatory cytokine model, the researchers identified distinct pathways leading to a positive inflammatory response after IVIg at the cellular and molecular levels.
Pro-inflammatory cytokines are signaling molecules secreted by immune cells that trigger or exacerbate inflammation. However, overproduction of pro-inflammatory cytokines can be harmful to the body.
The researchers found that sialylation of IgG from healthy donors suppressed joint inflammation. The sialylation process helps pathogens adhere to and invade cells and evade the body’s immune response, and it was previously reported to exert a pronounced anti-inflammatory effect in the body. However, IVIg prevented bone degeneration in both animal models independently of sialylation.
“This bone degeneration caused by an inflammatory response leads to severe joint damage in patients with rheumatoid arthritis,” said Falk Nimmerjahn, corresponding author of the study. “The results of this study now show for the first time how antibodies inhibit this process at the molecular level.”
A surprising finding by the researchers was that molecules normally associated with fighting pathogens, such as bacteria and fungi, play a central role in IVIg’s anti-inflammatory effects. In mice lacking receptors that recognize self and nonself antigens (the foreign particles responsible for antibody production), IgG failed to prevent inflammation and bone loss.
The researchers say the study’s findings are important for the development of new treatments for autoimmune and inflammatory diseases. Further studies using humanized mouse models will validate these findings in the context of the human immune system.
The study was published in the journal immunity.
source: Friedrich Alexander University